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1. Profile of gut microbiota and serum metabolites associated with metabolic syndrome in a remote island most afflicted by obesity in Japan

Author

Tsugumi Uema, Jasmine F. Millman, Shiki Okamoto, Takehiro Nakamura, Kiyoto Yamashiro, Moriyuki Uehara, Ken-ichiro Honma, Minoru Miyazato, Asuka Ashikari, Seiichi Saito, Shiro Maeda, Minako Imamura, Hajime Ishida, Masayuki Matsushita, Koshi Nakamura, and Hiroaki Masuzaki

Subjects
Medicine, Science
Abstract

Abstract Numerous studies have revealed distinct differences in the profiles of gut microbiota between non-obese and obese individuals. To date, however, little is known if any disparities in the community of gut microbiota exist between metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO) subjects. We therefore aimed to comprehensively characterize the gut microbiota and circulating metabolites in serum from both MHO and MUO residing in the remote island, Kumejima, where the prevalence of obesity is one of the highest in Japan, and explored possible correlations between the gut microbiota profile and markers of metabolic syndrome. Results revealed that MUO showed significantly higher levels of genera such as g_Succinivibrio, g_Granulicatella, g_Brachyspira, g_Oribacterium and g_Atopobium in comparison to MHO. Moreover, abundance of g_Succinivibrio, g_Brachyspira and g_Atopobium were positively correlated with value of fasting insulin, HOMA-R, circulating triglycerides, diastolic blood pressure, BMI, body weight, waist circumference and HbA1c. In addition, MUO compared to MHO showed an imbalance of serum metabolites, with a significant elevation in 2-oxoisovaleric acid, pyruvic acid, 2-hydroxybutyric acid, and creatine. Our data highlight unmet needs in precision approaches for the treatment of obesity, targeting the gut microbiota profile and serum metabolites in a distinct population affected by obesity.

Published
2022
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2. Hypothalamic AMP-Activated Protein Kinase Regulates Biphasic Insulin Secretion from Pancreatic β Cells during Fasting and in Type 2 Diabetes

Author

Shinji Kume, Motoyuki Kondo, Shiro Maeda, Yoshihiko Nishio, Tsuyoshi Yanagimachi, Yukihiro Fujita, Masakazu Haneda, Keiko Kondo, Akihiro Sekine, Shin-ich Araki, Hisazumi Araki, Masami Chin-Kanasaki, Satoshi Ugi, Daisuke Koya, Sawako Kitahara, Kiyosumi Maeda, Atsunori Kashiwagi, Takashi Uzu, and Hiroshi Maegawa

Subjects
First-phase GSIS, Pancreatic β cell, Starvation, Diabetes, Insulin secretion, Medicine, Medicine (General), R5-920
Abstract

Glucose-stimulated insulin secretion (GSIS) by pancreatic β cells is biphasic. However, the physiological significance of biphasic GSIS and its relationship to diabetes are not yet fully understood. This study demonstrated that impaired first-phase GSIS follows fasting, leading to increased blood glucose levels and brain glucose distribution in humans. Animal experiments to determine a possible network between the brain and β cells revealed that fasting-dependent hyperactivation of AMP-activated protein kinase in the hypothalamus inhibited first-phase GSIS by stimulating the α-adrenergic pancreatic nerve. Furthermore, abnormal excitability of this brain-β cell neural axis was involved in diabetes-related impairment of first-phase GSIS in diabetic animals. Finally, pancreatic denervation improved first-phase GSIS and glucose tolerance and ameliorated severe diabetes by preventing β cell loss in diabetic animals. These results indicate that impaired first-phase GSIS is critical for brain distribution of dietary glucose after fasting. Furthermore, β cells in individuals with diabetes mistakenly sense that they are under conditions that mimic prolonged fasting. The present study provides additional insight into both β cell physiology and the pathogenesis of β cell dysfunction in type 2 diabetes.

Published
2016
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3. A variant within the FTO confers susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes.

Author

Makiko Taira, Minako Imamura, Atsushi Takahashi, Yoichiro Kamatani, Toshimasa Yamauchi, Shin-Ichi Araki, Nobue Tanaka, Natalie R van Zuydam, Emma Ahlqvist, Masao Toyoda, Tomoya Umezono, Koichi Kawai, Masahito Imanishi, Hirotaka Watada, Daisuke Suzuki, Hiroshi Maegawa, Tetsuya Babazono, Kohei Kaku, Ryuzo Kawamori, SUMMIT Consortium, Leif C Groop, Mark I McCarthy, Takashi Kadowaki, and Shiro Maeda

Subjects
Medicine, Science
Abstract

To explore novel genetic loci for diabetic nephropathy, we performed genome-wide association studies (GWAS) for diabetic nephropathy in Japanese patients with type 2 diabetes. We analyzed the association of 5,768,242 single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes, 2,380 nephropathy cases and 5,234 controls. We further performed GWAS for diabetic nephropathy using independent Japanese patients with type 2 diabetes, 429 cases and 358 controls and the results of these two GWAS were combined with an inverse variance meta-analysis (stage-1), followed by a de novo genotyping for the candidate SNP loci (p < 1.0 × 10(-4)) in an independent case-control study (Stage-2; 1,213 cases and 1,298 controls). After integrating stage-1 and stage-2 data, we identified one SNP locus, significantly associated with diabetic nephropathy; rs56094641 in FTO, P = 7.74 × 10(-10). We further examined the association of rs56094641 with diabetic nephropathy in independent Japanese patients with type 2 diabetes (902 cases and 1,221 controls), and found that the association of this locus with diabetic nephropathy remained significant after integrating all association data (P = 7.62 × 10(-10)). We have identified FTO locus as a novel locus for conferring susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes.

Published
2018
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4. Replication Study in a Japanese Population of Six Susceptibility Loci for Type 2 Diabetes Originally Identified by a Transethnic Meta-Analysis of Genome-Wide Association Studies.

Author

Ren Matsuba, Minako Imamura, Yasushi Tanaka, Minoru Iwata, Hiroshi Hirose, Kohei Kaku, Hiroshi Maegawa, Hirotaka Watada, Kazuyuki Tobe, Atsunori Kashiwagi, Ryuzo Kawamori, and Shiro Maeda

Subjects
Medicine, Science
Abstract

AIM:We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and six susceptibility loci (TMEM154, SSR1, FAF1, POU5F1, ARL15, and MPHOSPH9) originally identified by a transethnic meta-analysis of genome-wide association studies (GWAS) in 2014. METHODS:We genotyped 7,620 Japanese participants (5,817 type 2 diabetes patients and 1,803 controls) for each of the single nucleotide polymorphisms (SNPs) using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using logistic regression analysis. RESULTS:Of the six SNPs examined in this study, four (rs6813195 near TMEM154, rs17106184 in FAF1, rs3130501 in POU5F1 and rs4275659 near MPHOSPH9) had the same direction of effect as in the original reports, but two (rs9505118 in SSR1 and rs702634 in ARL15) had the opposite direction of effect. Among these loci, rs3130501 and rs4275659 were nominally associated with type 2 diabetes (rs3130501; p = 0.017, odds ratio [OR] = 1.113, 95% confidence interval [CI] 1.019-1.215, rs4275659; p = 0.012, OR = 1.127, 95% CI 1.026-1.238, adjusted for sex, age and body mass index), but we did not observe a significant association with type 2 diabetes for any of the six evaluated SNP loci in our Japanese population. CONCLUSIONS:Our results indicate that effects of the six SNP loci identified in the transethnic GWAS meta-analysis are not major among the Japanese, although SNPs in POU5F1 and MPHOSPH9 loci may have some effect on susceptibility to type 2 diabetes in this population.

Published
2016
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5. FTO Gene Polymorphism Is Associated with Type 2 Diabetes through Its Effect on Increasing the Maximum BMI in Japanese Men.

Author

Yutaka Kamura, Minoru Iwata, Shiro Maeda, Satomi Shinmura, Yukiko Koshimizu, Hisae Honoki, Kazuhito Fukuda, Manabu Ishiki, Isao Usui, Yasuo Fukushima, Atsuko Takano, Hiromi Kato, Shihou Murakami, Kiyohiro Higuchi, Chikaaki Kobashi, and Kazuyuki Tobe

Subjects
Medicine, Science
Abstract

Several studies have demonstrated that polymorphisms within the fat-mass and obesity-associated gene (FTO) are associated with type 2 diabetes (T2D). However, whether the effects of the FTO locus on T2D susceptibility are independent of fat-mass increases remains controversial. To investigate this issue, we examined the association of FTO variants with T2D and various aspects of BMI history during adult life in a Japanese population.We genotyped SNPs within FTO (rs1121980 and rs1558902) in 760 Japanese patients with T2D who had reached a lifetime maximum BMI (BMImax) before or at the time of diagnosis and 693 control individuals with information regarding their BMImax.The BMImax showed the strongest association with T2D risk among the BMIs evaluated in this study. In the sex-combined analysis, FTO SNPs were not associated with any of the BMI variables or with T2D, but in sex-stratified analyses, both SNPs were significantly associated with the BMImax and rs1558902 was associated with T2D in men. The association of the SNPs with T2D remained significant after adjustments for the current BMI and age, whereas the T2D association of the SNP was no longer significant after adjustments for BMImax and age.These results suggest that the effects of FTO polymorphisms on T2D susceptibility in Japanese men are mediated through their effect on increasing the BMImax before or at the time of diagnosis.

Published
2016
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6. Replication Study in a Japanese Population to Evaluate the Association between 10 SNP Loci, Identified in European Genome-Wide Association Studies, and Type 2 Diabetes.

Author

Ren Matsuba, Kensuke Sakai, Minako Imamura, Yasushi Tanaka, Minoru Iwata, Hiroshi Hirose, Kohei Kaku, Hiroshi Maegawa, Hirotaka Watada, Kazuyuki Tobe, Atsunori Kashiwagi, Ryuzo Kawamori, and Shiro Maeda

Subjects
Medicine, Science
Abstract

We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and 7 susceptibility loci originally identified by European genome-wide association study (GWAS) in 2012: ZMIZ1, KLHDC5, TLE1, ANKRD55, CILP2, MC4R, and BCAR1. We also examined the association of 3 additional loci: CCND2 and GIPR, identified in sex-differentiated analyses, and LAMA1, which was shown to be associated with non-obese European type 2 diabetes.We genotyped 6,972 Japanese participants (4,280 type 2 diabetes patients and 2,692 controls) for each of the 10 single nucleotide polymorphisms (SNPs): rs12571751 in ZMIZ1, rs10842994 near KLHDC5, rs2796441 near TLE1, rs459193 near ANKRD55, rs10401969 in CILP2, rs12970134 near MC4R, rs7202877 near BCAR1, rs11063069 near CCND2, rs8108269 near GIPR, and rs8090011 in LAMA1 using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using a logistic regression analysis.All SNPs examined in this study had the same direction of effect (odds ratio > 1.0, p = 9.77 × 10(-4), binomial test), as in the original reports. Among them, rs12571751 in ZMIZ1 was significantly associated with type 2 diabetes [p = 0.0041, odds ratio = 1.123, 95% confidence interval 1.037-1.215, adjusted for sex, age and body mass index (BMI)], but we did not observe significant association of the remaining 9 SNP loci with type 2 diabetes in the present Japanese population (p ≥ 0.005). A genetic risk score, constructed from the sum of risk alleles for the 7 SNP loci identified by un-stratified analyses in the European GWAS meta-analysis were associated with type 2 diabetes in the present Japanese population (p = 2.3 × 10(-4), adjusted for sex, age and BMI).ZMIZ1 locus has a significant effect on conferring susceptibility to type 2 diabetes also in the Japanese population.

Published
2015
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7. The construction of risk prediction models using GWAS data and its application to a type 2 diabetes prospective cohort.

Author

Daichi Shigemizu, Testuo Abe, Takashi Morizono, Todd A Johnson, Keith A Boroevich, Yoichiro Hirakawa, Toshiharu Ninomiya, Yutaka Kiyohara, Michiaki Kubo, Yusuke Nakamura, Shiro Maeda, and Tatsuhiko Tsunoda

Subjects
Medicine, Science
Abstract

Recent genome-wide association studies (GWAS) have identified several novel single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2D). Various models using clinical and/or genetic risk factors have been developed for T2D risk prediction. However, analysis considering algorithms for genetic risk factor detection and regression methods for model construction in combination with interactions of risk factors has not been investigated. Here, using genotype data of 7,360 Japanese individuals, we investigated risk prediction models, considering the algorithms, regression methods and interactions. The best model identified was based on a Bayes factor approach and the lasso method. Using nine SNPs and clinical factors, this method achieved an area under a receiver operating characteristic curve (AUC) of 0.8057 on an independent test set. With the addition of a pair of interaction factors, the model was further improved (p-value 0.0011, AUC 0.8085). Application of our model to prospective cohort data showed significantly better outcome in disease-free survival, according to the log-rank trend test comparing Kaplan-Meier survival curves (p--value 2:09 x 10(-11)). While the major contribution was from clinical factors rather than the genetic factors, consideration of genetic risk factors contributed to an observable, though small, increase in predictive ability. This is the first report to apply risk prediction models constructed from GWAS data to a T2D prospective cohort. Our study shows our model to be effective in prospective prediction and has the potential to contribute to practical clinical use in T2D.

Published
2014
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8. Replication study for the association of 9 East Asian GWAS-derived loci with susceptibility to type 2 diabetes in a Japanese population.

Author

Kensuke Sakai, Minako Imamura, Yasushi Tanaka, Minoru Iwata, Hiroshi Hirose, Kohei Kaku, Hiroshi Maegawa, Hirotaka Watada, Kazuyuki Tobe, Atsunori Kashiwagi, Ryuzo Kawamori, and Shiro Maeda

Subjects
Medicine, Science
Abstract

AimsEast Asian genome-wide association studies (GWAS) for type 2 diabetes identified 8 loci with genome-wide significance, and 2 loci with a borderline association. However, the associations of these loci except MAEA locus with type 2 diabetes have not been evaluated in independent East Asian cohorts. We performed a replication study to investigate the association of these susceptibility loci with type 2 diabetes in an independent Japanese population.MethodsWe genotyped 7,379 Japanese participants (5,315 type 2 diabetes and 2,064 controls) for each of the 9 single nucleotide polymorphisms (SNPs), rs7041847 in GLIS3, rs6017317 in FITM2-R3HDML-HNF4A, rs6467136 near GCCI-PAX4, rs831571 near PSMD6, rs9470794 in ZFAND3, rs3786897 in PEPD, rs1535500 in KCNK16, rs16955379 in CMIP, and rs17797882 near WWOX. Because the sample size in this study was not sufficient to replicate single SNP associations, we constructed a genetic risk score (GRS) by summing a number of risk alleles of the 9 SNPs, and examined the association of the GRS with type 2 diabetes using logistic regression analysis.ResultsWith the exception of rs1535500 in KCNK16, all SNPs had the same direction of effect (odds ratio [OR]>1.0) as in the original reports. The GRS constructed from the 9 SNPs was significantly associated with type 2 diabetes in the Japanese population (p = 4.0 × 10(-4), OR = 1.05, 95% confidence interval: 1.02-1.09). In quantitative trait analyses, rs16955379 in CMIP was nominally associated with a decreased homeostasis model assessment of β-cell function and with increased fasting plasma glucose, but neither the individual SNPs nor the GRS showed a significant association with the glycemic traits.ConclusionsThese results indicate that 9 loci that were identified in the East Asian GWAS meta-analysis have a significant effect on the susceptibility to type 2 diabetes in the Japanese population.

Published
2013
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9. The influence of a single nucleotide polymorphism within CNDP1 on susceptibility to diabetic nephropathy in Japanese women with type 2 diabetes.

Author

Mahiro Kurashige, Minako Imamura, Shin-Ichi Araki, Daisuke Suzuki, Tetsuya Babazono, Takashi Uzu, Tomoya Umezono, Masao Toyoda, Koichi Kawai, Masahito Imanishi, Kazushige Hanaoka, Hiroshi Maegawa, Yasuko Uchigata, Tatsuo Hosoya, and Shiro Maeda

Subjects
Medicine, Science
Abstract

BACKGROUND: Several linkage analyses have mapped a susceptibility locus for diabetic nephropathy to chromosome 18q22-23, and polymorphisms within the carnosine dipeptidase 1 gene (CNDP1), located on 18q22.3, have been shown to be associated with diabetic nephropathy in European subjects with type 2 diabetes. However, the association of this locus with diabetic nephropathy has not been evaluated in the Japanese population. In this study, we examined the association of polymorphisms within the CNDP1/CNDP 2 locus with diabetic nephropathy in Japanese subjects with type 2 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: We genotyped a leucine repeat polymorphism (D18S880) that is within CNDP1 along with 29 single nucleotide polymorphisms (SNPs) in the CNDP1/CNDP2 locus for 2,740 Japanese subjects with type 2 diabetes (1,205 nephropathy cases with overt nephropathy or with end-stage renal disease [ESRD], and 1,535 controls with normoalbuminuria). The association of each polymorphism with diabetic nephropathy was analysed by performing logistic regression analysis. We did not observe any association between D18S880 and diabetic nephropathy in Japanese subjects with type 2 diabetes. None of the 29 SNPs within the CNDP1/CNDP2 locus were associated with diabetic nephropathy, but a subsequent sex-stratified analysis revealed that 1 SNP in CNDP1 was nominally associated with diabetic nephropathy in women (rs12604675-A; p = 0.005, odds ratio [OR] = 1.76, 95% confidence interval [CI], 1.19-2.61). Rs12604675 was associated with overt proteinuria (p = 0.002, OR = 2.18, 95% CI, 1.32-3.60), but not with ESRD in Japanese women with type 2 diabetes. CONCLUSIONS/SIGNIFICANCE: Rs12604675-A in CNDP1 may confer susceptibility to overt proteinuria in Japanese women with type 2 diabetes.

Published
2013
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10. An ACACB variant implicated in diabetic nephropathy associates with body mass index and gene expression in obese subjects.

Author

Lijun Ma, Mariana Murea, James A Snipes, Alejandra Marinelarena, Jacqueline Krüger, Pamela J Hicks, Kurt A Langberg, Meredith A Bostrom, Jessica N Cooke, Daisuke Suzuki, Tetsuya Babazono, Takashi Uzu, Sydney C W Tang, Ashis K Mondal, Neeraj K Sharma, Sayuko Kobes, Peter A Antinozzi, Matthew Davis, Swapan K Das, Neda Rasouli, Philip A Kern, Nathan J Shores, Lawrence L Rudel, Matthias Blüher, Michael Stumvoll, Donald W Bowden, Shiro Maeda, John S Parks, Peter Kovacs, Robert L Hanson, Leslie J Baier, Steven C Elbein, and Barry I Freedman

Subjects
Medicine, Science
Abstract

Acetyl coenzyme A carboxylase B gene (ACACB) single nucleotide polymorphism (SNP) rs2268388 is reproducibly associated with type 2 diabetes (T2DM)-associated nephropathy (DN). ACACB knock-out mice are also protected from obesity. This study assessed relationships between rs2268388, body mass index (BMI) and gene expression in multiple populations, with and without T2DM. Among subjects without T2DM, rs2268388 DN risk allele (T) associated with higher BMI in Pima Indian children (n = 2021; p-additive = 0.029) and African Americans (AAs) (n = 177; p-additive = 0.05), with a trend in European Americans (EAs) (n = 512; p-additive = 0.09), but not Germans (n = 858; p-additive = 0.765). Association with BMI was seen in a meta-analysis including all non-T2DM subjects (n = 3568; p-additive = 0.02). Among subjects with T2DM, rs2268388 was not associated with BMI in Japanese (n = 2912) or EAs (n = 1149); however, the T allele associated with higher BMI in the subset with BMI≥30 kg/m(2) (n = 568 EAs; p-additive = 0.049, n = 196 Japanese; p-additive = 0.049). Association with BMI was strengthened in a T2DM meta-analysis that included an additional 756 AAs (p-additive = 0.080) and 48 Hong Kong Chinese (p-additive = 0.81) with BMI≥30 kg/m(2) (n = 1575; p-additive = 0.0033). The effect of rs2268388 on gene expression revealed that the T risk allele associated with higher ACACB messenger levels in adipose tissue (41 EAs and 20 AAs with BMI>30 kg/m(2); p-additive = 0.018) and ACACB protein levels in the liver tissue (mixed model p-additive = 0.03, in 25 EA bariatric surgery patients with BMI>30 kg/m(2) for 75 exams). The T allele also associated with higher hepatic triglyceride levels. These data support a role for ACACB in obesity and potential roles for altered lipid metabolism in susceptibility to DN.

Published
2013
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11. A single nucleotide polymorphism within DUSP9 is associated with susceptibility to type 2 diabetes in a Japanese population.

Author

Hisashi Fukuda, Minako Imamura, Yasushi Tanaka, Minoru Iwata, Hiroshi Hirose, Kohei Kaku, Hiroshi Maegawa, Hirotaka Watada, Kazuyuki Tobe, Atsunori Kashiwagi, Ryuzo Kawamori, and Shiro Maeda

Subjects
Medicine, Science
Abstract

The DUSP9 locus on chromosome X was identified as a susceptibility locus for type 2 diabetes in a meta-analysis of European genome-wide association studies (GWAS), and GWAS in South Asian populations identified 6 additional single nucleotide polymorphism (SNP) loci for type 2 diabetes. However, the association of these loci with type 2 diabetes have not been examined in the Japanese. We performed a replication study to investigate the association of these 7 susceptibility loci with type 2 diabetes in the Japanese population.We genotyped 11,319 Japanese participants (8,318 with type 2 diabetes and 3,001 controls) for each of the 7 SNPs-rs5945326 near DUSP9, rs3923113 near GRB14, rs16861329 in ST6GAL1, rs1802295 in VPS26A, rs7178572 in HMG20A, rs2028299 near AP3S2, and rs4812829 in HNF4A-and examined the association of each of these 7 SNPs with type 2 diabetes by using logistic regression analysis.All SNPs had the same direction of effect (odds ratio [OR]>1.0) as in the original reports. One SNP, rs5945326 near DUSP9, was significantly associated with type 2 diabetes at a genome-wide significance level (p = 2.21×10(-8); OR 1.39, 95% confidence interval [CI]: 1.24-1.56). The 6 SNPs derived from South Asian GWAS were not significantly associated with type 2 diabetes in the Japanese population by themselves (p≥0.007). However, a genetic risk score constructed from 6 South Asian GWAS derived SNPs was significantly associated with Japanese type 2 diabetes (p = 8.69×10(-4), OR = 1.06. 95% CI; 1.03-1.10).These results indicate that the DUSP9 locus is a common susceptibility locus for type 2 diabetes across different ethnicities, and 6 loci identified in South Asian GWAS also have significant effect on susceptibility to Japanese type 2 diabetes.

Published
2012
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12. Association of new loci identified in European genome-wide association studies with susceptibility to type 2 diabetes in the Japanese.

Author

Toshihiko Ohshige, Minoru Iwata, Shintaro Omori, Yasushi Tanaka, Hiroshi Hirose, Kohei Kaku, Hiroshi Maegawa, Hirotaka Watada, Atsunori Kashiwagi, Ryuzo Kawamori, Kazuyuki Tobe, Takashi Kadowaki, Yusuke Nakamura, and Shiro Maeda

Subjects
Medicine, Science
Abstract

BackgroundSeveral novel susceptibility loci for type 2 diabetes have been identified through genome-wide association studies (GWAS) for type 2 diabetes or quantitative traits related to glucose metabolism in European populations. To investigate the association of the 13 new European GWAS-derived susceptibility loci with type 2 diabetes in the Japanese population, we conducted a replication study using 3 independent Japanese case-control studies.Methodology/principal findingsWe examined the association of single nucleotide polymorphisms (SNPs) within 13 loci (MTNR1B, GCK, IRS1, PROX1, BCL11A, ZBED3, KLF14, TP53INP1, KCNQ1, CENTD2, HMGA2, ZFAND6 and PRC1) with type 2 diabetes using 4,964 participants (2,839 cases and 2,125 controls) from 3 independent Japanese samples. The association of each SNP with type 2 diabetes was analyzed by logistic regression analysis. Further, we performed combined meta-analyses for the 3 studies and previously performed Japanese GWAS data (4,470 cases vs. 3,071 controls). The meta-analysis revealed that rs2943641 in the IRS1 locus was significantly associated with type 2 diabetes, (P = 0.0034, OR = 1.15 95% confidence interval; 1.05-1.26) and 3 SNPs, rs10930963 in the MTNR1B locus, rs972283 in the KLF14 locus, and rs231362 in the KCNQ1 locus, had nominal association with type 2 diabetes in the present Japanese samples (PConclusionsThese results indicate that IRS1 locus may be common locus for type 2 diabetes across different ethnicities.

Published
2011
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13. The type 2 diabetes associated minor allele of rs2237895 KCNQ1 associates with reduced insulin release following an oral glucose load.

Author

Johan Holmkvist, Karina Banasik, Gitte Andersen, Hiroyuki Unoki, Thomas Skot Jensen, Charlotta Pisinger, Knut Borch-Johnsen, Annelli Sandbaek, Torsten Lauritzen, Sören Brunak, Shiro Maeda, Torben Hansen, and Oluf Pedersen

Subjects
Medicine, Science
Abstract

BackgroundPolymorphisms in the potassium channel, voltage-gated, KQT-like subfamily, member 1 (KCNQ1) have recently been reported to associate with type 2 diabetes. The primary aim of the present study was to investigate the putative impact of these KCNQ1 polymorphisms (rs2283228, rs2237892, rs2237895, and rs2237897) on estimates of glucose stimulated insulin release.Methodology/principal findingsGenotypes were examined for associations with serum insulin levels following an oral glucose tolerance test (OGTT) in a population-based sample of 6,039 middle-aged and treatment-naïve individuals. Insulin release indices estimated from the OGTT and the interplay between insulin sensitivity and insulin release were investigated using linear regression and Hotelling T2 analyses. Applying an additive genetic model the minor C-allele of rs2237895 was associated with reduced serum insulin levels 30 min (mean+/-SD: (CC) 277+/-160 vs. (AC) 280+/-164 vs. (AA) 299+/-200 pmol/l, p = 0.008) after an oral glucose load, insulinogenic index (29.6+/-17.4 vs. 30.2+/-18.7vs. 32.2+/-22.1, p = 0.007), incremental area under the insulin curve (20,477+/-12,491 vs. 20,503+/-12,386 vs. 21,810+/-14,685, p = 0.02) among the 4,568 individuals who were glucose tolerant. Adjustment for the degree of insulin sensitivity had no effect on the measures of reduced insulin release. The rs2237895 genotype had a similar impact in the total sample of treatment-naïve individuals. No association with measures of insulin release were identified for the less common diabetes risk alleles of rs2237892, rs2237897, or rs2283228.ConclusionThe minor C-allele of rs2237895 of KCNQ1, which has a prevalence of about 42% among Caucasians was associated with reduced measures of insulin release following an oral glucose load suggesting that the increased risk of type 2 diabetes, previously reported for this variant, likely is mediated through an impaired beta cell function.

Published
2009
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14. Effect of a mobile digital intervention to enhance physical activity in individuals with metabolic disorders on voiding patterns measured by 24-h voided volume monitoring system: Kumejima Digital Health Project (KDHP)

Author

Kiyoto Yamashiro, Tsugumi Uema, Takehiro Nakamura, Seiichi Saito, Hiroaki Masuzaki, Minoru Miyazato, Moriyuki Uehara, Shiro Maeda, Asuka Ashikari, Hajime Ishida, Koshi Nakamura, and Masayuki Matsushita

Subjects
Adult, Male, medicine.medical_specialty, Urology, 030232 urology & nephrology, Urination, Urine, Excretion, 03 medical and health sciences, 0302 clinical medicine, Polyuria, Intervention (counseling), medicine, Blood test, Nocturia, Humans, Prospective Studies, Exercise, Monitoring, Physiologic, 030219 obstetrics & reproductive medicine, medicine.diagnostic_test, Urology - Original Paper, business.industry, Metabolic diseases, Middle Aged, Lifestyle, Digital health, Mobile Applications, Voided volume, Blood pressure, Nephrology, Physical therapy, Female, medicine.symptom, business
Abstract

Purpose:To evaluate the effect of a mobile digital intervention on voiding patterns, we performed 24-h voided volume monitoring in individuals with metabolic disorders.\nMethods:Participants with metabolic disorders were grouped into either the intervention group (n = 17), who had access to a smartphone app (CARADA), or the non-intervention group (n = 11), who did not. Urine monitoring was conducted for 24 h using a novel digital self-health monitoring system for urine excretion (s-HMSU). Body weight, abdominal circumference, blood pressure, and biomarkers were measured.\nResults:Physical findings and blood test results at baseline and 6 months indicated no significant between-group differences. Night-time frequency did not change between baseline and 6 months in the intervention group but significantly worsened at 6 months in the non-intervention group, as compared to baseline (1.0 ± 0.7 vs. 1.5 ± 0.5, p, 論文

Published
2021

15. Genome-wide association studies identify two novel loci conferring susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes

Author

Minoru Iwata, Jeeyun Ahn, Masao Toyoda, Shin-ichi Araki, Lucia Sobrin, Momoko Horikoshi, M Imamura, Gayatri Susarla, Shiro Maeda, Sanghoon Moon, Atsushi Takahashi, Hiroshi Maegawa, Masatoshi Matsunami, Toshimasa Yamauchi, Jinhwa Kong, Takashi Kadowaki, Kazuyuki Tobe, and Kyu Hyung Park

Subjects
Genotype, Genome-wide association study, Single-nucleotide polymorphism, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Asian People, Gene Frequency, Japan, Meta-Analysis as Topic, Genetics, medicine, Genetic predisposition, Humans, SNP, Genetic Predisposition to Disease, Association Studies Article, Molecular Biology, Alleles, Genetics (clinical), 030304 developmental biology, Genetic association, 0303 health sciences, Diabetic Retinopathy, 030305 genetics & heredity, Membrane Proteins, Correction, General Medicine, Diabetic retinopathy, Phosphoproteins, medicine.disease, Diabetes Mellitus, Type 2, Hexosyltransferases, Genetic Loci, Genome-Wide Association Study, Retinopathy
Abstract

Several reports have suggested that genetic susceptibility contributes to the development and progression of diabetic retinopathy. We aimed to identify genetic loci that confer susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. We analysed 5 790 508 single nucleotide polymorphisms (SNPs) in 8880 Japanese patients with type 2 diabetes, 4839 retinopathy cases and 4041 controls, as well as 2217 independent Japanese patients with type 2 diabetes, 693 retinopathy cases and 1524 controls. The results of these two genome-wide association studies (GWAS) were combined with an inverse variance meta-analysis (Stage-1), followed by de novo genotyping for the candidate SNP loci (P

Published
2021

16. Randomized trial of an intensified, multifactorial intervention in patients with advanced‐stage diabetic kidney disease: Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan)

Author

Kenichi Shikata, Masakazu Haneda, Toshiharu Ninomiya, Daisuke Koya, Yoshiki Suzuki, Daisuke Suzuki, Hitoshi Ishida, Hiroaki Akai, Yasuhiko Tomino, Takashi Uzu, Motonobu Nishimura, Shiro Maeda, Daisuke Ogawa, Satoshi Miyamoto, Hirofumi Makino, and the Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) collaborative group

Subjects
Blood Glucose, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Population, Type 2 diabetes, Diabetic nephropathy, 030204 cardiovascular system & hematology, Lower risk, Diseases of the endocrine glands. Clinical endocrinology, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Diabetes mellitus, Internal medicine, Early Medical Intervention, Internal Medicine, Medicine, Humans, Diabetic Nephropathies, 030212 general & internal medicine, Prospective Studies, Diabetic kidney disease, education, Creatinine, education.field_of_study, business.industry, Hazard ratio, Remission Induction, General Medicine, Articles, Middle Aged, medicine.disease, RC648-665, Prognosis, Clinical Trial, Diabetic Nephropathy Remission and Regression Team Trial in Japan, Clinical Science and Care, chemistry, Diabetes Mellitus, Type 2, Female, business, Biomarkers, Follow-Up Studies
Abstract

Aims/Introduction We evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD). Materials and Methods The Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population. Results The IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P, The Diabetic Nephropathy Remission and Regression Team Trial in Japan was designed to clarify the beneficial effects of multifactorial intensified intervention by the team approach with medical staffs at each institution. There was an overall trend toward a lower risk on the development of kidney events in the intensive treatment group than in the conventional treatment group in this trial, but the benefit of intensive treatment could not be confirmed statistically. Lipid control by statin was associated with lower risk of kidney events in addition to strict control of blood glucose and blood pressure.

Published
2020

17. Emergence of a multidrug-resistant plasmid encoding bla NDM-1, bla OXA-420 and armA in a clinical isolate of Acinetobacter variabilis in Japan

Author

Ami Takahashi, Teruo Kirikae, Tatsuya Tada, Kohei Uechi, Takaaki Tome, Takeshi Kinjo, Mari Tohya, Shiro Maeda, and Jiro Fujita

Subjects
Microbiology (medical), Imipenem, Acinetobacter variabilis, General Medicine, Biology, medicine.disease_cause, Microbiology, Meropenem, Ciprofloxacin, Multiple drug resistance, Plasmid, Amikacin, medicine, Arbekacin, medicine.drug
Abstract

Acinetobacter variabilis (formerly genospecies 15 sensu Tjernberg and Ursing) has been isolated from humans and animals and was proposed to be a novel species in 2015. A multidrug-resistant A. variabilis isolate, RYU24, was obtained in 2012 from an inpatient in Okinawa, Japan, with no record of overseas travel. The isolate was resistant to carbapenems, aminoglycosides and ciprofloxacin, with minimum inhibitory concentrations (MICs) of 32 µg ml−1 for imipenem and meropenem; > 1024 µg ml−1 for amikacin, arbekacin, gentamicin and tobramycin; and 8 µg ml−1 for ciprofloxacin. The isolate was found to harbour a 68-kbp plasmid carrying bla NDM-1, which encodes New Delhi metallo-β-lactamase-1 (NDM-1); bla OXA-420, which encodes an OXA-58-like carbapenemase and; armA, which encodes ArmA 16S rRNA methylase conferring pan-aminoglycoside resistance. To our knowledge, this is the first report of a plasmid harbouring the three major drug-resistance genes, bla NDM-1, bla OXA-420 and armA.

Published
2021

18. CACNB2 Is a Novel Susceptibility Gene for Diabetic Retinopathy in Type 1 Diabetes

Author

Nadja Vuori, M Imamura, Anmol Kumar, Niina Sandholm, Kustaa Hietala, Per-Henrik Groop, FinnDiane Study, Shiro Maeda, Paula Summanen, Markku Lehto, Heli Skottman, Anna Syreeni, Kati Juuti-Uusitalo, Carol Forsblom, Department of Medicine, Nefrologian yksikkö, University of Helsinki, HUS Abdominal Center, Faculty of Medicine, CAMM - Research Program for Clinical and Molecular Metabolism, Research Programs Unit, Clinicum, HUS Head and Neck Center, Department of Ophthalmology and Otorhinolaryngology, Per Henrik Groop / Principal Investigator, University Management, Endokrinologian yksikkö, Lääketieteen ja terveysteknologian tiedekunta - Faculty of Medicine and Health Technology, and Tampere University

Subjects
0301 basic medicine, type 1 diabetes, Endocrinology, Diabetes and Metabolism, BETA(2) SUBUNIT, CUMULATIVE INCIDENCE, PROGRESSION, Genome-wide association study, L-tyypin kalsiumkanava, chemistry.chemical_compound, 0302 clinical medicine, CACNB2, linkage study, RISK, Sisätaudit - Internal medicine, Genetics/Genomes/Proteomics/Metabolomics, sequencing, Diabetic retinopathy, VEGF, Diabeettinen retinopatia, 3. Good health, Vascular endothelial growth factor, diabetic retinopathy, geneettinen assosiaatio, medicine.medical_specialty, Biolääketieteet - Biomedicine, 030209 endocrinology & metabolism, 03 medical and health sciences, Genetiikka, kehitysbiologia, fysiologia - Genetics, developmental biology, physiology, Diabetes mellitus, Internal medicine, LINKAGE, Internal Medicine, medicine, GENOME-WIDE ASSOCIATION, Genetic association, Diabetes Complication, Type 1 diabetes, CHANNELS, business.industry, Case-control study, tyyppi 1 diabetes, medicine.disease, 030104 developmental biology, Endocrinology, chemistry, 3121 General medicine, internal medicine and other clinical medicine, ENDOTHELIAL GROWTH-FACTOR, CELLS, PROLIFERATIVE RETINOPATHY, business
Abstract

Diabetic retinopathy is a common diabetes complication that threatens the eyesight and may eventually lead to acquired visual impairment or blindness. While a substantial heritability has been reported for proliferative diabetic retinopathy (PDR), only a few genetic risk factors have been identified. Using genome-wide sib pair linkage analysis including 361 individuals with type 1 diabetes, we found suggestive evidence of linkage with PDR at chromosome 10p12 overlapping the CACNB2 gene (logarithm of odds = 2.73). Evidence of association between variants in CACNB2 and PDR was also found in association analysis of 4,005 individuals with type 1 diabetes with an odds ratio of 0.83 and P value of 8.6 x 10(-4) for rs11014284. Sequencing of CACNB2 revealed two coding variants, R476C/rs202152674 and S502L/rs137886839. CACNB2 is abundantly expressed in retinal cells and encodes the beta 2 subunit of the L-type calcium channel. Blocking vascular endothelial growth factor (VEGF) by intravitreous anti-VEGF injections is a promising clinical therapy to treat PDR. Our data show that L-type calcium channels regulate VEGF expression and secretion from retinal pigment epithelial cells (ARPE19) and support the role of CACNB2 via regulation of VEGF in the pathogenesis of PDR. However, further genetic and functional studies are necessary to consolidate the findings.

Published
2019

19. Trans-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

Author

Anubha Mahajan, Cassandra N Spracklen, Weihua Zhang, Maggie CY Ng, Lauren E Petty, Hidetoshi Kitajima, Grace Z Yu, Sina Rüeger, Leo Speidel, Young Jin Kim, Momoko Horikoshi, Josep M Mercader, Daniel Taliun, Sanghoon Moon, Soo-Heon Kwak, Neil R Robertson, Nigel W Rayner, Marie Loh, Bong-Jo Kim, Joshua Chiou, Irene Miguel-Escalada, Pietro della Briotta Parolo, Kuang Lin, Fiona Bragg, Michael H Preuss, Fumihiko Takeuchi, Jana Nano, Xiuqing Guo, Amel Lamri, Masahiro Nakatochi, Robert A Scott, Jung-Jin Lee, Alicia Huerta-Chagoya, Mariaelisa Graff, Jin-Fang Chai, Esteban J Parra, Jie Yao, Lawrence F Bielak, Yasuharu Tabara, Yang Hai, Valgerdur Steinthorsdottir, James P Cook, Mart Kals, Niels Grarup, Ellen M Schmidt, Ian Pan, Tamar Sofer, Matthias Wuttke, Chloe Sarnowski, Christian Gieger, Darryl Nousome, Stella Trompet, Jirong Long, Meng Sun, Lin Tong, Wei-Min Chen, Meraj Ahmad, Raymond Noordam, Victor JY Lim, Claudia HT Tam, Yoonjung Yoonie Joo, Chien-Hsiun Chen, Laura M Raffield, Cécile Lecoeur, Nisa M Maruthur, Bram Peter Prins, Aude Nicolas, Lisa R Yanek, Guanjie Chen, Richard A Jensen, Salman Tajuddin, Edmond Kabagambe, Ping An, Anny H Xiang, Hyeok Sun Choi, Brian E Cade, Jingyi Tan, Fernando Abaitua, Linda S Adair, Adebowale Adeyemo, Carlos A Aguilar-Salinas, Masato Akiyama, Sonia S Anand, Alain Bertoni, Zheng Bian, Jette Bork-Jensen, Ivan Brandslund, Jennifer A Brody, Chad M Brummett, Thomas A Buchanan, Mickaël Canouil, Juliana CN Chan, Li-Ching Chang, Miao-Li Chee, Ji Chen, Shyh-Huei Chen, Yuan-Tsong Chen, Zhengming Chen, Lee-Ming Chuang, Mary Cushman, Swapan K Das, H. Janaka de Silva, George Dedoussis, Latchezar Dimitrov, Ayo P Doumatey, Shufa Du, Qing Duan, Kai-Uwe Eckardt, Leslie S Emery, Daniel S Evans, Michele K Evans, Krista Fischer, James S Floyd, Ian Ford, Myriam Fornage, Oscar H Franco, Timothy M Frayling, Barry I Freedman, Christian Fuchsberger, Pauline Genter, Hertzel C Gerstein, Vilmantas Giedraitis, Clicerio González-Villalpando, Maria Elena González-Villalpando, Mark O Goodarzi, Penny Gordon-Larsen, David Gorkin, Myron Gross, Yu Guo, Sophie Hackinger, Sohee Han, Andrew T Hattersley, Christian Herder, Annie-Green Howard, Willa Hsueh, Mengna Huang, Wei Huang, Yi-Jen Hung, Mi Yeong Hwang, Chii-Min Hwu, Sahoko Ichihara, Mohammad Arfan Ikram, Martin Ingelsson, Md. Tariqul Islam, Masato Isono, Hye-Mi Jang, Farzana Jasmine, Guozhi Jiang, Jost B Jonas, Marit E Jørgensen, Torben Jørgensen, Yoichiro Kamatani, Fouad R Kandeel, Anuradhani Kasturiratne, Tomohiro Katsuya, Varinderpal Kaur, Takahisa Kawaguchi, Jacob M Keaton, Abel N Kho, Chiea-Chuen Khor, Muhammad G Kibriya, Duk-Hwan Kim, Katsuhiko Kohara, Jennifer Kriebel, Florian Kronenberg, Johanna Kuusisto, Kristi Läll, Leslie A Lange, Myung-Shik Lee, Nanette R Lee, Aaron Leong, Liming Li, Yun Li, Ruifang Li-Gao, Symen Ligthart, Cecilia M Lindgren, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Adam E Locke, Tin Louie, Jian’an Luan, Andrea O Luk, Xi Luo, Jun Lv, Valeriya Lyssenko, Vasiliki Mamakou, K Radha Mani, Thomas Meitinger, Andres Metspalu, Andrew D Morris, Girish N. Nadkarni, Jerry L Nadler, Michael A Nalls, Uma Nayak, Ioanna Ntalla, Yukinori Okada, Lorena Orozco, Sanjay R Patel, Mark A Pereira, Annette Peters, Fraser J Pirie, Bianca Porneala, Gauri Prasad, Sebastian Preissl, Laura J Rasmussen-Torvik, Alexander P Reiner, Michael Roden, Rebecca Rohde, Katheryn Roll, Charumathi Sabanayagam, Maike Sander, Kevin Sandow, Naveed Sattar, Sebastian Schönherr, Claudia Schurmann, Mohammad Shahriar, Jinxiu Shi, Dong Mun Shin, Daniel Shriner, Jennifer A Smith, Wing Yee So, Alena Stančáková, Adrienne M Stilp, Konstantin Strauch, Ken Suzuki, Atsushi Takahashi, Kent D Taylor, Barbara Thorand, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Brian Tomlinson, Jason M Torres, Fuu-Jen Tsai, Jaakko Tuomilehto, Teresa Tusie-Luna, Miriam S Udler, Adan Valladares-Salgado, Rob M van Dam, Jan B van Klinken, Rohit Varma, Marijana Vujkovic, Niels Wacher-Rodarte, Ellie Wheeler, Eric A Whitsel, Ananda R Wickremasinghe, Konstantin Willems van Dijk, Daniel R Witte, Chittaranjan S Yajnik, Ken Yamamoto, Toshimasa Yamauchi, Loïc Yengo, Kyungheon Yoon, Canqing Yu, Jian-Min Yuan, Salim Yusuf, Liang Zhang, Wei Zheng, null FinnGen, Leslie J Raffel, Michiya Igase, Eli Ipp, Susan Redline, Yoon Shin Cho, Lars Lind, Michael A Province, Craig L Hanis, Patricia A Peyser, Erik Ingelsson, Alan B Zonderman, Bruce M Psaty, Ya-Xing Wang, Charles N Rotimi, Diane M Becker, Fumihiko Matsuda, Yongmei Liu, Eleftheria Zeggini, Mitsuhiro Yokota, Stephen S Rich, Charles Kooperberg, James S Pankow, James C Engert, Yii-Der Ida Chen, Philippe Froguel, James G Wilson, Wayne HH Sheu, Sharon LR Kardia, Jer-Yuarn Wu, M Geoffrey Hayes, Ronald CW Ma, Tien-Yin Wong, Leif Groop, Dennis O Mook-Kanamori, Giriraj R Chandak, Francis S Collins, Dwaipayan Bharadwaj, Guillaume Paré, Michèle M Sale, Habibul Ahsan, Ayesha A Motala, Xiao-Ou Shu, Kyong-Soo Park, J Wouter Jukema, Miguel Cruz, Roberta McKean-Cowdin, Harald Grallert, Ching-Yu Cheng, Erwin P Bottinger, Abbas Dehghan, E-Shyong Tai, Josee Dupuis, Norihiro Kato, Markku Laakso, Anna Köttgen, Woon-Puay Koh, Colin NA Palmer, Simin Liu, Goncalo Abecasis, Jaspal S Kooner, Ruth JF Loos, Kari E North, Christopher A Haiman, Jose C Florez, Danish Saleheen, Torben Hansen, Oluf Pedersen, Reedik Mägi, Claudia Langenberg, Nicholas J Wareham, Shiro Maeda, Takashi Kadowaki, Juyoung Lee, Iona Y Millwood, Robin G Walters, Kari Stefansson, Simon R Myers, Jorge Ferrer, Kyle J Gaulton, James B Meigs, Karen L Mohlke, Anna L Gloyn, Donald W Bowden, Jennifer E Below, John C Chambers, Xueling Sim, Michael Boehnke, Jerome I Rotter, Mark I McCarthy, and Andrew P Morris

Subjects
0303 health sciences, Transferability, Translation (biology), Type 2 diabetes, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Evolutionary biology, Global health, medicine, Genetic risk, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract

We assembled an ancestrally diverse collection of genome-wide association studies of type 2 diabetes (T2D) in 180,834 cases and 1,159,055 controls (48.9% non-European descent). We identified 277 loci at genome-wide significance (p-8), including 237 attaining a more stringent trans-ancestry threshold (p-9), which were delineated to 338 distinct association signals. Trans-ancestry meta-regression offered substantial enhancements to fine-mapping, with 58.6% of associations more precisely localised due to population diversity, and 54.4% of signals resolved to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying foundations for functional investigations. Trans-ancestry genetic risk scores enhanced transferability across diverse populations, providing a step towards more effective clinical translation to improve global health.

Published
2020

20. Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control

Author

Mark I. McCarthy, Weihua Meng, Brian L. Yaspan, M Imamura, Mark W. Christiansen, Niina Sandholm, Yii-Der Ida Chen, Sharon G. Adler, Lucia Sobrin, Craig L. Hanis, Valeriya Lyssenko, Shiro Maeda, Yang Hai, Paul Mitchell, Roberta McKean-Cowdin, Xiuqing Guo, John R. Sedor, David S. Siscovick, Sudha K. Iyengar, Heather Hancock, Jane Z. Kuo, Barbara E.K. Klein, David-Alexandre Tregouet, Elisabet Agardh, Kent D. Taylor, Andrew D. Morris, S. Mohsen Hosseini, Andrew D. Paterson, I-Te Lee, Wayne Huey-Herng Sheu, Emma Ahlqvist, Kathryn P. Burdon, Leif Groop, Ayellet V. Segrè, Samy Hadjadj, Samaneh Davoudi, Lynn K. Stanwyck, Emily Y. Chew, Xiaohui Li, Michael A. Grassi, Jie Jin Wang, Samuela Pollack, Albert V. Smith, Kyu Hyung Park, Michiaki Kubo, Mary Frances Cotch, Yucheng Jia, Ching J. Chen, Colin N. A. Palmer, Helen M. Colhoun, Alan D. Penman, R. Varma, Per-Henrik Groop, Tien Yin Wong, Barry I. Freedman, Eli Ipp, Alex S. F. Doney, Gavin Tan, Ronald Klein, Kaanan P. Shah, Jamie E Craig, Donald W. Bowden, Jerome I. Rotter, Robert P. Igo, Darryl Nousome, Ching-Yu Cheng, Michel Marre, Maggie C.Y. Ng, Latchezar Dimitrov, Jeeyun Ahn, Atsushi Takahashi, Richard A. Jensen, Aaron Leong, Jihye Kim, Iiro Toppila, Elizabeth J. Rossin, Alkes L. Price, Diabetes and Obesity Research Program, University of Helsinki, Department of Medicine, Nefrologian yksikkö, Research Programs Unit, Clinicum, HUS Abdominal Center, and Per Henrik Groop / Principal Investigator

Subjects
Blood Glucose, 0301 basic medicine, Oncology, medicine.medical_specialty, Genotype, Endocrinology, Diabetes and Metabolism, LOCI, 030209 endocrinology & metabolism, Genome-wide association study, VARIANTS, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Meta-Analysis as Topic, RESOURCE, Internal medicine, Diabetes mellitus, REVEALS, Genetic variation, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, CHINESE PATIENTS, Allele, METAANALYSIS, POLYMORPHISMS, Glycemic, Glycated Hemoglobin, Diabetic Retinopathy, business.industry, Diabetic retinopathy, medicine.disease, PREVALENCE, 3. Good health, SEVERITY, 030104 developmental biology, Diabetes Mellitus, Type 2, 3121 General medicine, internal medicine and other clinical medicine, Multiple comparisons problem, RISK-FACTORS, Medical genetics, Erratum, business, Genome-Wide Association Study, Protein Binding
Abstract

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value

Published
2018

21. アシネトバクター属菌およびシュードモナス属菌におけるカルバペネマーゼ検出法、カルバペネム不活化法、CIMTrisの考案

Author

Tatsuya Tada, Teruo Kirikae, Kayo Shimada, Shiro Maeda, Takaaki Tome, Kyoko Kuwahara-Arai, Jiro Fujita, Kohei Uechi, Momoko Arakaki, and Isamu Nakasone

Subjects
0301 basic medicine, Microbiology (medical), Bacteriological Techniques, Carbapenem, Acinetobacter, Diagnostic Tests, Routine, 030106 microbiology, Bacteriology, Biology, biology.organism_classification, Sensitivity and Specificity, beta-Lactamases, Microbiology, 03 medical and health sciences, Bacterial Proteins, Pseudomonas species, Pseudomonas, medicine, Acinetobacter species, Bacteria, medicine.drug, Carbapenem resistance
Abstract

The carbapenem inactivation method (CIM) and modified CIM (mCIM) are simple and economical phenotypic screening methods for detecting carbapenemase production in Gram-negative bacteria. Although the mCIM has been recommended by the Clinical and Laboratory Standards Institute, both the CIM and mCIM have limitations. This study describes another modified CIM, called CIMTris, in which carbapenemase was extracted from bacteria with 0.5 M Tris-HCl (pH 7.6) buffer. The ability of the CIMTris to detect carbapenemase production was examined in Acinetobacter and Pseudomonas species. The CIMTris had an overall sensitivity of 97.6% and an overall specificity of 92.6%, whereas the mCIM had a sensitivity of 45.1% and a specificity of 100% for the isolates tested. These findings indicate that the CIMTris is useful for detecting carbapenemase production in Acinetobacter and Pseudomonas species.

Published
2017

22. Long-term dietary nitrite and nitrate deficiency causes the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice

Author

Akihide Tanimoto, Taro Uchida, Shiro Maeda, Tadashi Kaname, Yuji Taira, Akira Arasaki, Hiroaki Masuzaki, Katsuhiko Noguchi, Kimio Satoh, Masayuki Matsushita, Yuichi Totsuka, Chisayo Kozuka, Toshihiro Matsuzaki, Junichi Omura, Masato Tsutsui, Haruaki Kubota, Shin ichiro Kina, Nobuyuki Yanagihara, Junko Nakasone, Mika Kina-Tanada, Mayuko Sakanashi, Hiroaki Shimokawa, Hajime Sunakawa, Masayoshi Ishida, and Yusuke Ohya

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Nitric Oxide, Endothelial NOS, Cardiovascular System, Nitric oxide, Mice, 03 medical and health sciences, chemistry.chemical_compound, Insulin resistance, Nitrate, Internal medicine, Internal Medicine, Animals, Medicine, Endothelial dysfunction, Nitrite, Nitrites, Metabolic Syndrome, Nitrates, business.industry, medicine.disease, Dietary Nitrite, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, chemistry, Biochemistry, Metabolic syndrome, business
Abstract

Nitric oxide (NO) is synthesised not only from l-arginine by NO synthases (NOSs), but also from its inert metabolites, nitrite and nitrate. Green leafy vegetables are abundant in nitrate, but whether or not a deficiency in dietary nitrite/nitrate spontaneously causes disease remains to be clarified. In this study, we tested our hypothesis that long-term dietary nitrite/nitrate deficiency would induce the metabolic syndrome in mice. To this end, we prepared a low-nitrite/nitrate diet (LND) consisting of an amino acid-based low-nitrite/nitrate chow, in which the contents of l-arginine, fat, carbohydrates, protein and energy were identical with a regular chow, and potable ultrapure water. Nitrite and nitrate were undetectable in both the chow and the water. Three months of the LND did not affect food or water intake in wild-type C57BL/6J mice compared with a regular diet (RD). However, in comparison with the RD, 3 months of the LND significantly elicited visceral adiposity, dyslipidaemia and glucose intolerance. Eighteen months of the LND significantly provoked increased body weight, hypertension, insulin resistance and impaired endothelium-dependent relaxations to acetylcholine, while 22 months of the LND significantly led to death mainly due to cardiovascular disease, including acute myocardial infarction. These abnormalities were reversed by simultaneous treatment with sodium nitrate, and were significantly associated with endothelial NOS downregulation, adiponectin insufficiency and dysbiosis of the gut microbiota. These results provide the first evidence that long-term dietary nitrite/nitrate deficiency gives rise to the metabolic syndrome, endothelial dysfunction and cardiovascular death in mice, indicating a novel pathogenetic role of the exogenous NO production system in the metabolic syndrome and its vascular complications.

Published
2017

23. Identification of type 2 diabetes loci in 433,540 East Asian individuals

Author

Chien-Hsiun Chen, Anna L. Gloyn, Atsushi Takahashi, Sohee Han, Ken Suzuki, Mark A Pereira, Shi Jinxiu, Fiona Bragg, Yii-Der Ida Chen, Robin G. Walters, Takashi Kadowaki, Charumathi Sabanayagam, Annie-Green Howard, Mark I. McCarthy, Zheng Bian, Zhengming Chen, E-Shyong Tai, Chii-Min Hwu, Cassandra N. Spracklen, Yuan-Tsong Chen, Linda S. Adair, Momoko Horikoshi, Guozhi Jiang, Ching-Yu Cheng, Mi Yeong Hwang, Andrew P. Morris, Karen L. Mohlke, John C. Chambers, Jian-Min Yuan, Woon-Puay Koh, Hyeok Sun Choi, Ju Young Lee, Bong-Jo Kim, Masato Akiyama, Sahoko Ichihara, Xueling Sim, Norihiro Kato, Kuang Lin, Jirong Long, Xiuqing Guo, Fumihiko Takeuchi, Penny Gordon-Larsen, Hannah J Perrin, Young Jin Kim, Lee-Ming Chuang, Weihua Zhang, Rob M. van Dam, Andrea O.Y. Luk, Masahiro Nakatochi, Yukinori Okada, Katsuhiko Kohara, Yoichiro Kamatani, Jerome I. Rotter, Iona Y Millwood, Jer-Yuarn Wu, Canqing Yu, Wayne Huey-Herng Sheu, Shiro Maeda, Jost B. Jonas, Yasuharu Tabara, Mitsuhiro Yokota, Li-Ching Chang, Toshimasa Yamauchi, Shufa Du, Yu Guo, Yoon Shin Cho, Yi-Jen Hung, Jie Yao, Soo Heon Kwak, Hye-Mi Jang, Maggie C.Y. Ng, Xiao-Ou Shu, Myung-Shik Lee, Kyungheon Yoon, Sarah M Brotman, Sanghoon Moon, Tien Yin Wong, Martijn van de Bunt, Michiya Igase, Claudia H. T. Tam, Fumihiko Matsuda, Wei Zheng, Liang Zhang, Yong-Bing Xiang, Victor Jun Yu Lim, Ronald Cw Ma, Liming Li, Tomohiro Katsuya, Jianjun Liu, Jun Lv, Jennifer E. Below, Anubha Mahajan, Kyong-Soo Park, Masato Isono, Wing-Yee So, Nanette R. Lee, Brian Tomlinson, Juliana C.N. Chan, Lauren E. Petty, Chiea Chuen Khor, Miao-Li Chee, Ken Yamamoto, Wei Huang, Michael Boehnke, Jin-Fang Chai, Donald W. Bowden, Apoorva K Iyengar, Dong Mun Shin, Myron D. Gross, Takahisa Kawaguchi, Ya Xing Wang, and Fuu Jen Tsai

Subjects
Ankyrins, Male, 0301 basic medicine, Transcription, Genetic, endocrine system diseases, Nerve Tissue Proteins, 030209 endocrinology & metabolism, Locus (genetics), Genome-wide association study, Type 2 diabetes, Biology, Article, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Asian People, ANK1, medicine, Humans, Genetic Predisposition to Disease, RNA, Messenger, Allele, Eye Proteins, Gene, Alleles, 030304 developmental biology, ALDH2, Genetic association, 2. Zero hunger, Homeodomain Proteins, Genetics, 0303 health sciences, Multidisciplinary, Asia, Eastern, Aldehyde Dehydrogenase, Mitochondrial, Case-control study, nutritional and metabolic diseases, medicine.disease, Europe, 030104 developmental biology, Diabetes Mellitus, Type 2, Case-Control Studies, Meta-analysis, Expression quantitative trait loci, Female, Body mass index, 030217 neurology & neurosurgery, Genome-Wide Association Study, Transcription Factors
Abstract

SUMMARYMeta-analyses of genome-wide association studies (GWAS) have identified >240 loci associated with type 2 diabetes (T2D), however most loci have been identified in analyses of European-ancestry individuals. To examine T2D risk in East Asian individuals, we meta-analyzed GWAS data in 77,418 cases and 356,122 controls. In the main analysis, we identified 298 distinct association signals at 178 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 56 loci newly implicated in T2D predisposition. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. New associations include signals in/near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect muscle and adipose differentiation. At another locus, eQTLs at two overlapping T2D signals act through two genes, NKX6-3 and ANK1, in different tissues. Association studies in diverse populations identify additional loci and elucidate disease genes, biology, and pathways.Type 2 diabetes (T2D) is a common metabolic disease primarily caused by insufficient insulin production and/or secretion by the pancreatic β cells and insulin resistance in peripheral tissues1. Most genetic loci associated with T2D have been identified in populations of European (EUR) ancestry, including a recent meta-analysis of genome-wide association studies (GWAS) of nearly 900,000 individuals of European ancestry that identified >240 loci influencing the risk of T2D2. Differences in allele frequency between ancestries affect the power to detect associations within a population, particularly among variants rare or monomorphic in one population but more frequent in another3,4. Although smaller than studies in European populations, a recent T2D meta-analysis in almost 200,000 Japanese individuals identified 28 additional loci4. The relative contributions of different pathways to the pathophysiology of T2D may also differ between ancestry groups. For example, in East Asian (EAS) populations, T2D prevalence is greater than in European populations among people of similar body mass index (BMI) or waist circumference5. We performed the largest meta-analysis of East Asian individuals to identify new genetic associations and provide insight into T2D pathogenesis.

Published
2019
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24. Genome-Wide Association Study for Type 2 Diabetes

Author

Shiro Maeda, Momoko Horikoshi, and M Imamura

Subjects
Missing heritability problem, business.industry, Diabetes mellitus, Pharmacogenomics, medicine, Genetic predisposition, Genome-wide association study, Type 2 diabetes, medicine.disease, Bioinformatics, business, Glycemic, Genetic association
Abstract

Genome-wide association studies (GWAS) have facilitated a substantial and rapid rise in the number of confirmed genetic susceptibility variants for type 2 diabetes (T2D) and glycemic traits. Approximately 90 variants for conferring susceptibility to T2D and 80 variants for glycemic traits have been identified until the end of 2016. This success has led to widespread hope that the findings will translate into improved clinical care for the increasing numbers of patients with diabetes. Potential areas or clinical translation include risk prediction and subsequent disease prevention, pharmacogenomics, and the development of novel therapeutics. In contrast, worldwide efforts to identify susceptibility loci to diabetic nephropathy have not been successful so far, and most of heritability for diabetic nephropathy remains to be elucidated. Uncovering the missing heritability is essential to the progress of T2D genetic studies and to the translation of genetic information into clinical practice.

Published
2019

25. A variant within the FTO confers susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes

Author

Takashi Kadowaki, Hirotaka Watada, Kohei Kaku, Mark I. McCarthy, Masao Toyoda, Hiroshi Maegawa, Tetsuya Babazono, Tomoya Umezono, Masahito Imanishi, Nobue Tanaka, Ryuzo Kawamori, Shin-ichi Araki, Koichi Kawai, Shiro Maeda, Daisuke Suzuki, Leif Groop, Natalie R. van Zuydam, Atsushi Takahashi, Makiko Taira, Yoichiro Kamatani, Toshimasa Yamauchi, M Imamura, Emma Ahlqvist, Centre of Excellence in Complex Disease Genetics, Institute for Molecular Medicine Finland, University of Helsinki, and HUS Abdominal Center

Subjects
Male, 0301 basic medicine, Physiology, Genome-wide association study, Type 2 diabetes, Gastroenterology, Diabetic nephropathy, MELLITUS, Endocrinology, Mathematical and Statistical Techniques, Japan, Chronic Kidney Disease, Medicine and Health Sciences, Diabetic Nephropathies, COMPLICATIONS, Multidisciplinary, Statistics, Genomics, Metaanalysis, Middle Aged, Type 2 Diabetes, 3. Good health, Physiological Parameters, Nephrology, OBESITY, Physical Sciences, Medicine, Female, Research Article, medicine.medical_specialty, Endocrine Disorders, Science, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Single-nucleotide polymorphism, Research and Analysis Methods, Polymorphism, Single Nucleotide, Nephropathy, Molecular Genetics, 03 medical and health sciences, Internal medicine, Diabetes mellitus, Diabetes Mellitus, Genome-Wide Association Studies, Genetics, medicine, Humans, Genetic Predisposition to Disease, Statistical Methods, GENOME-WIDE ASSOCIATION, Molecular Biology, Aged, Genetic association, business.industry, Body Weight, Case-control study, Biology and Life Sciences, Computational Biology, Human Genetics, Genome Analysis, medicine.disease, GENE, POLYMORPHISM, RENAL-DISEASE, 030104 developmental biology, Diabetes Mellitus, Type 2, Genetic Loci, Metabolic Disorders, Case-Control Studies, 3111 Biomedicine, business, Mathematics, Genome-Wide Association Study
Abstract

To explore novel genetic loci for diabetic nephropathy, we performed genome-wide association studies (GWAS) for diabetic nephropathy in Japanese patients with type 2 diabetes. We analyzed the association of 5,768,242 single nucleotide polymorphisms (SNPs) in Japanese patients with type 2 diabetes, 2,380 nephropathy cases and 5,234 controls. We further performed GWAS for diabetic nephropathy using independent Japanese patients with type 2 diabetes, 429 cases and 358 controls and the results of these two GWAS were combined with an inverse variance meta-analysis (stage-1), followed by a de novo genotyping for the candidate SNP loci (p < 1.0 x 10^) in an independent case-control study (Stage-2; 1,213 cases and 1,298 controls). After integrating stage-1 and stage-2 data, we identified one SNP locus, significantly associated with diabetic nephropathy; rs56094641 in FTO, P = 7.74 x 10^. We further examined the association of rs56094641 with diabetic nephropathy in independent Japanese patients with type 2 diabetes (902 cases and 1,221 controls), and found that the association of this locus with diabetic nephropathy remained significant after integrating all association data (P = 7.62 x 10^). We have identified FTO locus as a novel locus for conferring susceptibility to diabetic nephropathy in Japanese patients with type 2 diabetes., 論文

Published
2018

26. An improved carbapenem inactivation method, CIMTrisII, for carbapenemase production by Gram-negative pathogens

Author

Tatsuya Tada, Jun-ichiro Sekiguchi, Khin Nyein Zan, Takaaki Tome, Kohei Uechi, Teruo Kirikae, San Mya, Jiro Fujita, Kyoko Kuwahara-Arai, Izumi Yanagisawa, Isamu Nakasone, Shiro Maeda, and Htay Htay Tin

Subjects
0301 basic medicine, Microbiology (medical), DNA, Bacterial, Carbapenem, Time Factors, 030106 microbiology, Microbial Sensitivity Tests, medicine.disease_cause, Microbiology, Meropenem, Sensitivity and Specificity, beta-Lactamases, Incubation period, 03 medical and health sciences, Bacterial Proteins, Enterobacteriaceae, Japan, Nepal, Pseudomonas, medicine, Humans, Asia, Southeastern, Gram, biology, Acinetobacter, Pseudomonas aeruginosa, General Medicine, Bacterial Infections, Sequence Analysis, DNA, biology.organism_classification, Anti-Bacterial Agents, Imipenem, 030104 developmental biology, Carbapenems, Bacteria, medicine.drug
Abstract

The modified carbapenem inactivation method (mCIM) is a simple phenotypic screening method for detecting carbapenemase production by Enterobacteriaceae and Pseudomonas aeruginosa. We recently developed another modified carbapenem inactivation method (CIMTris), in which carbapenemase is extracted from bacteria with Tris-HCl buffer, to detect carbapenemase production by Acinetobacter and Pseudomonas species. This study describes an improved carbapenem inactivation method, CIMTrisII, for detecting carbapenemase production by Gram-negative pathogens, including Enterobacteriaceae, Acinetobacter and Pseudomonas species. CIMTrisII was different from CIMTris in the concentration of Meropenem disks (5-µg MEM disks vs. 10-µg MEM disks), the inoculum volume of the bacteria (a 5-µl loopful vs. a 10 µl loopful) and the incubation time (1 vs. 2 h). CIMTrisII showed an overall sensitivity of 99.3 % and an overall specificity of 95.0 % for tested isolates. In comparison, CIMTris showed a sensitivity of 96.1 % and a specificity of 96.3 %, and mCIM showed a sensitivity of 67.1 % and a specificity of 100 %. CIMTrisII is thus deemed useful for detecting carbapenemase production by Gram-negative pathogens.

Published
2018

27. Hypothalamic AMP-Activated Protein Kinase Regulates Biphasic Insulin Secretion from Pancreatic β Cells during Fasting and in Type 2 Diabetes

Author

Masakazu Haneda, Masami Chin-Kanasaki, Satoshi Ugi, Yukihiro Fujita, Tsuyoshi Yanagimachi, Shinji Kume, Keiko Kondo, Takashi Uzu, Sawako Kitahara, Shin-ich Araki, Hisazumi Araki, Shiro Maeda, Daisuke Koya, Akihiro Sekine, Atsunori Kashiwagi, Motoyuki Kondo, Hiroshi Maegawa, Kiyosumi Maeda, and Yoshihiko Nishio

Subjects
0301 basic medicine, SNS, sympathetic nervous system, Male, Sympathetic Nervous System, Time Factors, 18F-FDG, 2-[fluorine-18]-2-deoxy-d-glucose, OGTT, oral glucose tolerance test, Insulins, lcsh:Medicine, Type 2 diabetes, AMP-Activated Protein Kinases, ACC, acetyl CoA carboxylase, IPITT, intraperitoneal insulin tolerance test, chemistry.chemical_compound, 0302 clinical medicine, AMP-activated protein kinase, Insulin-Secreting Cells, Pancreatic β cell, Kg, glucose disappearance rate, lcsh:R5-920, biology, Insulin secretion, Diabetes, GIP, glucose-dependent insulinotropic polypeptide, LETO, Long-Evans Tokushima Otsuka, Brain, GLP-1, glucagon-like peptide-1, General Medicine, Fasting, Glucagon-like peptide-1, Denervation, CT, computed tomography, Organ Specificity, OLETF, Otsuka Long-Evans Tokushima Fatty, SNPs, single nucleotide polymorphisms, First-phase GSIS, lcsh:Medicine (General), Research Paper, Cell physiology, HOMA-β, homeostasis model assessment beta-cell function index, medicine.medical_specialty, endocrine system, FSIVGTT, frequently sampled intravenous glucose tolerance test, SUV, standardized uptake value, Hypothalamus, 2-DG, 2-deoxy-d-glucose, General Biochemistry, Genetics and Molecular Biology, PET, positron emission tomography, AIR, acute insulin response, GSIS, glucose-stimulated insulin secretion, 03 medical and health sciences, Fluorodeoxyglucose F18, Internal medicine, Diabetes mellitus, medicine, Animals, Humans, Secretion, Protein kinase A, Pancreas, ICV, intracerebroventricular, business.industry, lcsh:R, SD, Sprague-Dawley, AICAR, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside, PNx, pancreatic denervation, Glucose Tolerance Test, medicine.disease, Rats, AMPK, AMP-activated protein kinase, Disease Models, Animal, 030104 developmental biology, Endocrinology, Glucose, chemistry, Diabetes Mellitus, Type 2, Starvation, Positron-Emission Tomography, biology.protein, business, 2-Deoxy-D-glucose, Tomography, X-Ray Computed, 030217 neurology & neurosurgery
Abstract

Glucose-stimulated insulin secretion (GSIS) by pancreatic β cells is biphasic. However, the physiological significance of biphasic GSIS and its relationship to diabetes are not yet fully understood. This study demonstrated that impaired first-phase GSIS follows fasting, leading to increased blood glucose levels and brain glucose distribution in humans. Animal experiments to determine a possible network between the brain and β cells revealed that fasting-dependent hyperactivation of AMP-activated protein kinase in the hypothalamus inhibited first-phase GSIS by stimulating the α-adrenergic pancreatic nerve. Furthermore, abnormal excitability of this brain-β cell neural axis was involved in diabetes-related impairment of first-phase GSIS in diabetic animals. Finally, pancreatic denervation improved first-phase GSIS and glucose tolerance and ameliorated severe diabetes by preventing β cell loss in diabetic animals. These results indicate that impaired first-phase GSIS is critical for brain distribution of dietary glucose after fasting. Furthermore, β cells in individuals with diabetes mistakenly sense that they are under conditions that mimic prolonged fasting. The present study provides additional insight into both β cell physiology and the pathogenesis of β cell dysfunction in type 2 diabetes., Highlights • Fasting-induced hypothalamic AMPK activation inhibited first-phase GSIS by stimulating the α-adrenergic nerve. • The brain-pancreas neural axis was involved in β cell dysfunction and glucose intolerance in diabetes. • Pancreatic denervation improved first-phase GSIS, glucose tolerance and β cell survival in type 2 diabetic animals. Glucose-stimulated insulin secretion (GSIS) from pancreatic β cells is biphasic. Furthermore, first-phase GSIS is inhibited in type 2 diabetes. This study revealed that fasting reduced first-phase GSIS by signaling via the brain-pancreatic β cell neural axis, which is essential for maintaining glucose supply to the brain at re-feeding after fasting. Abnormal excitability of this neural axis was also associated with impaired first-phase GSIS in type 2 diabetes. Surgical pancreatic denervation improved diabetes in an animal study. The present data reveal that diabetic β cells exist under conditions that mimic starvation and provide a therapeutic potency of pancreatic denervation against diabetes., Graphical Abstract Image 2

Published
2016

28. Erratum. Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control. Diabetes 2019;68:441—456

Author

Aaron Leong, Yii-Der Ida Chen, Iiro Toppila, Elizabeth J. Rossin, Alan D. Penman, I-Te Lee, Kathryn P. Burdon, Yucheng Jia, Sudha K. Iyengar, Helen M. Colhoun, Michael A. Grassi, Jie Jin Wang, Tien Yin Wong, Barry I. Freedman, Kaanan P. Shah, Ching J. Chen, Weihua Meng, Brian L. Yaspan, Samaneh Davoudi, David S. Siscovick, Per-Henrik Groop, Samy Hadjadj, Michel Marre, Ching-Yu Cheng, John R. Sedor, Xiuqing Guo, Albert V. Smith, Robert P. Igo, Kyu Hyung Park, Jerome I. Rotter, Andrew D. Paterson, Samuela Pollack, Sharon G. Adler, Alkes L. Price, Emily Y. Chew, Emma Ahlqvist, Eli Ipp, Jamie E Craig, Richard A. Jensen, Barbara E.K. Klein, Maggie C.Y. Ng, Leif Groop, Craig L. Hanis, Xiaohui Li, Atsushi Takahashi, Roberta McKean-Cowdin, Mark P. Christiansen, Lynn K. Stanwyck, Paul Mitchell, Shiro Maeda, Alex S. F. Doney, Darryl Nousome, Ronald Klein, Yang Hai, Mark I. McCarthy, Niina Sandholm, Kent D. Taylor, Andrew D. Morris, Rohit Varma, David-Alexandre Trégouët, Jihye Kim, Valeriya Lyssenko, Colin N. A. Palmer, Mary Frances Cotch, Jane Z. Kuo, Elisabet Agardh, S. Mohsen Hosseini, Michiaki Kubo, Jeeyun Ahn, Gavin Tan, Minako Imamura, Lucia Sobrin, Heather Hancock, Wayne Huey-Herng Sheu, Donald W. Bowden, Ayellet V. Segrè, and Latchezar Dimitrov

Subjects
Pediatrics, medicine.medical_specialty, Complications, business.industry, Endocrinology, Diabetes and Metabolism, Genome-wide association study, Diabetic retinopathy, medicine.disease, Diabetes mellitus, Internal Medicine, medicine, Duration (project management), business, Glycemic
Abstract

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value

Published
2020

29. LPA Variants Are Associated With Residual Cardiovascular Risk in Patients Receiving Statins

Author

Jonathan D. Mosley, Yukihide Momozawa, George Hripcsak, Dan M. Roden, Shiro Maeda, Peggy L. Peissig, Eric B. Larson, David Cronkite, Ming Ta Michael Lee, Michiaki Kubo, Jerome I. Rotter, Sarah T. Bland, Gail P. Jarvik, Jennifer A. Pacheco, Todd L. Edwards, David R. Crosslin, Christian M. Shaffer, Eric A Larson, Ning Shang, Marc S. Williams, Xiaohui Li, Momoko Horikoshi, QiPing Feng, Laura J. Rasmussen-Torvik, Iftikhar J. Kullo, Joshua C. Denny, Wei-Qi Wei, C. Michael Stein, Nancy J. Cox, Ronald M. Krauss, Elizabeth W. Karlson, Marylyn D. Ritchie, and Russell A. Wilke

Subjects
0301 basic medicine, Time Factors, Hydroxymethylglutaryl-CoA, Coronary Disease, 030204 cardiovascular system & hematology, hydroxymethylglutaryl-CoA, Cardiorespiratory Medicine and Haematology, Cardiovascular, chemistry.chemical_compound, 0302 clinical medicine, Gene Frequency, Risk Factors, Lysophosphatidic acid, Databases, Genetic, Medicine, Electronic Health Records, 2.1 Biological and endogenous factors, Aetiology, Lipoprotein cholesterol, Cause of death, Incidence (epidemiology), Single Nucleotide, Treatment Outcome, Phenotype, Heart Disease, Cardiology, Public Health and Health Services, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Clinical Sciences, Polymorphism, Single Nucleotide, Risk Assessment, Article, 03 medical and health sciences, Databases, Genetic, Clinical Research, Physiology (medical), Internal medicine, Genetics, Humans, In patient, Genetic Predisposition to Disease, cardiovascular diseases, Polymorphism, Heart Disease - Coronary Heart Disease, Dyslipidemias, Cholesterol, business.industry, Human Genome, cholesterol, Atherosclerosis, Coronary heart disease, LDL reductase inhibitors, 030104 developmental biology, chemistry, Cardiovascular System & Hematology, Case-Control Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, lysophosphatidic acid, Lipoprotein(a), Genome-Wide Association Study
Abstract

Background: Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with statins decreases circulating levels of low-density lipoprotein cholesterol and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown. Methods: We performed a 2-stage genome-wide association study of CHD events during statin therapy. We first identified 3099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7681 controls without CHD events during comparable intensity and duration of statin therapy from 4 sites in the Electronic Medical Records and Genomics Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth Electronic Medical Records and Genomics site, which joined the network after the initial genome-wide association study. Finally, we performed a phenome-wide association study for other traits linked to the most significant locus. Results: The meta-analysis identified 7 single nucleotide polymorphisms at a genome-wide level of significance within the LPA/PLG locus associated with CHD events on statin treatment. The most significant association was for an intronic single nucleotide polymorphism within LPA/PLG (rs10455872; minor allele frequency, 0.069; odds ratio, 1.58; 95% confidence interval, 1.35–1.86; P =2.6×10 − 10 ). In the replication cohort, rs10455872 was also associated with CHD events (odds ratio, 1.71; 95% confidence interval, 1.14–2.57; P =0.009). The association of this single nucleotide polymorphism with CHD events was independent of statin-induced change in low-density lipoprotein cholesterol (odds ratio, 1.62; 95% confidence interval, 1.17–2.24; P =0.004) and persisted in individuals with low-density lipoprotein cholesterol ≤70 mg/dL (odds ratio, 2.43; 95% confidence interval, 1.18–4.75; P =0.015). A phenome-wide association study supported the effect of this region on coronary heart disease and did not identify noncardiovascular phenotypes. Conclusions: Genetic variations at the LPA locus are associated with CHD events during statin therapy independently of the extent of low-density lipoprotein cholesterol lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins.

Published
2018

30. ALDH2 Polymorphism rs671, but Not ADH1B Polymorphism rs1229984, Increases Risk for Hypo-HDL-Cholesterolemia in a/a Carriers Compared to the G/G Carriers

Author

Ghislain Rocheleau, Loic Yengo, Takuya Imatoh, Motonobu Miyazaki, Shiro Maeda, Philippe Froguel, and Seiichiro Kamimura

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Longitudinal study, Heterozygote, Hypercholesterolemia, Single-nucleotide polymorphism, 030204 cardiovascular system & hematology, Biology, Logistic regression, Biochemistry, Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Japan, Risk Factors, Internal medicine, medicine, Humans, Longitudinal Studies, Allele, ALDH2, Aged, medicine.diagnostic_test, Aldehyde Dehydrogenase, Mitochondrial, Organic Chemistry, Confounding, Cholesterol, HDL, Alcohol Dehydrogenase, ADH1B, Cell Biology, Middle Aged, Healthy Volunteers, 030104 developmental biology, Endocrinology, lipids (amino acids, peptides, and proteins), Lipid profile
Abstract

It has been reported that polymorphisms within the gene-encoding enzymes related to alcohol metabolism are associated with levels of serum HDL-cholesterol (HDL-C) in East Asian populations. We evaluated the effects of genetic variants within the aldehyde dehydrogenase-2 (ALDH2) gene and the alcohol dehydrogenase-1B (ADH1B) gene on changes in the lipid profile in an 11-year longitudinal study. We genotyped rs1229984 within ADH1B and rs671 within ALDH2. We combined the genetic data with longitudinal clinical and biochemical data from 2002 to 2013 and designed a retrospective longitudinal study of 1436 Japanese males. There were significant negative relationships between rs671 within ALDH2 and HDL-C levels according to multiple linear regression analysis. Next, we assessed the association between the development of hypo-HDL cholesterolemia and rs1229984 within ADH1B or rs671 within ALDH2. In logistic regression analysis, rs671 A allele homozygote carriers have 2.65 times higher risk of developing hypo-HDL cholesterolemia than G allele homozygote carriers. Even after adjusting for possible confounding factors, a significant association was observed. However, no association between rs1229984 within ADH1B and the development of hypo-HDL cholesterolemia was observed. Rs671 within ALDH2 but not rs1229984 within ADH1B was associated with lower HDL-C levels in Japanese males.

Published
2018

31. Replication study of the association of rs7578597 in THADA, rs10886471 in GRK5, and rs7403531 in RASGRP1 with susceptibility to type 2 diabetes among a Japanese population

Author

Kazuyuki Tobe, Shiro Maeda, Hirotaka Watada, Kensuke Sakai, Kohei Kaku, Minoru Iwata, Yasushi Tanaka, Hiroshi Maegawa, Ryuzo Kawamori, Hiroshi Hirose, Atsunori Kashiwagi, and Minako Imamura

Subjects
Genetics, business.industry, Endocrinology, Diabetes and Metabolism, Type 2 Diabetes Mellitus, Single-nucleotide polymorphism, Type 2 diabetes, Japanese population, medicine.disease, Diabetes mellitus, Replication (statistics), Internal Medicine, Medicine, SNP, business
Abstract

Aims To evaluate the association of rs7578597 in THADA, rs10886471 in GRK5, rs7403531 in RASGRP1, and rs6723108 in TMEM163 with type 2 diabetes among the Japanese we performed a replication study of the association of these single nucleotide polymorphism (SNP) loci.

Published
2015

32. Overexpression of acetyl CoA carboxylase β exacerbates podocyte injury in the kidney of streptozotocin-induced diabetic mice

Author

Naoko Takeda, Shinji Kume, Masami Chin-Kanasaki, Keiji Isshiki, Shin-ichi Araki, Itsuki Oshima, Takashi Uzu, Satoshi Ugi, Yuki Tanaka, Shiro Maeda, Hiroshi Maegawa, and Norihisa Osawa

Subjects
0301 basic medicine, medicine.medical_specialty, 030232 urology & nephrology, Biophysics, Mice, Transgenic, Biochemistry, Gene Expression Regulation, Enzymologic, Podocyte, Diabetic nephropathy, 03 medical and health sciences, Mice, 0302 clinical medicine, Internal medicine, medicine, Animals, Diabetic Nephropathies, Molecular Biology, Cells, Cultured, ACACB, biology, Chemistry, Podocytes, Acetyl-CoA carboxylase, AMPK, Cell Biology, Streptozotocin, medicine.disease, Up-Regulation, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Podocin, biology.protein, Synaptopodin, medicine.drug, Acetyl-CoA Carboxylase
Abstract

A single nucleotide polymorphism (SNP) within the acetyl CoA carboxylase (ACC) β gene (ACACB), rs2268388, has been shown to be associated with susceptibility to development of proteinuria in patients with type 2 diabetes. To investigate the biological roles of ACCβ in the pathogenesis of diabetic nephropathy, we examined the effects of overexpression of ACACB using podocyte-specific ACACB-transgenic mice or ACACB-overexpressing murine podocytes. Podocyte-specific ACACB-transgenic mice or littermate mice were treated with streptozotocin (STZ) to induce diabetes, and 12 weeks after induction of diabetes, we examined the expression of podocyte markers to evaluate the degree of podocyte injury in these mice. We also examined the effects of ACCβ on podocyte injury in ACACB- or LacZ-overexpressing murine podocytes. Podocyte-specific ACACB overexpression did not cause visible podocyte injury in non-diabetic mice. In STZ-induced diabetic mice, ACACB-transgenic mice showed a significant increase in urinary albumin excretion, accompanied by decreased synaptopodin expression and podocin mislocalization in podocytes, compared with wild-type mice. In cultured murine podocytes, overexpression of ACACB significantly decreased synaptopodin expression and reorganized stress fibers under high glucose conditions, but not in normal glucose conditions. The decrease of synaptopodin expression and reorganized stress fibers observed in ACACB overexpressing cells cultured under high glucose conditions was reversed by a treatment of 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), activator of AMP-activated protein kinase (AMPK). The excess of ACCβ might contribute to exacerbation of podocyte injury in the kidney of an animal model for diabetes mellitus, and the AMPK/ACCβ pathway may be a novel therapeutic target for the prevention of diabetes-related podocyte injury.

Published
2017

33. Genetic Variants in Transcription Factors Are Associated With the Pharmacokinetics and Pharmacodynamics of Metformin

Author

Dan M. Roden, Joel Mefford, Radojka M. Savic, Wen Cc, Sook Wah Yee, Kathleen M. Giacomini, Srijib Goswami, Sophie L. Stocker, Monique M. Hedderson, Jonathan D. Mosley, Claire M. Brett, John S. Witte, Robert L. Davis, Xiaomin Liang, Richard A. Castro, M. D. Simpson, Michiaki Kubo, and Shiro Maeda

Subjects
Male, endocrine system diseases, Genome-wide association study, Type 2 diabetes, Models, 80 and over, Pharmacology (medical), Pharmacology & Pharmacy, Aged, 80 and over, education.field_of_study, Diabetes, Homozygote, Single Nucleotide, Pharmacology and Pharmaceutical Sciences, Middle Aged, Metformin, Hepatocyte nuclear factors, Phenotype, Treatment Outcome, Hepatocyte Nuclear Factor 4, Female, Type 2, medicine.drug, Adult, medicine.medical_specialty, Sp1 Transcription Factor, Population, Biology, Models, Biological, Polymorphism, Single Nucleotide, Article, Young Adult, Clinical Research, Internal medicine, Diabetes Mellitus, Genetics, medicine, Humans, Hypoglycemic Agents, PPAR alpha, Polymorphism, education, Transcription factor, Metabolic and endocrine, Aged, Retrospective Studies, Glycated Hemoglobin, Pharmacology, Sp1 transcription factor, Human Genome, nutritional and metabolic diseases, Biological, medicine.disease, United States, Endocrinology, Diabetes Mellitus, Type 2, Pharmacogenetics, Multivariate Analysis, Biomarkers, Genome-Wide Association Study, Transcription Factors
Abstract

One-third of type 2 diabetes patients do not respond to metformin. Genetic variants in metformin transporters have been extensively studied as a likely contributor to this high failure rate. Here, we investigate, for the first time, the effect of genetic variants in transcription factors on metformin pharmacokinetics (PK) and response. Overall, 546 patients and healthy volunteers contributed their genome-wide, pharmacokinetic (235 subjects), and HbA1c data (440 patients) for this analysis. Five variants in specificity protein 1 (SP1), a transcription factor that modulates the expression of metformin transporters, were associated with changes in treatment HbA1c (P < 0.01) and metformin secretory clearance (P < 0.05). Population pharmacokinetic modeling further confirmed a 24% reduction in apparent clearance in homozygous carriers of one such variant, rs784888. Genetic variants in other transcription factors, peroxisome proliferator-activated receptor-α and hepatocyte nuclear factor 4-α, were significantly associated with HbA1c change only. Overall, our study highlights the importance of genetic variants in transcription factors as modulators of metformin PK and response.

Published
2014

34. A comprehensive search for mutations in thePKD1andPKD2in Japanese subjects with autosomal dominant polycystic kidney disease

Author

Shiro Maeda, Mahiro Kurashige, Hasegawa T, Takashi Udagawa, Yoshindo Kawaguchi, Kazushige Hanaoka, Tatsuo Hosoya, Takashi Yokoo, and M Imamura

Subjects
medicine.medical_specialty, PKD1, urogenital system, business.industry, Autosomal dominant polycystic kidney disease, Renal function, urologic and male genital diseases, medicine.disease, Gastroenterology, Phenotype, female genital diseases and pregnancy complications, Internal medicine, Genotype, Genetics, medicine, In patient, business, Genetics (clinical)
Abstract

To elucidate the genotypic and phenotypic characteristics of autosomal dominant polycystic kidney disease (ADPKD) in Japanese populations, we performed a comprehensive search for mutations in PKD1 and PKD2 in 180 Japanese ADPKD patients from 161 unrelated families. We identified 112 (89 PKD1 and 23 PKD2) mutations within 135 families. Patients with PKD2 mutations account for 23.6% of all Japanese ADPKD families in this study. Seventy-five out of the 112 mutations have not been reported previously. The estimated glomerular filtration rate (eGFR) decline was significantly faster in patients with PKD1 mutations than in those with PKD2 mutations (-3.25 and -2.08 ml min(-1) year(-1) for PKD1 and PKD2, respectively, p

Published
2014

35. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility

Author

Tazeen H. Jafar, Lars Lind, Peter Almgren, Wendy Winckler, Eitaro Nakashima, Young Min Cho, Annette Peters, Rona J. Strawbridge, Ananda R. Wickremasinghe, Katharine R. Owen, Lee-Ming Chuang, Tien-Jyun Chang, Graeme I. Bell, James B. Meigs, Bill Musk, Timo A. Lakka, Elin Grundberg, Wei Lu, Sarah Edkins, George Dedoussis, Weiping Jia, Danish Saleheen, Suthesh Sivapalaratnam, Maria Samuel, Tien Yin Wong, Lu Qi, Pierre Fontanillas, Momoko Horikoshi, Jirong Long, Abdul Basit, Anubha Mahajan, Andrew T. Hattersley, Markus M. Nöthen, Denis Rybin, Inger Njølstad, S. Krithika, Miguel Cruz, Delilah Zabaneh, Leena Peltonen, Jasmina Kravic, Sangsoo Kim, David Couper, Lori L. Bonnycastle, Heather M. Stringham, Yi-Cheng Chang, Paul Elliott, Eric J.G. Sijbrands, Nita G. Forouhi, Alena Stančáková, Ghazala Mirza, Robert W. Lawrence, Ruth J. F. Loos, Norman Klopp, Shiro Maeda, Martina Müller-Nurasyid, Jer-Yuarn Wu, Jianjun Liu, Kee Seng Chia, Elodie Eury, Loukianos S. Rallidis, Timothy M. Frayling, Ken Yamamoto, David Altshuler, Gunnar Sigurosson, Harald Grallert, Jackie F. Price, Barbara Thorand, Jouko Saramies, Malene M. Kristensen, Sonali Pechlivanis, Inês Barroso, Jong-Young Lee, Melissa Parkin, Josée Dupuis, Stéphane Lobbens, Jesús Kumate, Elena Tremoli, Sudhir Kowlessur, Xueling Sim, Norihiro Kato, Philippe Froguel, Kathleen Stirrups, Eero Lindholm, Alex S. F. Doney, Andres Metspalu, Yu-Tang Gao, Roman Wennauer, Xiao-Ou Shu, Marilyn C. Cornelis, Veikko Salomaa, Nanette R. Lee, Johanna Kuusisto, Caroline S. Fox, Man Li, James Scott, Wing-Yee So, Andrew R. Wood, Inga Prokopenko, Oddgeir L. Holmen, Tin Aung, Ryoichi Takayanagi, Chen Suo, Hara Kazuo, Carl G. P. Platou, Ann M. Kelly, Teresa Ferreira, Karl-Heinz Jöckel, Wei-Yen Lim, James F. Wilson, Tom Forsén, Qi Sun, Valur Emilsson, Gonçalo R. Abecasis, Fan Zhang, Timo Saaristo, Harry Campbell, Ying Wu, Mark Seielstad, Wei Zheng, Han Chen, Stavroula Kanoni, Yuqian Bao, Jose C. Florez, Wan Ting Tay, Ronald C. 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Subjects
CHROMATIN, endocrine system diseases, South Asian Type 2 Diabetes (SAT2D) Consortium, SCALE ASSOCIATION ANALYSIS, Medizin, LOCI, Genome-wide association study, VARIANTS, 0302 clinical medicine, Risk Factors, IMPUTATION, Glucose homeostasis, 11 Medical and Health Sciences, Genetics & Heredity, Genetics, 0303 health sciences, IDENTIFY, Hispanic or Latino, 3. Good health, MAP, POPULATIONS, Medical genetics, Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium, Hispanic Americans, Life Sciences & Biomedicine, Asian Continental Ancestry Group, medicine.medical_specialty, European Continental Ancestry Group, TRANSETHNIC METAANALYSIS, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, Sykursýki, 03 medical and health sciences, Asian People, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Allele, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, Alleles, 030304 developmental biology, Genetic association, Science & Technology, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, 06 Biological Sciences, Arfgengi, Genetic architecture, INDIVIDUALS, Diabetes Mellitus, Type 2, Case-Control Studies, GLUCOSE-HOMEOSTASIS, ASSOCIATION ANALYSES, Imputation (genetics), Developmental Biology, Genome-Wide Association Study
Abstract

To access publisher's full text version of this article click on the hyperlink at the bottom of the page To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry. Canadian Institutes of Health Research Medical Research Council UK G0601261 Mexico Convocatoria SSA/IMMS/ISSSTE-CONACYT 2012-2 clave 150352 IMSS R-2011-785-018 CONACYT Salud-2007-C01-71068 US National Institutes of Health DK062370 HG000376 DK085584 DK085545 DK073541 DK085501 Wellcome Trust WT098017 WT090532 WT090367 WT098381 WT081682 WT085475 info:eu-repo/grantAgreement/EC/FP7/201413

Published
2014

36. CCDC3 is specifically upregulated in omental adipose tissue in subjects with abdominal obesity

Author

Satoshi Ugi, Masatomo Rokushima, Osamu Sekine, Shiro Maeda, Hiroshi Maegawa, Atsunori Kashiwagi, Katsutaro Morino, Toru Tani, Hiroshi Yamamoto, Takeshi Yoshizaki, Yoshihiro Kawamura, Masaaki Kobayashi, and Minako Imamura

Subjects
medicine.medical_specialty, Candidate gene, Nutrition and Dietetics, Microarray analysis techniques, business.industry, Endocrinology, Diabetes and Metabolism, Medicine (miscellaneous), Adipose tissue, medicine.disease, Obesity, Blot, Endocrinology, Secretory protein, Internal medicine, medicine, medicine.symptom, business, Body mass index, Abdominal obesity
Abstract

Objective The aim of this study was to search for novel markers of visceral adiposity. Methods Visceral (omental) and subcutaneous adipose tissues were obtained from 43 Japanese men. Microarray analysis using total RNA from visceral and subcutaneous adipose tissues obtained from five men with abdominal obesity and five nonobese men was first conducted. Then the expression pattern of candidate genes identified in the human study in mouse models of adiposity was examined. Results Among 30,500 genes evaluated, the mRNA expression of CCDC3 (encoding coiled-coil domain-containing protein 3) was upregulated in omental adipose tissues from abdominally obese subjects (3.07-fold) but not in subcutaneous adipose tissues (0.89-fold). Similar expression patterns were found in two distinct mouse models of obesity. In the analysis of all 43 men, CCDC3 mRNA levels in omental, but not in subcutaneous adipose tissue, were positively correlated with waist circumference and body mass index. CCDC3 was predicted to be a secretory protein, which was confirmed by western blotting, as overexpressed CCDC3 was secreted into the culture media. Conclusions The expression of CCDC3 is specifically increased in visceral adipose tissues in abdominally obese subjects. These results suggest that CCDC3 is a potential biomarker for estimating visceral adiposity.

Published
2013

37. Replication study for the association of 3 SNP loci identified in a genome-wide association study for diabetic nephropathy in European type 1 diabetes with diabetic nephropathy in Japanese patients with type 2 diabetes

Author

Masao Toyoda, Masahito Imanishi, Shin-ichi Araki, Mahiro Kurashige, Kazushige Hanaoka, Takashi Uzu, Tetsuya Babazono, Minako Imamura, Hiroshi Maegawa, Shiro Maeda, Tomoya Umezono, Tatsuo Hosoya, Koichi Kawai, Daisuke Suzuki, and Yasuko Uchigata

Subjects
Male, medicine.medical_specialty, Receptor, ErbB-4, Physiology, Nerve Tissue Proteins, Genome-wide association study, Type 2 diabetes, GPI-Linked Proteins, Polymorphism, Single Nucleotide, White People, Nephropathy, Diabetic nephropathy, Asian People, Physiology (medical), Diabetes mellitus, Internal medicine, medicine, Humans, Diabetic Nephropathies, Genetic Predisposition to Disease, Aged, Type 1 diabetes, Proteinuria, business.industry, Nuclear Proteins, Odds ratio, Middle Aged, medicine.disease, ErbB Receptors, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Nephrology, Kidney Failure, Chronic, Female, medicine.symptom, business, Genome-Wide Association Study
Abstract

A recent genome-wide association study for diabetic nephropathy in European type 1 diabetes identified 3 candidate loci for diabetic nephropathy. In this study, we examined the association of the 3 single nucleotide polymorphism (SNP) loci with susceptibility to diabetic nephropathy in Japanese subjects with type 2 diabetes. We genotyped 3 SNPs, rs7583877 in AFF3, rs12437854 in the RGMA-MCTP2 locus and rs7588550 in ERBB4, for 2,300 Japanese patients with type 2 diabetes [initial study, 1,055 nephropathy cases with overt proteinuria or with end-stage renal disease (ESRD) and 1,245 control patients with normoalbuminuria]. The association of these SNPs with diabetic nephropathy was examined by using a logistic regression analysis. We observed a significant association of rs7588550 in ERBB4 with diabetic nephropathy in the Japanese patients with type 2 diabetes, although the effect direction was not consistent with that in the European study [p = 0.0126, odds ratio (OR) = 0.79, 95 % confidence interval (CI): 0.65–0.95]. We further examined the association of rs7588550 with diabetic nephropathy in an independent Japanese cohort (596 nephropathy cases and 311 controls) and observed the same trend of the association with the initial study. We did not observe any association of the remaining 2 SNP loci with diabetic nephropathy in the present Japanese sample. The association of SNP loci derived from GWAS in European type 1 diabetes with diabetic nephropathy was not replicated in the Japanese patients with type 2 diabetes, although the ERBB4 locus may have some effect also in Japanese type 2 diabetes.

Published
2013

38. A Longitudinal HbA1c Model Elucidates Genes Linked to Disease Progression on Metformin

Author

Kathleen M. Giacomini, Fei Xu, Dan M. Roden, Shiro Maeda, Sook Wah Yee, Jonathan Jd Mosley, Michiaki Kubo, Atsushi Takahashi, Monique M. Hedderson, Radojka M. Savic, Sneha B. Sridhar, Robert L. Davis, and Srijib Goswami

Subjects
0301 basic medicine, Male, Candidate gene, Glycated Hemoglobin A, Pharmacogenomic Variants, Bioinformatics, Polymorphism (computer science), 80 and over, 2.1 Biological and endogenous factors, Pharmacology (medical), Longitudinal Studies, Pharmacology & Pharmacy, Aetiology, Aged, 80 and over, Diabetes, Organic Cation Transporter 2, Single Nucleotide, Pharmacology and Pharmaceutical Sciences, Middle Aged, Metformin, Disease Progression, Female, Type 2, medicine.drug, Adult, Organic Cation Transport Proteins, Single-nucleotide polymorphism, and over, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Young Adult, Clinical Research, Diabetes mellitus, medicine, Diabetes Mellitus, Genetics, SNP, Humans, Hypoglycemic Agents, Allele, Polymorphism, Aged, Pharmacology, Glycated Hemoglobin, Tumor Suppressor Proteins, Prevention, Membrane Proteins, medicine.disease, 030104 developmental biology, Good Health and Well Being, Diabetes Mellitus, Type 2, Nonlinear Dynamics
Abstract

© 2016 American Society for Clinical Pharmacology and Therapeutics One-third of type-2 diabetic patients respond poorly to metformin. Despite extensive research, the impact of genetic and nongenetic factors on long-term outcome is unknown. In this study we combine nonlinear mixed effect modeling with computational genetic methodologies to identify predictors of long-term response. In all, 1,056 patients contributed their genetic, demographic, and long-term HbA1c data. The top nine variants (of 12,000 variants in 267 candidate genes) accounted for approximately one-third of the variability in the disease progression parameter. Average serum creatinine level, age, and weight were determinants of symptomatic response; however, explaining negligible variability. Two single nucleotide polymorphisms (SNPs) in CSMD1 gene (rs2617102, rs2954625) and one SNP in a pharmacologically relevant SLC22A2 gene (rs316009) influenced disease progression, with minor alleles leading to less and more favorable outcomes, respectively. Overall, our study highlights the influence of genetic factors on long-term HbA1c response and provides a computational model, which when validated, may be used to individualize treatment.

Published
2016

39. Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin

Author

Kathleen M. Giacomini, Adriaan Kooy, Coen D.A. Stehouwer, MetGen Investigators, Valdis Pirags, Daniel M. Rotroff, Ivan Tkáč, Huan-Chieh Chien, Michael J. Wagner, Shiro Maeda, Federico Innocenti, Joline W.J. Beulens, Monique M. Hedderson, Eric L. Seiser, Sook Wah Yee, Bruno H. Stricker, Accord Investigators, Jozef Židzik, Leen M 't Hart, Rury R. Holman, Alison A. Motsinger-Reif, Jose C. Florez, Albert Hofman, Mattijs Out, Albert M. Levin, Christopher J. Groves, Michiaki Kubo, Longyang Wu, Catherine E. de Keyser, Ewan R. Pearson, Lisa Logie, Calum Sutherland, Sabina Semiz, Tanja Dujic, John S. Witte, Amanda J. Bennett, Kathleen A. Jablonski, Linda Zaharenko, Nienke van Leeuwen, Ling Chen, Dpp Investigators, Roger Tavendale, Ruth L. Coleman, Amber A. van der Heijden, Colin N. A. Palmer, Janis Klovins, Martin Javorský, Ron H.N. van Schaik, Mark I. McCarthy, L. Keoki Williams, Kaixin Zhou, Epidemiology, Clinical Chemistry, General practice, EMGO - Lifestyle, overweight and diabetes, Epidemiology and Data Science, MUMC+: HVC Pieken Maastricht Studie (9), RS: CARIM - R3.01 - Vascular complications of diabetes and the metabolic syndrome, Interne Geneeskunde, and MUMC+: MA Interne Geneeskunde (3)

Subjects
Blood Glucose, 0301 basic medicine, medicine.medical_specialty, endocrine system diseases, Genome-wide association study, Type 2 diabetes, Polymorphism, Single Nucleotide, White People, Body Mass Index, 03 medical and health sciences, Quantitative Trait, Heritable, Internal medicine, Diabetes mellitus, Genetics, medicine, Humans, Hypoglycemic Agents, Allele, Glycemic, Glucose Transporter Type 2, Glycated Hemoglobin, biology, Glucose transporter, nutritional and metabolic diseases, medicine.disease, Metformin, 3. Good health, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, biology.protein, GLUT2, Genome-Wide Association Study, medicine.drug
Abstract

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear(1). Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 x 10(-14)) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine.

Published
2016

40. Replication Study in a Japanese Population of Six Susceptibility Loci for Type 2 Diabetes Originally Identified by a Transethnic Meta-Analysis of Genome-Wide Association Studies

Author

Atsunori Kashiwagi, Minako Imamura, Hiroshi Hirose, Hirotaka Watada, Minoru Iwata, Ryuzo Kawamori, Kohei Kaku, Kazuyuki Tobe, Hiroshi Maegawa, Shiro Maeda, Yasushi Tanaka, and Ren Matsuba

Subjects
0301 basic medicine, Male, Heredity, Epidemiology, lcsh:Medicine, Genome-wide association study, Type 2 diabetes, 0302 clinical medicine, Endocrinology, Mathematical and Statistical Techniques, Japan, Medicine and Health Sciences, lcsh:Science, Genetics, education.field_of_study, Multidisciplinary, Genomics, Middle Aged, Type 2 Diabetes, Genetic Mapping, Physical Sciences, Regression Analysis, Female, Statistics (Mathematics), Research Article, Genotype, Endocrine Disorders, Population, 030209 endocrinology & metabolism, Locus (genetics), Single-nucleotide polymorphism, Variant Genotypes, Biology, Research and Analysis Methods, Polymorphism, Single Nucleotide, Ethnic Epidemiology, 03 medical and health sciences, Asian People, medicine, Diabetes Mellitus, Genome-Wide Association Studies, SNP, Humans, Genetic Predisposition to Disease, Statistical Methods, education, Genetic association, Aged, lcsh:R, Biology and Life Sciences, Computational Biology, Human Genetics, Odds ratio, medicine.disease, Genome Analysis, 030104 developmental biology, Diabetes Mellitus, Type 2, Genetic Loci, Metabolic Disorders, lcsh:Q, Octamer Transcription Factor-3, Mathematics, Meta-Analysis, Genome-Wide Association Study
Abstract

Aim We performed a replication study in a Japanese population to evaluate the association between type 2 diabetes and six susceptibility loci (TMEM154, SSR1, FAF1, POU5F1, ARL15, and MPHOSPH9) originally identified by a transethnic meta-analysis of genome-wide association studies (GWAS) in 2014. Methods We genotyped 7,620 Japanese participants (5,817 type 2 diabetes patients and 1,803 controls) for each of the single nucleotide polymorphisms (SNPs) using a multiplex polymerase chain reaction invader assay. The association of each SNP locus with the disease was evaluated using logistic regression analysis. Results Of the six SNPs examined in this study, four (rs6813195 near TMEM154, rs17106184 in FAF1, rs3130501 in POU5F1 and rs4275659 near MPHOSPH9) had the same direction of effect as in the original reports, but two (rs9505118 in SSR1 and rs702634 in ARL15) had the opposite direction of effect. Among these loci, rs3130501 and rs4275659 were nominally associated with type 2 diabetes (rs3130501; p = 0.017, odds ratio [OR] = 1.113, 95% confidence interval [CI] 1.019–1.215, rs4275659; p = 0.012, OR = 1.127, 95% CI 1.026–1.238, adjusted for sex, age and body mass index), but we did not observe a significant association with type 2 diabetes for any of the six evaluated SNP loci in our Japanese population. Conclusions Our results indicate that effects of the six SNP loci identified in the transethnic GWAS meta-analysis are not major among the Japanese, although SNPs in POU5F1 and MPHOSPH9 loci may have some effect on susceptibility to type 2 diabetes in this population.

Published
2016

41. Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Author

Peter Kovacs, Alan F. Wright, Stephen Turner, Michèle M. Sale, Siim Sõber, Janoš Terzić, Elin Org, Richard S. Cooper, Alena Stančáková, Jerome I. Rotter, W. H. Linda Kao, Albert Hofman, Andrew B. Singleton, Florian Kronenberg, Jianjun Liu, Nicole L. Glazer, Christopher W. Knouff, Jennifer L. Bragg-Gresham, Juha Karjalainen, Li Ching Chang, Benjamin J. Wright, Jacqueline C.M. Witteman, Martin G. Larson, Klaus Stark, Richard J. Rodeheffer, Sharon L.R. Kardia, Douglas M. Ruderfer, Sheila Ulivi, Madhumathi Rao, Andrew A. Hicks, Eva Brand, Viviane Nicaud, Stephen G. Ball, Anna Köttgen, Germaine C. Verwoert, Anders Hamsten, Nick Shrine, Uwe Völker, Stefan Kloiber, Stephen Hancock, Emelia J. Benjamin, Bok Ghee Han, Kenneth Rice, Mark Woodward, Veronique Vitart, Karl Andersen, Nicholas J. Wareham, Robert Roberts, Maja Barbalić, David Couper, Yukinori Okada, André G. Uitterlinden, Sekar Kathiresan, Leo-Pekka Lyytikäinen, Pankaj Arora, Tatijana Zemunik, David S. Siscovick, Simonetta Guarrera, Dawn M. Waterworth, Tatjana Stojakovic, Braxton D. Mitchell, Devin Absher, Carmen A. Peralta, Mika Kivimäki, Xueling Sim, Norihiro Kato, Philippe Froguel, Keith L. Keene, Donna K. Arnett, Naoyuki Kamatani, Tazeen H. Jafar, Idris Guessous, Gunnar Jacobs, Michael M. Hoffmann, Kari Stefansson, Christian Hengstenberg, Tomonori Okamura, Inga Prokopenko, Christina Willenborg, Peter S. Braund, Rainer Rettig, Francesco U.S. Mattace-Raso, Vikal Tripathy, F. Gerald R. Fowkes, Laura R. Loehr, Harry Campbell, Margherita Cavalieri, Olle Melander, Hao Mei, I. Mateo Leach, Nicholette D. Palmer, Eva Albrecht, Naoharu Iwai, Stefan Martin Brand, Toshiko Tanaka, Jackie A. Cooper, Omri Gottesman, Manuela Uda, Angelo Scuteri, Aroon D. Hingorani, Cristiano Fava, Yusuke Nakamura, Jiang He, Min Jin Go, Serge Hercberg, Wendy L. McArdle, Philipp S. Wild, Florian Ernst, Paul Mitchell, Wolfgang Koenig, Caroline S. Fox, S. J.Cathy Fann, Janine F. Felix, Anna F. Dominiczak, Mike A. Nalls, Erik Ingelsson, Mario A. Morken, Susana Eyheramendy, Christopher Newton-Cheh, Igor Rudan, D. G. Vinay, Christopher P. Nelson, Ervin R. Fox, Xiuqing Guo, Jing Hua Zhao, Rick Twee-Hee Ong, Margaret M. Redfield, Oscar H. Franco, Yongmei Liu, Fulvio Ricceri, Mark A. Hlatky, Bernhard Paulweber, Mingyao Li, Themistocles L. Assimes, Karl Winkler, Inês Barroso, Sylvia E. Rosas, M Walker, Richard W Morris, Bo Hedblad, Hakon Hakonarson, Sonny Dandona, Peter H. Whincup, Martin Adam, Vilmundur Gudnason, Daniel Ackermann, Qiong Yang, Cuno S. P. M. Uiterwaal, Paul M. Ridker, George Davey Smith, Li Chen, C. Sinning, Terri L. Young, Jer-Yuarn Wu, Walter Palmas, Will Longstreth, Joe Devaney, Pavel Hamet, Xiaofeng Zhu, Fredrik Nyberg, Wilfried Renner, Anuj Goel, L. Adrienne Cupples, Nish Chaturvedi, Iftikhar J. Kullo, Nicholas D. Hastie, Aude Saint-Pierre, Panos Deloukas, Smita R. Kulkarni, Eric Boerwinkle, Wolfram Goessling, Gian Andri Thun, Eric J.G. Sijbrands, Shih-Jen Hwang, Carole Proust, Hirotsugu Ueshima, Kristian Hveem, Pierre Meneton, Joshua C. Denny, Olivier Devuyst, Kerri L. Wiggins, Ming-Huei Chen, Robert W. Lawrence, Robert L. Wilensky, Andre Franke, Nicole Soranzo, Simon Heath, Margot Haun, Karlhans Endlich, David Altshuler, Harald Grallert, Laurence Tiret, Luigi Ferrucci, Caroline Hayward, Sudha Seshadri, Bénédicte Stengel, Lynne E. Wagenknecht, John Attia, Andreas Ziegler, Renate B. Schnabel, Stefan Schreiber, Santosh Dahgam, Kurt Lohman, Christian M. Shaffer, Barbara Ludwig, Katalin Susztak, Chien-Hsiun Chen, Michele K. Evans, Paolo Vineis, Guo Li, Thomas J. Wang, Meena Kumari, Heather M. Stringham, Bruce M. Psaty, Norman Klopp, Halit Ongen, Ben A. Oostra, Stefan Coassin, Petra Bruse, Wei-Min Chen, Unnur Thorsteinsdottir, Charles N. Rotimi, Robert J. Carroll, Muredach P. Reilly, Niek Verweij, Dena G. Hernandez, Amy J. Swift, Barbara Kollerits, Hyung Lae Kim, Cristian Pattaro, Ivana Kolcic, Ronit Katz, John M. C. Connell, Dan E. Arking, Albert W. Dreisbach, Peter Vollenweider, C. S. Janipalli, Jian'an Luan, Erkki Vartiainen, James T. Willerson, John R. Thompson, Daniela Toniolo, Lyle J. Palmer, Alexander Teumer, Serkalem Demissie-Banjaw, Stella Trompet, James E. Hixson, Sue Shaw-Hawkins, Rossella Sorice, Bernhard R. Winkelmann, John Danesh, Anthony J. Balmforth, Toshio Ogihara, Jyotika K. Fernandes, Ulf Gyllensten, Ville Aalto, Åsa Johansson, Andres Metspalu, John F. Peden, Diana Kuh, Medea Imboden, Antonio Lupo, Su Chi Lim, Young-Jin Kim, Giovanni Malerba, Yurii S. Aulchenko, Satoshi Umemura, Ioanna Tzoulaki, Alan B. Weder, Helena Schmidt, Gerjan Navis, Susan R. Heckbert, Hans J. Rupprecht, Edward G. Lakatta, Christian Gieger, Najaf Amin, Paul Muntner, Lenore J. Launer, Ivana Persico, Hugh Watkins, Ian Ford, K. Radha Mani, Sylvia Stracke, Johanna Kuusisto, John Chalmers, Muhammad Islam, Lars Lind, Stefan R. Bornstein, Marjo-Riitta Järvelin, J. H. Young, Reiner Biffar, Santhi K. Ganesh, Kazuhiko Yamamoto, Annette Peters, Linda S. Adair, Tõnu Esko, Rebecca Hardy, Olga Jarinova, Antonietta Robino, Ruth McPherson, Benjamin F. Voight, Anne U. Jackson, Gang Shi, Stefania Bandinelli, Peter J. van der Most, John S. Gottdiener, Ying A. Wang, Mariza de Andrade, Joshua C. Bis, Leslie J. Raffel, Man Li, Jemma C. Hopewell, Bernhard O. Böhm, Aaron R. Folsom, Noël P. Burtt, S. Sidney, Diana Zelenika, Yuri Milaneschi, Pilar Galan, Iris M. Heid, Bernhard K. Krämer, Jean-Michel Gaspoz, Lynda M. Rose, Massimiliano Cocca, Jaap W. Deckers, Martin Farrall, Kent D. Taylor, Albert V. Smith, Candace Guiducci, Alan R. Shuldiner, Shiro Maeda, Liming Qu, Marilyn C. Cornelis, Xiaoling Wang, Daniel Shriner, Jutta Palmen, Yingchang Lu, Heyo K. Kroemer, Pio D'Adamo, Stephan J. L. Bakker, Tamara B. Harris, Myriam Rheinberger, Tetsuro Miki, Audrey Y. Chu, Ramachandran S. Vasan, Fuu Jen Tsai, Jan A. Staessen, Daniel I. Chasman, Jan Stritzke, Jasmin Divers, Meredith C. Foster, Jeanette M. Stafford, Maksim Struchalin, Arne Schillert, Jacques S. Beckmann, Mark E. Cooper, Jean-Charles Lambert, Mario Pirastu, Katja Butterbach, Carl G. P. Platou, Yan V. Sun, Marcus Fischer, Maciej Tomaszewski, Karl Werdan, Peng Chen, Daniel J. Rader, Thomas Münzel, Lowell F. Satler, Tom R. Gaunt, Brenda W.J.H. Penninx, William H. Matthai, John Whitfield, Rita P.S. Middelberg, Margus Viigimaa, Toshihiro Tanaka, Ida Yii Der Chen, Morris J. Brown, Valur Emilsson, J. Viikari, Wolfgang Lieb, Stephen E. Epstein, Harald Dobnig, Aravinda Chakravarti, Patrick Linsel-Nitschke, Stefan Pilz, Angela Doering, Sarah H. Wild, Patricia B. Munroe, Megan E. Rudock, Nicole Probst-Hensch, Danish Saleheen, Diederick E. Grobbee, Anke Tönjes, Narisu Narisu, Annika Rosengren, Masato Isono, Catherine Helmer, M. J.Kranthi Kumar, Alanna C. Morrison, Kay-Tee Khaw, Tanja Zeller, Jeffrey R. O'Connell, Christian Müller, Georg Homuth, Giriraj R. Chandak, Pankaj Sharma, Marcus Dörr, Veikko Salomaa, Paul F. O'Reilly, David Hadley, Hermann Brenner, Paolo Gasparini, Nanette R. Lee, Bamidele O. Tayo, Robert Clarke, Henri Wallaschofski, Marketa Sjögren, Abbas Dehghan, Melanie Waldenberger, Neil Risch, Vasyl Pihur, Jessica D. Faul, François Cambien, Christian Fuchsberger, Nicholas G. Martin, John C. Chambers, Zouhair Aherrahrou, Karl J. Lackner, Leif Groop, Matthias Olden, Wiek H. van Gilst, Mathias Gorski, Yvonne T. van der Schouw, Patrick Diemert, Christoph Bickel, Yik Ying Teo, Giorgio Pistis, Ruth J. F. Loos, Gudrun Veldre, Thorsten Reffelmann, Lude Franke, Karen L. Mohlke, Stefan Blankenberg, Massimo Mangino, Ian N. M. Day, Atsushi Takahashi, Alan B. Zonderman, Hua Tang, Reijo Laaksonen, Holly Kramer, Gary C. Curhan, Adrienne Tin, Talin Haritunians, Loic Yengo, Philip Howard, Arnika Kathleen Wagner, Anna Maria Corsi, Yen Pei C. Chang, Karin Halina Greiser, Jeanette Erdmann, Solveig Gretarsdottir, Sanjay Kinra, Alex Parker, Belen Ponte, Marina Ciullo, Michael Preuss, Tin Aung, Nicholas L. Smith, Michiaki Kubo, Richard N. Bergman, Alan S. Go, Patricia P. Chang, Gudmundur Thorgeirsson, Christa Meisinger, Gonçalo R. Abecasis, Maria Blettner, Jaana Laitinen, Daniel Taliun, Carlos Iribarren, Paavo Zitting, Thomas Lumley, Andreas Meinitzer, Wayne D. Rosamond, Daehee Kang, Johanne Tremblay, Stephan B. Felix, Colin A. McKenzie, Yuan-Tsong Chen, Lyudmyla Kedenko, Mladen Boban, Fadi J. Charchar, Adebowale Adeyemo, Brendan M. Buckley, Jennifer A. Smith, Reinhold Schmidt, Jaspal S. Kooner, Gavin Lucas, Paul Elliott, Dorairajan Prabhakaran, Tune H. Pers, Tunde Salako, Terrence Forrester, Paul Burton, Jeffrey R. Gulcher, Kelly A. Volcik, Richard M. Myers, Andreas Tomaschitz, H.-Erich Wichmann, Jie Yao, Giuseppe Matullo, Carsten A. Böger, Henry Völzke, Daniela Ruggiero, Federico Murgia, Yoshikuni Kita, Augustine Kong, Giovanni Gambaro, Cinzia Sala, Peter P. Pramstaller, James Scott, Maris Laan, Laura J. Scott, Alistair S. Hall, Sanaz Sedaghat, James F. Wilson, Joanne M. Murabito, Yi-An Ko, Honghuang Lin, Mark Seielstad, Leena Peltonen, Sven Bergmann, Thomas Meitinger, Matthias Nauck, María Soler Artigas, Thomas Illig, Nanette I. Steinle, Samer S. Najjar, Christina Loley, Debbie A Lawlor, Steven C. Hunt, Yali Li, Weihua Zhang, Jie Jin Wang, Daniele Cusi, Marco Orrù, Stephen P. Fortmann, Melissa Garcia, Barry I. Freedman, Joseph M. Lindsay, Juan P. Casas, Tomohiro Katsuya, Grant W. Montgomery, Hubert Scharnagl, Khanh-Dung H. Nguyen, Steven M. Schwartz, Afshin Parsa, Elizabeth G. Holliday, Murielle Bochud, Kiran Musunuru, Bruno H. Stricker, Lori L. Bonnycastle, Ilja M. Nolte, Timothy M. Frayling, Stefan Enroth, Michiel L. Bots, Mark J. Caulfield, Laura Portas, Vincent Chouraki, Carl D. Langefeld, Eran Halperin, Shufeng Chen, Philippa J. Talmud, Terho Lehtimäki, Steve E. Humphries, Gudmar Thorleifsson, Anika Grosshennig, Norbert Watzinger, Fumihiko Takeuchi, Pim van der Harst, Takayoshi Ohkubo, Nabila Bouatia-Naji, Erwin P. Bottinger, Roberto Elosua, Andrew Wong, Vladan Mijatovic, Maija K. Garnaas, Robert Zweiker, Joel N. Hirschhorn, Winfried März, Nilesh J. Samani, Inke R. König, Frank B. Hu, Marcus E. Kleber, Francis S. Collins, Elena Rochtchina, Ewa Zukowska-Szczechowska, Yong Li, Ayse Demirkan, Gina Hilton, G. Ehret, Thomas H. Mosley, Markus Perola, Alexandre F.R. Stewart, Josef Coresh, Olli T. Raitakari, Feng Zhang, Mark Lathrop, Michael Marmot, Yanbin Dong, Christopher J. O'Donnell, Kristin D. Marciante, Asif Rasheed, Mary F. Feitosa, Mary Susan Burnett, Rory Collins, J. Wouter Jukema, Nele Friedrich, Aida Karina Dieffenbach, Ying Wu, Yoon Shin Cho, Aaron Isaacs, Haidong Zhu, Marie Metzger, Myriam Alexander, Tanja B. Grammer, Tatiana Kuznetsova, Dabeeru C. Rao, Jayashri Aragam, Augusto D. Pichard, Jaakko Tuomilehto, Louise V. Wain, Elizabeth J. Atkinson, Tim D. Spector, Reedik Mägi, Tiit Nikopensius, Kenneth M. Kent, Guangju Zhai, Andrew D. Johnson, Menno Pruijm, David P. Strachan, Martin D. Tobin, Joban Sehmi, Janja Nahrstedt, E. Shyong Tai, Thor Aspelund, Jürgen Grässler, Hilma Holm, Matthew Denniff, Joshua W. Knowles, Tien Yin Wong, Erika Salvi, James F. Meschia, Dongfeng Gu, Ron Waksman, Stacey Gabriel, Judith A. Hoffman Bolton, Michael Boehnke, Johannes Haerting, Darina Czamara, Heribert Schunkert, Thomas Quertermous, Peter M. Nilsson, Jong-Young Lee, Yasuharu Tabara, Chittaranjan S. Yajnik, Daniel Levy, John Beilby, Fernando Rivadeneira, Claire Perret, Gudny Eiriksdottir, Jingzhong Ding, George A. Wells, Harold Snieder, Ayo P. Doumatey, Dag S. Thelle, Anja Medack, N. Charlotte Onland-Moret, Michael Stumvoll, David Ellinghaus, Ingrid B. Borecki, Tatsuhiko Tsunoda, Ian H. de Boer, M. Arfan Ikram, Andrew M. Taylor, Johannes H. Smit, Gary F. Mitchell, Anna-Liisa Hartikainen, Markku Laakso, Mark McEvoy, Andrew S. Plump, Toby Johnson, Cornelia M. van Duijn, Ozren Polasek, Wilmar Igl, Vincent Mooser, Rodney J. 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L., Lindsay, JM., Waksman, R., Knouff, CW., Waterworth, DM., Walker, MC., Epstein, SE., Rader, DJ., Nelson, CP., Wright, BJ., Balmforth, AJ., Ball, SG., Loehr, LR., Rosamond, WD., Benjamin, E., Haritunians, T., Couper, D., Murabito, J., Wang, YA., Stricker, BH., Chang, PP., Willerson, JT., Felix, SB., Watzinger, N., Aragam, J., Zweiker, R., Lind, L., Rodeheffer, RJ., Greiser, KH., Deckers, JW., Stritzke, J., Ingelsson, E., Kullo, I., Haerting, J., Reffelmann, T., Redfield, MM., Werdan, K., Mitchell, GF., Arnett, DK., Gottdiener, JS., Blettner, M., and Friedrich, N.

Subjects
0301 basic medicine, Nephrology, Genetics and Molecular Biology (all), estimated glomerular filtration rate, estimated glomerular filtration rate, chronic kidney disease, genetic determinants, General Physics and Astronomy, Kidney development, Genome-wide association study, Biochemistry, Settore MED/14 - NEFROLOGIA, Renal Insufficiency, Chronic, Genetics, AGEN Consortium, ddc:616, education.field_of_study, Kidney, Stage renal-disease, Multidisciplinary, Genome-wide association, CHARGe-Heart Failure Group, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Renal Insufficiency, Chronic, Genetic Predisposition to Disease, Biochemistry, Genetics and Molecular Biology (all), Chemistry (all), Physics and Astronomy (all), Metaanalysis, Renal Insufficiency, Chronic/genetics, Biological sciences, Serum creatinine, medicine.anatomical_structure, Efficient, Ronyons -- Fisiologia, Hypertension, ICBP Consortium, Transmembrane transporter activity, genetic association, loci, kidney function, CARDIOGRAM, Human, medicine.medical_specialty, Science, Population, Renal function, ECHOGen Consortium, Replication, Biology, Environment, Research Support, General Biochemistry, Genetics and Molecular Biology, N.I.H, genetic determinants, 03 medical and health sciences, GENOME-WIDE ASSOCIATION, FALSE DISCOVERY RATES, STAGE RENAL-DISEASE, SERUM CREATININE, METAANALYSIS, VARIANTS, INDIVIDUALS, POPULATION, RISK, HYPERTENSION, Kidney function, Research Support, N.I.H., Extramural, Internal medicine, MD Multidisciplinary, medicine, Journal Article, eGFRcrea, eGFRcys, ddc:610, Genetik, Mortality, education, ddc:613, urogenital system, Individuals, Extramural, General Chemistry, ta3121, medicine.disease, R1, 030104 developmental biology, 570 Life sciences, biology, Genètica, chronic kidney disease, Kidney disease, Meta-Analysis
Abstract

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. J.T. and P.H. are consultants for Servier. J.C. received research grants and honoraria from Servier. K.S. obtained research support from Boehringer Ingelheim. The remaining authors declared no competing financial interests.

Published
2016

42. Genetic Risk Score Constructed Using 14 Susceptibility Alleles for Type 2 Diabetes Is Associated With the Early Onset of Diabetes and May Predict the Future Requirement of Insulin Injections Among Japanese Individuals

Author

Hiromi Kato, Minoru Iwata, Atsuko Takano, Shiro Maeda, Kazuo Hara, Takashi Kadowaki, Shihou Murakami, Atsushi Takahashi, Yutaka Kamura, Kiyohiro Higuchi, Kazuyuki Tobe, and Hayato Fujita

Subjects
Oncology, Male, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Type 2 diabetes, 0302 clinical medicine, Insulin, Age of Onset, Cation Transport Proteins, Original Research, 0303 health sciences, tRNA Methyltransferases, SLC30A8, biology, Middle Aged, 3. Good health, KCNQ1 Potassium Channel, Female, Transcription Factor 7-Like 2 Protein, medicine.medical_specialty, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Zinc Transporter 8, Polymorphism, Single Nucleotide, 03 medical and health sciences, Asian People, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Humans, Genetic Predisposition to Disease, Potassium Channels, Inwardly Rectifying, Pathophysiology/Complications, CDKAL1, Alleles, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Aged, Cyclin-Dependent Kinase Inhibitor p15, Advanced and Specialized Nursing, Homeodomain Proteins, business.industry, fungi, Proteins, Cyclin-Dependent Kinase 5, medicine.disease, PPAR gamma, Endocrinology, Diabetes Mellitus, Type 2, Ubiquitin-Conjugating Enzymes, biology.protein, Insulin Receptor Substrate Proteins, Age of onset, business, TCF7L2, Transcription Factors
Abstract

OBJECTIVE We evaluated the clinical usefulness of a genetic risk score (GRS) based on 14 well-established variants for type 2 diabetes. RESEARCH DESIGN AND METHODS We analyzed 14 SNPs at HHEX, CDKAL1, CDKN2B, SLC30A8, KCNJ11, IGF2BP2, PPARG, TCF7L2, FTO, KCNQ1, IRS-1, GCKR, UBE2E2, and C2CD4A/B in 1,487 Japanese individuals (724 patients with type 2 diabetes and 763 control subjects). A GRS was calculated according to the number of risk alleles by counting all 14 SNPs (T-GRS) as well as 11 SNPs related to β-cell function (β-GRS) and then assessing the association between each GRS and the clinical features. RESULTS Among the 14 SNPs, 4 SNPs were significantly associated with type 2 diabetes in the present Japanese sample (P < 0.0036). The T-GRS was significantly associated with type 2 diabetes (P = 5.9 × 10−21). Among the subjects with type 2 diabetes, the β-GRS was associated with individuals receiving insulin therapy (β = 0.0131, SE = 0.006, P = 0.0431), age at diagnosis (β = −0.608, SE = 0.204, P = 0.0029), fasting serum C-peptide level (β = −0.032, SE = 0.0140, P = 0.022), and C-peptide index (β = −0.031, SE = 0.012, P = 0.0125). CONCLUSIONS Our data suggest that the β-GRS is associated with reduced β-cell functions and may be useful for selecting patients who should receive more aggressive β-cell–preserving therapy.

Published
2012

43. KCNQ1 SNPS and susceptibility to diabetic nephropathy in East Asians with type 2 diabetes

Author

Xiu-Li Lim, E-Shyong Tai, Daniel P.K. Ng, Siti Nurbaya, Shiro Maeda, Agus Salim, and Yusuke Nakamura

Subjects
Blood Glucose, Male, medicine.medical_specialty, Genotype, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Renal function, Single-nucleotide polymorphism, Type 2 diabetes, urologic and male genital diseases, Polymorphism, Single Nucleotide, Cohort Studies, Diabetic nephropathy, chemistry.chemical_compound, Asian People, Gene Frequency, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Albuminuria, Humans, Diabetic Nephropathies, Genetic Predisposition to Disease, Allele frequency, Aged, Singapore, Creatinine, urogenital system, business.industry, Genetic Variation, Middle Aged, medicine.disease, Endocrinology, Diabetes Mellitus, Type 2, chemistry, KCNQ1 Potassium Channel, Female, medicine.symptom, business, Glomerular Filtration Rate
Abstract

A Japanese study had earlier reported that KCNQ1 single-nucleotide polymorphisms (SNPs) may be associated with diabetic nephropathy. To further investigate this finding, we analysed three SNPs, rs2237895, rs2237897 and rs2283228, within the KCNQ1 locus for association with albuminuria among Chinese type 2 diabetic patients residing in Singapore. Albuminuria was analysed as both categorical (micro- and macroalbuminuria) and continuous traits (log(e) albumin/creatinine ratio [ACR]).A total of 752 Chinese patients with type 2 diabetes were included in the study. Albuminuria was determined by ACR using spot urine samples, and renal function was approximated using estimated GFR. Genotyping was performed using invader and Taqman assays as appropriate. Multivariate regression analyses were used to analyse the associations between SNPs and renal traits.Significant associations were detected between rs2283228 and macroalbuminuria (p0.001, corrected p0.01), as well as log(e) ACR (p = 0.004, corrected p = 0.036) after multiple hypothesis testing and adjustment for potential confounding. A trend of increasing OR was observed with increasing severity of diabetic nephropathy (low and high microalbuminuria, macroalbuminuria). rs2237897, previously implicated in the earlier Japanese study, was also associated with macroalbuminuria, but this finding did not remain significant after correction for multiple testing. Meta-analyses of the Chinese and Japanese studies revealed both SNPs to be significantly associated with macroalbuminuria.Together with the previous Japanese study, our findings support the hypothesis that, in addition to KCNQ1 being an established type 2 diabetes gene, genetic variation in this gene may contribute to susceptibility to diabetic nephropathy in East Asians.

Published
2012

44. Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes

Author

Marina Sirota, Satoru Yamada, Rong Chen, Hara Kazuo, Atul J. Butte, Junichiro Irie, Momoko Horikoshi, Takashi Kadowaki, Shiro Maeda, Hiroshi Ohtsu, Alexander A. Morgan, Keiichi Kodama, and Kyoko Toda

Subjects
Blood Glucose, Male, medicine.medical_specialty, Panniculitis, Microarray, Gene Expression, Adipose tissue, Genome-wide association study, Inflammation, Type 2 diabetes, Biology, Mice, Insulin resistance, Internal medicine, Diabetes mellitus, medicine, Animals, Humans, Obesity, Gene, Aged, Oligonucleotide Array Sequence Analysis, Mice, Knockout, Multidisciplinary, Macrophages, Biological Sciences, Middle Aged, medicine.disease, Dietary Fats, Mice, Inbred C57BL, Hyaluronan Receptors, Endocrinology, Adipose Tissue, Diabetes Mellitus, Type 2, Case-Control Studies, Immunology, Female, Insulin Resistance, medicine.symptom, Genome-Wide Association Study
Abstract

Type 2 diabetes (T2D) is a complex, polygenic disease affecting nearly 300 million people worldwide. T2D is primarily characterized by insulin resistance, and growing evidence has indicated the causative link between adipose tissue inflammation and the development of insulin resistance. Genetic association studies have successfully revealed a number of important genes consistently associated with T2D to date. However, these robust T2D-associated genes do not fully elucidate the mechanisms underlying the development and progression of the disease. Here, we report an alternative approach, gene expression-based genome-wide association study (eGWAS): searching for genes repeatedly implicated in functional microarray experiments (often publicly available). We performed an eGWAS across 130 independent experiments (totally 1,175 T2D case-control microarrays) to find additional genes implicated in the molecular pathogenesis of T2D and identified the immune-cell receptor CD44 as our top candidate ( P = 8.5 × 10 −20 ). We found CD44 deficiency in a diabetic mouse model ameliorates insulin resistance and adipose tissue inflammation and also found that anti-CD44 antibody treatment decreases blood glucose levels and adipose tissue macrophage accumulation in a high-fat, diet-fed mouse model. Further, in humans, we observed CD44 is expressed in inflammatory cells in obese adipose tissue and discovered serum CD44 levels were positively correlated with insulin resistance and glycemic control. CD44 likely plays a causative role in the development of adipose tissue inflammation and insulin resistance in rodents and humans. Genes repeatedly implicated in publicly available experimental data may have unique functionally important roles in T2D and other complex diseases.

Published
2012

45. SOLID STATE NMR STUDY ON MICROBIAL POLY(ε-<font>L</font>-LYSINE)/CARBOXYMETHYL CELLULOSE BLENDS

Author

Ko-Ki Kunimoto, Mina Kobayashi, Kumiko Kato, Ken Takagi, and Shiro Maeda

Subjects
Aqueous solution, Lysine, Statistical and Nonlinear Physics, Condensed Matter Physics, Miscibility, Carboxymethyl cellulose, Sodium salt, chemistry.chemical_compound, chemistry, Solid-state nuclear magnetic resonance, Chemical engineering, Carbon dioxide, medicine, Polymer blend, medicine.drug
Abstract

The miscibility of microbial poly(ε- L -lysine)/carboxymethyl cellulose sodium salt (ε-PL/CMC) blends was investigated by solid-state nuclear magnetic resonance methods. 1 H spin-lattice relaxation time in the laboratory frame T1, and in the rotating frame, T1ρ measurements indicate that the blends are miscible at all compositions on a scale of 2–5 nm. Formation of carbamates and its reversibility were examined. ε-PL/CMC hydrogel was formed by bubbling carbon dioxide gas into ε-PL and CMC aqueous solution mixture.

Published
2011

46. Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians

Author

Bok Ghee Han, Congrong Wang, Wing-Yee So, Ying Wu, Rong Zhang, Xueling Sim, Norihiro Kato, Eitaro Nakashima, Qiuyin Cai, Tien-Jyun Chang, Jiro Nakamura, Wei Lu, Mark Seielstad, Yu-Tang Gao, Juliana C.N. Chan, Fumihiko Takeuchi, Jer-Yuarn Wu, Lee-Ming Chuang, Young Min Cho, Hyung Lae Kim, Yik Ying Teo, Andrew P. Morris, Nam H. Cho, Daniel P.K. Ng, Rick Twee-Hee Ong, Cheng Hu, Kyong Soo Park, Sangsoo Kim, Shiro Maeda, Toshimasa Yamauchi, Fuu Jen Tsai, Yoon Shin Cho, Hiroshi Ikegami, Ronald C.W. Ma, Jirong Long, Ken Yamamoto, Yi-Cheng Chang, Xiao-Ou Shu, Karen L. Mohlke, Wei Zheng, Mitsuhiro Yokota, Soo Heon Kwak, Yuan-Tsong Chen, Chien Hsiun Chen, Linda S. Adair, Yun Li, Nanette R. Lee, Young-Jin Kim, Jeannette Lee, Li Ching Chang, Keizo Ohnaka, Ryoichi Takayanagi, Min Jin Go, Wan Ting Tay, Jianjun Liu, Tin Aung, Jong-Young Lee, Hara Kazuo, Yuqian Bao, Weiping Jia, Tien Yin Wong, E. Shyong Tai, Takashi Kadowaki, Mark I. McCarthy, Åsa K. Hedman, and Frank B. Hu

Subjects
Genetics, endocrine system, education.field_of_study, endocrine system diseases, PEPD, Population, Case-control study, Genome-wide association study, Type 2 diabetes, Biology, medicine.disease, Polymorphism (computer science), Diabetes mellitus, medicine, education, Genetic association
Abstract

We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D.

Published
2011

47. Association between single nucleotide polymorphisms within genes encoding sirtuin families and diabetic nephropathy in Japanese subjects with type 2 diabetes

Author

Yusuke Nakamura, Atsunori Kashiwagi, Koichi Kawai, Masahito Imanishi, Shin-ichi Araki, Tomoya Umezono, Hiroshi Maegawa, Masao Toyoda, Daisuke Koya, Daisuke Suzuki, Yasuhiko Iwamoto, Shiro Maeda, Takashi Uzu, and Tetsuya Babazono

Subjects
SIRT3, Physiology, Single-nucleotide polymorphism, Diabetic nephropathy, Type 2 diabetes, Polymorphism, Single Nucleotide, SIRT1, Asian People, Gene Frequency, Sirtuin 1, Single nucleotide polymorphism (SNP), Physiology (medical), medicine, Humans, Sirtuins, Diabetic Nephropathies, Genetics, Proteinuria, biology, business.industry, Haplotype, Middle Aged, medicine.disease, Association study, Diabetes Mellitus, Type 2, Nephrology, Sirtuin, biology.protein, Original Article, medicine.symptom, business
Abstract

Background Sirtuin is a member of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, and has been reported to play a pivotal role in energy expenditure, mitochondrial function and pathogenesis of metabolic diseases, including aging kidneys. In this study, we focused on the genes encoding sirtuin families, and examined the association between single nucleotide polymorphisms (SNPs) within genes encoding sirtuin families and diabetic nephropathy. Methods We examined 52 SNPs within the SIRT genes (11 in SIRT1, 7 in SIRT2, 14 in SIRT3, 7 in SIRT4, 9 in SIRT5, and 4 in SIRT6) in 3 independent Japanese populations with type 2 diabetes (study 1: 747 cases (overt proteinuria), 557 controls; study 2: 455 cases (overt proteinuria) and 965 controls; study 3: 300 cases (end-stage renal disease) and 218 controls). The associations between these SNPs were analyzed by the Cochran–Armitage trend test, and results of the 3 studies were combined with a meta-analysis. We further examined an independent cohort (195 proteinuria cases and 264 controls) for validation of the original association. Results We identified 4 SNPs in SIRT1 that were nominally associated with diabetic nephropathy (P

Published
2011

48. Common variation in GPC5 is associated with acquired nephrotic syndrome

Author

Hodaka Suzuki, Tsuyoshi Watanabe, Katsushi Tokunaga, Akihiko Mabuchi, Shiro Maeda, Atsushi Takahashi, Eisei Noiri, Toshiro Fujita, Koji Okamoto, Yusuke Nakamura, Michiaki Kubo, Nao Nishida, Kent Doi, and Tetsuo Katoh

Subjects
Adult, Male, Nephrotic Syndrome, Nephrosis, Genome-wide association study, Disease, Biology, Polymorphism, Single Nucleotide, Podocyte, Mice, Glypicans, Genetics, medicine, Animals, Humans, RNA, Messenger, RNA, Small Interfering, Congenital nephrotic syndrome, Aged, DNA Primers, Proteinuria, Base Sequence, Models, Genetic, Podocytes, Case-control study, Middle Aged, medicine.disease, Disease Models, Animal, medicine.anatomical_structure, Case-Control Studies, Gene Knockdown Techniques, Immunology, Female, medicine.symptom, Nephrotic syndrome, Genome-Wide Association Study
Abstract

Severe proteinuria is a defining factor of nephrotic syndrome irrespective of the etiology. Investigation of congenital nephrotic syndrome has shown that dysfunction of glomerular epithelial cells (podocytes) plays a crucial role in this disease. Acquired nephrotic syndrome is also assumed to be associated with podocyte injury. Here we identify an association between variants in GPC5, encoding glypican-5, and acquired nephrotic syndrome through a genome-wide association study and replication analysis (P value under a recessive model (P(rec)) = 6.0 × 10(-11), odds ratio = 2.54). We show that GPC5 is expressed in podocytes and that the risk genotype is associated with higher expression. We further show that podocyte-specific knockdown and systemic short interfering RNA injection confers resistance to podocyte injury in mouse models of nephrosis. This study identifies GPC5 as a new susceptibility gene for nephrotic syndrome and implicates GPC5 as a promising therapeutic target for reducing podocyte vulnerability in glomerular disease.

Published
2011

49. Genetics of type 2 diabetes: the GWAS era and future perspectives [Review]

Author

Minako Imamura and Shiro Maeda

Subjects
Genetics, endocrine system diseases, Endocrinology, Diabetes and Metabolism, MEDLINE, nutritional and metabolic diseases, Genome-wide association study, Type 2 diabetes, Biology, medicine.disease, Bioinformatics, Endocrinology, Diabetes Mellitus, Type 2, Missing heritability problem, Diabetes mellitus, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Pharmacogenetics, Genome-Wide Association Study, Genetic association
Abstract

Genome-wide association studies (GWAS) have facilitated a substantial and rapid rise in the number of confirmed genetic susceptibility variants for type 2 diabetes (T2D). Approximately 40 variants have been identified so far, many of which were discovered through GWAS. This success has led to widespread hope that the findings will translate into improved clinical care for the increasing numbers of patients with diabetes. Potential areas or clinical translation include risk prediction and subsequent disease prevention, pharmacogenetics, and the development of novel therapeutics. However, the genetic loci so far identified account for only a small fraction (approximately 10%) of the overall heritable risk for T2D. Uncovering the missing heritability is essential to the progress of T2D genetic studies and to the translation of genetic information into clinical practice.

Published
2011

50. A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B

Author

Annelli Sandbæk, Masato Iwabu, Juliana C.N. Chan, Philippe Froguel, Atsushi Takahashi, Kyong Soo Park, Hiroshi Hirose, Toshihiko Ohshige, Hirotaka Watada, Toshimasa Yamauchi, Torben Hansen, Kohei Kaku, Hara Kazuo, Wing-Yee So, Stéphane Cauchi, Chikako Ito, Miki Okada-Iwabu, Daniel R. Witte, Yasushi Tanaka, Yusuke Nakamura, Naoyuki Kamatani, Delphine Beury, Ikuo Saito, Atsunori Kashiwagi, Hyoung Doo Shin, Ryuzo Kawamori, Hiroshi Maegawa, Shintaro Omori, Michiaki Kubo, Torsten Lauritzen, Gitte Andersen, Oluf Pedersen, Shiro Maeda, Tatsuhiko Tsunoda, Momoko Horikoshi, E. Shyong Tai, Masahiro Nakamura, Daniel P.K. Ng, Hayato Fujita, Kazuki Yasuda, Niels Grarup, Ronald C.W. Ma, Takashi Kadowaki, Masato Kasuga, Torben Jørgensen, and Nobuhiro Shojima

Subjects
Asian Continental Ancestry Group, Genotype, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Type 2 diabetes, Biology, Polymorphism, Single Nucleotide, Asian People, Diabetes mellitus, Genetics, medicine, Humans, Genetic Predisposition to Disease, Comparative genomics, Chromosomes, Human, Pair 15, Genome, Human, Case-control study, Nuclear Proteins, medicine.disease, Diabetes Mellitus, Type 2, Case-Control Studies, Ubiquitin-Conjugating Enzymes, Chromosomes, Human, Pair 3, Genome-Wide Association Study, Transcription Factors
Abstract

We conducted a genome-wide association study of type 2 diabetes (T2D) using 459,359 SNPs in a Japanese population with a three-stage study design (stage 1, 4,470 cases and 3,071 controls; stage 2, 2,886 cases and 3,087 controls; stage 3, 3,622 cases and 2,356 controls). We identified new associations in UBE2E2 on chromosome 3 and in C2CD4A-C2CD4B on chromosome 15 at genome-wide significant levels (rs7612463 in UBE2E2, combined P = 2.27 × 10⁻⁹; rs7172432 in C2CD4A-C2CD4B, combined P = 3.66 × 10⁻⁹). The association of these two loci with T2D was replicated in other east Asian populations. In the European populations, the C2CD4A-C2CD4B locus was significantly associated with T2D, and a combined analysis of all populations gave P = 8.78 × 10⁻¹⁴, whereas the UBE2E2 locus did not show association to T2D. In conclusion, we identified two new loci at UBE2E2 and C2CD4A-C2CD4B associated with susceptibility to T2D.

Published
2010

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