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Because increased oxidative stress may mediate the detrimental actions of enhanced sympathetic nervous activity on renal function and vice versa, we investigated the effect of the polymorphic Arg16Gly in the β2 -adrenoceptor (ADRB2) gene, Trp64Arg in the β3 -adrenoceptor (ADRB3) gene and C242T in the NADPH oxidase p22phox (CYBA) gene on estimated glomerular filtration rate (eGFR) in a Chinese population. Initially recruited from different outpatient services of HeBei General Hospital in northern China, 668 individuals were finally included in the study, with complete demographic information. Laboratory tests were performed and estimated glomerular filtration rate (eGFR) was derived from the Modification of Diet in Renal Disease (MDRD) equation for the Chinese population. Plasma noradrenaline levels and genotype were determined by HPLC and the TaqMan method, respectively. Only across the Arg16Gly polymorphism did eGFR show significant difference: it was lower in individuals with the Gly16Gly variation, who also had the highest plasma noradrenaline levels. This polymorphism remained a significant determinant of eGFR after multivariate analysis. Of importance, the multifactor dimensionality reduction method further detected a significant synergism between the Arg16Gly and C242T polymorphisms in reducing eGFR. These observations clarify the effects of the studied polymorphisms on eGFR and exemplify gene-gene interactions influencing renal function., (© 2014 Wiley Publishing Asia Pty Ltd.)

Congenital heart malformation (CHM) is the most common form of congenital human birth anomaly and is the leading cause of infant mortality. Although some causative genes have been identified, little progress has been made in identifying genes in which low-penetrance susceptibility variants occur in the majority of sporadic CHM cases. To identify common genetic variants associated with sporadic non-syndromic CHM in Han Chinese populations, we performed a multistage genome-wide association study (GWAS) in a total of 4,225 CHM cases and 5,112 non-CHM controls. The GWAS stage included 945 cases and 1,246 controls and was followed by 2-stage validation with 2,160 cases and 3,866 controls. The combined analyses identified significant associations (P < 5.0 × 10⁻⁸) at 1p12 (rs2474937 near TBX15; odds ratio (OR) = 1.40; P = 8.44 × 10⁻¹⁰) and 4q31.1 (rs1531070 in MAML3; OR = 1.40; P = 4.99 × 10⁻¹²). These results extend current knowledge of genetic contributions to CHM in Han Chinese populations.

Background: Polycystic ovary syndrome (PCOS) is a common complex genetic endocrinopathy. It has high heritability, and twin studies indicate that it is a complex polygenic disorder. Searching for major genes of PCOS is crucial to clarify its molecular pathogenesis. A previous genome-wide association study in Chinese women with PCOS identified a region on chromosome 2p16.3 that encodes the follicle-stimulating hormone receptor (FSHR) genes as a reproducible PCOS susceptibility locus. In the present study, we performed a replication analysis of the association between two common variants of the FSHR gene and PCOS in Northern Chinese Han women., Results: We recruited 384 unrelated PCOS patients and 768 healthy individuals from the Shaanxi province in the northern part of China. Two polymorphisms (Ala307Thr and Ser680Asn) of the FSHR gene and the clinical characteristics of the study subjects were analyzed in the case-control sample. The frequency of FSHR Ala307Thr and Ser680Asn variants along with the haplotype was not significantly different between the PCOS patients and the controls; however, the Ser680 variants may be associated with high levels of FSH and low E2 levels., Conclusion: The variant of Ser680 was not associated with PCOS but it may be related to high FSH levels. The present study suggests that the two variants of the FSHR gene are not a causative factor of PCOS in Northern Chinese Han women.

Matrix metalloproteinase 9 (MMP9) plays a critical role in cancer aggression, and its overexpression is associated with a poor prognosis in breast cancer. Because common genetic variants can alter the expression or function of MMPs, we hypothesized that potentially functional single-nucleotide polymorphisms (SNPs) in the MMP9 gene may be associated with the survival of patients with invasive breast cancer. In this case-cohort follow-up study, a total of 245 breast cancer patients in southeast China were investigated, and five haplotype tagging SNPs (htSNPs) in the MMP9 gene were genotyped by using matrix-assisted laser desorption/ionization mass spectrometry and polymerase chain reaction-restriction fragment length polymorphism methods. Disease-free survival (DFS) and distance disease-free survival (DDFS) analyses were used to identify the SNPs associated with prognosis and determine their interdependence with the recognized prognostic factors. We found that the MMP9 rs3787268 GA+AA genotypes were significantly associated with poor DFS and DDFS of patients with breast cancer (log-rank p-values 0.045 and 0.028, respectively), especially in some subgroups of patients. Multivariate Cox regression and stepwise COX regression analyses suggested that rs3787268 may be a candidate independent biomarker to predict breast cancer survival in this population. Further, among estrogen receptor (ER)+/epidermal growth receptor 2 (HER-2)- patients, the rs3787268 GA+AA genotypes and rs17577 GG genotype showed a locus-dosage effect between combined the genotypes and decreased survival (adjusted HR 2.59, 95% confidence interval [CI] 1.29-5.19 and adjusted HR 3.25, 95% CI 1.39-7.58, respectively, for DFS and DDFS). Our results suggest that the polymorphisms in the MMP9 gene may be genetic modifiers for breast cancer prognosis in this Chinese population.

Objective: The aim of the study was to identify the causative gene defects associated with familial adenomatous polyposis (FAP) in two Chinese pedigrees., Methods: The diagnosis of FAP patients was confirmed by clinical manifestations, family histories, colonoscopy and pathology examinations. Blood samples were collected and genomic DNA was extracted. The mutation analysis of the adenomatous polyposis coli (APC) and human mutY homolog (MUTYH) genes was conducted by direct polymerase chain reaction (PCR) sequencing and multiplex ligation-dependent probe amplification (MLPA)., Results: In pedigree A, the results of direct PCR sequencing revealed a heterozygous insertion mutation at codon 610 in exon 15 of APC gene (c.1828&#95;1829insG), which resulted in frameshift change (p.Asp610GlyfsX23) in all 4 patients, but was absent in the unaffected familial members and controls. In pedigree B, we didn't identify that causative mutations cosegregated with the clinical phenotype in the APC and MUTYH genes., Conclusions: We identified a novel insertion mutation as the pathogenic gene of FAP in Chinese population, which could enrich the germline mutation spectrum of APC gene, and the prophylactic proctocolectomy for the mutation carrier in family should be considered., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Insufficiency of the pulmonary surfactant system is the primary cause of respiratory distress syndrome (RDS) in preterm infants. Genetic factors, including specific single-nucleotide polymorphisms in the genetic components of surfactant protein A (SP-A1 and SP-A2), affect protein structure and function, as well as risk of RDS., Objective: We investigated the association between variations in SP-A genotypes and RDS within the genetically homogeneous Korean population., Methods: We used TaqMan® real-time polymerase chain reaction technology to assess nine single-nucleotide polymorphisms of SP-A in 261 full-term and 152 preterm infants. Among the preterm infants, 76 infants with RDS were matched with 76 control infants with respect to gestation, use of antenatal steroids and gender., Results: The SP-A2 1A(0) variant and the homozygous 1A(0)/1A(0) genotype were associated with protection from RDS (OR 0.31, 95% CI 0.13-0.78). In addition, the 1A(1) carrier genotype (containing one copy of the 1A(1) variant) was associated with increased risk of RDS (OR 2.42, 95% CI 1.06-5.52). The significance of these results is that the association of patterns with RDS was opposite to the findings of previous research with Finnish and North American study populations., Conclusions: We have identified associations between specific variants of the SP-A genes and RDS risk in the Korean preterm study population. Our data strongly support SP-A as a candidate gene for susceptibility to RDS, and reveal the dissimilarity of the associated risk/protective genetic variants between different ethnic study populations., (Copyright © 2012 S. Karger AG, Basel.)

Objective: Methyl-CpG binding domain 4 (MBD4) protein functions as a DNA repair enzyme and plays an important role in maintaining genome integrity and carcinogenesis. The polymorphisms in the MBD4 gene may be associated with differences in DNA repair capacity and thereby influence an individual's susceptibility to cervical cancer. To verify this hypothesis, we examined the potential association between the MBD4 Glu346Lys polymorphism (rs140693, G>A) and the risk of cervical cancer in a Chinese population., Methods: We genotyped the MBD4 Glu346Lys polymorphism in 146 cervical cancer cases and 320 healthy female subjects using polymerase chain reaction-based restriction fragment length polymorphism method. Unconditional logistic regression analysis was used to estimate the association between the genotypes and the risk of cervical cancer., Results: We observed a significantly decreased risk of cervical cancer associated with the heterozygous Lys/Glu genotype (odds ratio [OR], 0.60; 95% confidence interval [CI], 0.36-0.99; P = 0.046) and the homozygous Glu/Glu genotype (OR, 0.52; 95% CI, 0.30-0.89; P = 0.018), compared with the Lys/Lys homozygotes. Moreover, the reduced cervical cancer risk was more predominant among younger subjects or human papillomavirus-positive individuals carrying Glu/Glu genotypes (OR, 0.33; 95% CI, 0.14-0.78, P = 0.011; and OR, 0.27; 95% CI, 0.09-0.75, P = 0.013, respectively)., Conclusions: The MBD4 codon 346 polymorphism may play a role in cervical cancer susceptibility in the Chinese population. Further larger case-control and functional studies are needed to validate these findings.

Aims: We examined the risk association between single nucleotide polymorphisms (SNPs) in eleven candidate genes with type 2 diabetes (T2D). T2D-associated polymorphisms were also examined for prediction of incident CHD., Methods: 113 tagging SNPs were genotyped in stage 1 (467 T2D cases, 290 controls), and 15 SNPs were analyzed in the final cohort (1462 T2D cases, 600 controls). Three T2D-associated SNPs were further tested for prediction of CHD within a subset of 1417 T2D cases free of CHD at enrolment., Results: In the case-control analysis, PPARG rs1801282 (Pro12Ala) (OR=1.48 (1.02-2.16)), ADIPOQ rs1063539 (OR=1.17 (1.01-1.35)), and HNF4A rs1884614 (OR=1.16 (1.00-1.32) were associated with T2D (P(allelic)<0.05). Joint analysis of rs1801282-C, rs1063539-G, and rs1884614-T risk alleles showed an additive dosage effect (P for trend=0.001). Moreover, carriers with two PPARG rs1801282-C risk alleles were associated with an increased risk of incident CHD (HR=4.38 (1.03-18.57), P=0.045) in T2D patients in the prospective analysis., Conclusions: Genetic variants of PPARG, ADIPOQ and HNF4A were individually and jointly associated with T2D in Hong Kong Chinese. The PPARG Pro12 risk allele contributed to increased risk for both T2D and CHD., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Nasopharyngeal carcinoma (NPC) is a multi-factorial malignancy closely associated with environmental factors, genetic factors and Epstein-Barr virus infection. Human leukocyte antigen (HLA) complex, specially the region near HLA-A locus, was regarded as a major candidate region bearing NPC genetic susceptibility loci in many previous studies including two recent genome-wide association (GWA) studies. To provide further evidence for the NPC susceptibility in the region near HLA-A locus based on other previous studies, we carried out a two-stage hospital-based case control association study including 535 sporadic NPC patients and 525 cancer-free control subjects from Guangdong, a high prevalence area of NPC in China., Methods: 38 tag SNPs were initially selected by Heploview from the segment around HLA-A locus (from D6S211 to D6S510) and genotyped on GenomeLab SNPstream platform in 206 cases and 180 controls in the stage 1. Subsequently, the stage 1 significant SNPs and 17 additional SNPs were examined on another platform (Sequenom iPlex Assay) in another independent set of study population including 329 cases and 345 controls., Results: Totally eight SNPs from the segment from D6S211 to D6S510 within HLA complex were found to be significantly associated with NPC. Two of the most significant SNPs (rs9260734 and rs2517716) located near to HLA-A and HCG9 respectively were in strong LD with some other SNPs of this region reported by two previous GWA studies. Meanwhile, Meanwhile, novel independent susceptibility loci (rs9404952, Pcombined = 6.6 × 10-5, OR combined = 1.45) was found to be close to HLA-G., Conclusion: Therefore, our present study supports that the segment from D6S211 to D6S510 in HLA complex region might contain NPC susceptibility loci which indeed needs to be fully investigated in the future.

Background: Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder with gender biased and incomplete penetrance. The majority of LHON patients are caused by one of the three primary mutations (m.3460G > A, m.11778G > A and m.14484T > C). Rare pathogenic mutations have been occasionally reported in LHON patients., Methods: We screened mutation m.10680G > A in the MT-ND4L gene in 774 Chinese patients with clinical features of LHON but lacked the three primary mutations by using allele specific PCR (AS-PCR). Patients with m.10680G > A were further determined entire mtDNA genome sequence., Results: The optimal AS-PCR could detect as low as 10% heteroplasmy of mutation m.10680G > A. Two patients (Le1263 and Le1330) were identified to harbor m.10680G > A. Analysis of the complete mtDNA sequences of the probands suggested that they belonged to haplogroups B4a1 and D6a1. There was no other potentially pathogenic mutation, except for a few private yet reported variants in the MT-ND1 and MT-ND5 genes, in the two lineages. A search in reported mtDNA genome data set (n = 9277; excluding Chinese LHON patients) identified no individual with m.10680G > A. Frequency of m.10680G > A in Chinese LHON patients analyzed in this study and our previous studies (3/784) was significantly higher than that of the general populations (0/9277) (P = 0.0005)., Conclusion: Taken together, we speculated that m.10680G > A may be a rare pathogenic mutation for LHON in Chinese. This mutation should be included in future clinical diagnosis.

Folate consumption is inversely associated with the risk of oral and pharyngeal cancer (OPC) and potentially interacts with alcohol drinking in the risk of OPC. Aldehyde dehydrogenase 2 (ALDH2) gene polymorphism is known to interact with alcohol consumption. The aim of this study was to investigate potential interaction between folate, alcohol drinking, and ALDH2 polymorphism in the risk of OPC in a Japanese population. The study group comprised 409 head and neck cancer cases and 1227 age-matched and sex-matched noncancer controls; of these, 251 cases and 759 controls were evaluated for ALDH rs671 polymorphism. Associations were assessed by odds ratios and 95% confidence intervals in multiple logistic regression models. We observed an inverse association between folate consumption and OPC risk. The odds ratio for high folate intake was 0.53 (95% confidence interval: 0.36-0.77) relative to low intake (P trend=0.003). This association was consistent across strata of sex, age, smoking, and ALDH2 genotypes. Interaction between folate consumption, drinking, and ALDH2 genotype was remarkable (three-way interaction, P<0.001). We observed significant interaction among folate, drinking, and ALDH2 genotype in the Japanese population.

Polymorphisms in the human catechol-O-methyltransferase (COMT) gene have been widely studied for their role in pain and analgesia. In this study, sensitivity to potassium iontophoresis, visual analog scale measurements for fixed twofold pain threshold stimulation and pain threshold changes induced by transcutaneous electrical acupoint stimulation (TEAS) were assessed in a population of healthy Chinese males. These results were correlated with the alleles of six single nucleotide polymorphisms (SNP) or diplotypes of common haplotypes designated as low pain sensitive, average pain sensitive, and high pain sensitive in the COMT gene of these subjects. Our results reveal that the alleles of each SNP are not significantly correlated with pain perception except for the rs4633 allele in the 2 Hz TEAS session (P < 0.05). In addition, the six diplotypes of COMT haplotypes, which cover 92.5% of the Chinese population, are also not correlated with pain perception. Moreover, there were no significant differences in pain threshold changes induced by 2 and 100 Hz TEAS among the diplotypes of each SNP or the various haplotypes. These results suggest that COMT activity do not play a significant role in pain perception and TEAS-induced analgesia in the Chinese Han male population.

Background: The D variant phenotypes are often categorized into weak D types and partial D types. Although the molecular basis underlying the partial D phenotype has been investigated in several races, data from Chinese populations are rare., Study Design and Methods: We collected partial D samples from 1,274,540 blood donors, as well as from sporadic patients in the Chinese population, over a 4-year period. Samples with partial D phenotype were determined by commercial monoclonal anti-D panels and molecular methods. Blood samples with discrepant results of serologic and molecular methods were further investigated by polymerase chain reaction (PCR) with sequence-specific primers and nucleotide sequencing of RHD exons. The detection of antibodies was performed., Results: A total of 44 samples with partial D phenotypes were confirmed. Molecular typing revealed five different known aberrant alleles as well as four new RHD alleles. As described previously, DVI represented the most frequent partial D type in China with a total of 36 samples. However, discrepant results were observed in four DVI samples with serotyping and genotyping (i.e., DVI category identified by D-screen test and grossly intact RHD gene identified by multiplex PCR). We also found four novel alleles, termed DFR-4, DCS-3, DCC, and DLX., Conclusion: To date, this study presents the most comprehensive report on partial D in China. The distribution of partial D types in China was found to be complicated and polymorphic, whereas RhD genotyping of DVI-variant samples might give inaccurate results due to a relatively high incidence of RHD(1227G>A) in the Chinese population., (© 2012 American Association of Blood Banks.)

Background: Conotruncal heart defects (CTDs) are present in 75-85% of patients suffering from the 22q11.2 deletion syndrome. To date, no consistent phenotype has been consistently correlated with the 22q11.2 deletions. Genetic studies have implicated TBX1 as a critical gene in the pathogenesis of the syndrome. The aim of study was to determine the incidence of the 22q11.2 deletion in Chinese patients with CTDs and the possible mechanism for pathogenesis of CTDs., Methods: We enrolled 212 patients with CTDs and 139 unrelated healthy controls. Both karyotypic analysis and multiplex ligation-dependent probe amplification were performed for all CTDs patients. Fluorescence in situ hybridization was performed for the patients with genetic deletions and their relatives. The TBX1 gene was sequenced for all patients and healthy controls. The χ2 and Fisher's exact test were used in the statistical analysis., Results: Thirteen of the 212 patients with CTDs (6.13%) were found to have the 22q11.2 deletion syndrome. Of the 13 cases, 11 presented with a hemizygous interstitial microdeletion from CLTCL1 to LZTR1; one presented with a regional deletion from CLTCL1 to DRCR8; and one presented with a regional deletion from CDC45L to LZTR1. There were eight sequence variants in the haploid TBX1 genes of the del22q11 CTDs patients. The frequency of one single nucleotide polymorphism (SNP) in the del22q11 patients was different from that of the non-del patients (P < 0.05), and the frequencies of two other SNPs were different between the non-del CTDs patients and controls (P < 0.05)., Conclusions: CTDs, especially pulmonary atresia with ventricular septal defect and tetralogy of Fallot, are the most common disorders associated with the 22q11.2 deletion syndrome. Those patients with both CTDs and 22q11.2 deletion generally have a typical or atypical deletion region within the TBX1 gene. Our results indicate that TBX1 genetic variants may be associated with CTDs.

Recent genomewide association studies have successfully identified several genotypes susceptible to type 2 diabetes mellitus (T2DM). However, only a few studies have investigated whether these variations confer a risk of the future development of T2DM. We conducted a longitudinal genetic epidemiological study to clarify the prognostic significance of the T2DM-associated variants. The sample population consisted of 2037 middle-aged to elderly community residents. Personal health records were obtained from a clinical database administered by the local government. Genotype risk score was calculated by the following variants, namely, KCNQ1, TCF7L2, CDKAL1, HHEX, IGF2BP2, CDKN2AB, SLC30A8, KCNJ11, PPARG, and GCKR. Susceptibility of these variants in Japanese has been confirmed by association analysis. Among the 1824 subjects who did not have T2DM at baseline, 95 cases of T2DM were newly diagnosed during the 9.4-year follow-up period. Mean genotype risk score in these subjects was significantly higher than that in the subjects who remained nondiabetic (9.5 ± 1.8 vs 9.1 ± 2.0, P = .042). Although the initial mean body mass index (24.7 ± 3.2 vs 23.0 ± 2.8, P < .001) and initial glucose (106 ± 18 vs 90 ± 13, P < .001) were also significantly higher in those subjects who developed T2DM, the genotype risk score remained an independent determinant of the development of T2DM even after adjustment for these parameters and possible confounding factors. Per-allele odds ratio for the development of T2DM was 1.12 (95% confidence interval, 1.00-1.25; P = .049). Type 2 diabetes mellitus-susceptible genetic variants identified by a cross-sectional genomewide association study were significantly associated with the future development of T2DM in a general population sample., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Carboxylesterase 1 (CES1) is involved in the metabolic activation of a variety of prodrugs into active derivatives and plays an important role in pharmacokinetics and pharmacodynamics. A single-nucleotide polymorphism, A(-816)C, of the CES1A2 gene has been shown to enhance transcription efficiency and increase enzyme activity. The aim of this study was to develop an easy method to detect this polymorphism. For this we used the mutation-sensitive molecular switch method to investigate the polymorphism distribution in the Chinese Han and Yao populations. The method was well validated by direct sequencing. In 204 Han individuals, the percentages of the distribution of CES1A2 A(-816)C genotypes are AA 58.33% (n=119), AC 35.78% (n=73), and CC 5.88% (n=12). The genotype frequencies are AA 47.76% (n=96), AC 42.79% (n=86), and CC 9.45% (n=19) in 201 Yaos. The frequency of the mutant C allele in the Yao population is significantly higher than that in the Han population (30.85% vs. 23.77%, p=0.0239). The method can be easily used for the detection of the single-nucleotide polymorphism in CES1A2, and we found that there is a marked difference in mutant C allele between Chinese Han and Yao populations, suggesting individual and ethnic differences of CES1 drug metabolism between these two populations.

Methamphetamine (MAP) dependence is a highly heritable and aberrant dopaminergic signaling that has been implicated in the disease. Glial cell line-derived neurotrophic factor (GDNF), which plays an important role in the survival of dopaminergic neurons, may be involved in this disorder. In this study, we examined the association between GDNF and MAP dependence using a Japanese population-based sample. We selected eight single nucleotide polymorphisms (SNPs) in the GDNF locus for the association analysis. When patients with MAP dependence were divided into two subgroups consisting of multi-substance and MAP-only users, we detected a significant association between these two groups and the tagging SNP, rs2910704 (after Bonferroni's correction; allele P=0.034). Thus, GDNF is likely to be related to the severity of MAP use in the Japanese population., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Polycystic ovary syndrome (PCOS) is a complex disease having both genetic and environmental components. Candidate genes with insulin metabolism have been hypothesized to be involved in the etiology of this syndrome. In the present study, we investigated the genetic association between polymorphisms in the insulin receptor (INSR) gene and PCOS., Methods: A total of 260 family trios were recruited and performed a family-based analysis to assess linkage and association between four single nucleotide polymorphisms (SNPs) (rs1799817, rs2059807, rs8108622 and rs10500204) of INSR gene and PCOS., Results: Using the transmission disequilibrium test (TDT), we failed to find that rs1799817 (p = 0.486), rs2059807 (p = 0.195), rs8108622 (p = 0.866) and rs10500204 (p = 1.0) were significantly overtransmitted to PCOS offspring from their parents., Conclusion: No significant evidence of association or linkage was found in the four tested markers, indicating that our family samples did not support susceptibility of the INSR gene to PCOS.

The primary aim of the present study was to evaluate the effect of the genotype of vitamin K epoxide reductase complex 1 (VKORC1) on warfarin dose requirements in Japanese pediatric patients. Forty-eight pediatric patients (0.42-19.25 years old) in whom stable anticoagulation was achieved by warfarin were enrolled in this study, and the polymorphic alleles of VKORC1 and CYP2C9 were determined for each subject. The relative impact of covariates on the anticoagulant effect of warfarin was evaluated by multiple regression analysis. It was found that VKORC1 genotype and age were major factors affecting the relationship between the weight-normalized warfarin dose and the therapeutic prothrombin time-international normalized ratio (PT-INR). Because only one patient had the CYP2C9*3 allele, we could not evaluate the effect of CYP2C9 polymorphisms on the anticoagulant effect of warfarin. In contrast, the anticoagulant effect of warfarin in patients with the VKORC1 1173CT or 1173CC genotype was 52.3% of that in patients with the 1173TT genotype. In addition, the anticoagulant effect of warfarin was shown to increase by 10.5% per year in Japanese pediatric patients. In conclusion, genotyping of VKORC1 will be useful in establishing individual anticoagulant therapy with warfarin, and it should be noted that a higher weight-normalized dose of warfarin is required in younger pediatric patients.

We evaluated the pharmacokinetics of routinely administered bosentan in 46 Japanese pediatric patients with pulmonary arterial hypertension. Plasma samples were taken twice at times corresponding to the peak and trough concentrations following repetitive oral administration. The population pharmacokinetic parameters of bosentan were estimated by use of the NONMEM program, in which a one-compartment model with repetitive bolus dosing was parameterized in terms of the oral clearance (CL/F) and elimination rate constant (k). Polymorphisms of CYP3A5, SLCO1B1, SLCO1B3, and SLCO2B1 had no significant effect on the disposition of bosentan. In addition, the pharmacokinetics of bosentan was not altered by heart failure or coadministration of sildenafil. In contrast, weight (WT)-normalized values of CL/F were correlated negatively with age (AGE). The final population mean values of CL/F and k were estimated to be 0.409 · (1 - 0.0377 · (AGE - 3.81)) · WT L/h and 0.175 h(-1), respectively.

Background: The human apurinic/apyrimidinic endonuclease 1/Redox effector factor-1 (APE1/Ref-1) is implicated in tumor development and progression. Recently, the APE1/Ref-1 promoter -141T/G variant (rs1760944) has been reported to be associated with lung cancer risk. Given the importance of APE1/Ref-1 in both DNA repair and redox activity, we speculate that the -141T/G polymorphism may confer individual susceptibility to gliomas or its subtypes., Methods: The APE1/Ref-1 -141T/G polymorphism was analyzed in a case-control study including 766 glioma patients (among them 241 glioblastoma, 284 astrocytomas except for glioblastoma and 241 other gliomas) and 824 cancer-free controls from eastern China. Genotyping was performed with Sequenom MassARRAY iPLEX platform by use of allele-specific MALDI-TOF mass spectrometry assay. We estimated odds ratios (ORs) and 95% confidence intervals (95% CIs) using unconditional logistic regression. A test of trend was calculated using the genotype as an ordinal variable in the regression model. For each statistically significant association identified, we estimated the false positive reporting probability (FPRP). FPRP values less than 0.2 were consider to indicate robust associations., Results: The significant association between the APE1/Ref-1 promoter -141T/G polymorphism and glioma risk was not observed. However, the stratified analysis by histology revealed the variant allele G significantly decreased glioblastoma risk (OR = 0.80, 95% CI = 0.65-0.98, P = 0.032). Individuals with the homozygous -141GG genotype exhibited 46% reduced risk of glioblastoma (adjusted OR = 0.54, 95% CI 0.34-0.87, P = 0.012), compared with the TT homozygote. This result remained robust given the prior probabilities of 25% (FPRP = 0.052) and 10% (FPRP = 0.140), but not with a prior probability of 1% (FPRP = 0.643). The P-associated with the trend test was 0.014., Conclusions: Our results suggest that a specific genetic variant located in the APE1/Ref-1 promoter may modulate risk of glioblastoma, but not for other histological gliomas. Larger studies with more APE1 polymorphisms are required to validate these preliminary findings.

Nucleotide sequence of HLA-B*40:128 has a single nucleotide difference at position 539 T>G compared with that of HLA-B*40:01:01, with an amino acid change from Leu to Arg at codon 156., (© 2011 John Wiley & Sons A/S.)

Since their arrival in the Tibetan Plateau during the Neolithic Age, Tibetans have been well-adapted to extreme environmental conditions and possess genetic variation that reflect their living environment and migratory history. To investigate the origin of Tibetans and the genetic basis of adaptation in a rigorous environment, we genotyped 30 Tibetan individuals with more than one million SNP markers. Our findings suggested that Tibetans, together with the Yi people, were descendants of Tibeto-Burmans who diverged from ancient settlers of East Asia. The valleys of the Hengduan Mountain range may be a major migration route. We also identified a set of positively-selected genes that belong to functional classes of the embryonic, female gonad, and blood vessel developments, as well as response to hypoxia. Most of these genes were highly correlated with population-specific and beneficial phenotypes, such as high infant survival rate and the absence of chronic mountain sickness.

Background: Baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5, also called as survivin) is a member of the inhibitor of apoptosis protein (IAP) family, which plays an important role in the occurrence and progression of cancer. Recently, a polymorphism in the promoter of BIRC5, -31C/G (rs9904341), was shown to influence BIRC5 expression., Methods: We examined whether the -31C/G was related to the risk of developing nasopharyngeal carcinoma (NPC) in a case-control population from Guangxi province in southern China, which consists of 855 patients with NPC and 1036 controls. This polymorphism was genotyped by TaqMan assay. The genetic associations with the occurrence and progression of NPC were estimated by logistic regression., Results: We observed a statistically significant increased occurrence of NPC associated with the CC genotype (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.13-1.73; P=0.0020) compared with the genotypes containing G allele (CG + GG genotype). However, no significant association was observed for the -31C/G with the severity of NPC (as measured by tumor-node-metastasis staging system)., Conclusion: Our findings suggest that the functional polymorphism -31C/G in the promoter of BIRC5 gene may play a role in mediating the susceptibility to NPC among Chinese.

Background/aims: The prevalence of lifestyle-related chronic diseases is increasing and gene-diet interaction studies are limited among the Malaysian population. This study was conducted to evaluate the association and interaction effects of vascular endothelial growth factor receptor-2(VEGFR2) gene polymorphisms and dietary patterns on anthropometric and biochemical risk factors of chronic diseases in 179 Chinese Malaysian adults., Methods: Genotyping of rs1870377 and rs2071559 was performed by real-time PCR using TaqMan probes. Dietary patterns were constructed from the food frequency questionnaire using factor analysis. Anthropometric measurements: body mass index (BMI), systolic and diastolic blood pressure and biomarkers: blood glucose, glycated hemoglobin A1c (HbA1c) and lipids were obtained., Results: Two dietary patterns: 'Balanced diet' and 'Meat, rice and noodles diet' (MRND) were extracted. MRND was associated with higher BMI, blood pressure, blood glucose and lipids, while T alleles in both rs1870377 and rs2071559 were associated with higher blood lipids (p < 0.05). The interaction of MRND and rs1870377 had a borderline effect on blood HbA1c after adjusting for confounders (p = 0.057)., Conclusions: A dietary pattern of MRND and VEGFR2 gene polymorphisms were both associated with increased health risks of lifestyle-related chronic diseases particularly blood glucose and lipid levels in Chinese Malaysian adults., (Copyright © 2012 S. Karger AG, Basel.)

Background and Objectives: Warfarin inhibits vitamin K epoxide reductase, of which microsomal epoxide hydrolase is a putative member. Several studies have found signals of association with warfarin maintenance dose in the EPHX1 gene. The aim of this study was to determine the effects of EPHX1 variants on warfarin maintenance dose in a multiethnic Asian population., Methods: We sequenced the exons of EPHX1 using PCR and direct sequencing in 279 patients consisting of three major ethnic groups receiving maintenance warfarin with a stable international normalized ratio. The effects of EPHX1 variants were assessed using multiple linear regression., Results: An association between an intronic SNP rs1877724 and warfarin maintenance dose was found, with homozygous variant carriers requiring approximately 0.5 mg/day lower than wild type and heterozygotes after adjustment for covariates. However, its contribution is small, explaining only an additional 0.8% of the dose variability. Rare variants were pooled but there was no association between their presence and warfarin maintenance dose. However, the presence of noncoding rare SNPs was significantly associated with warfarin maintenance dose., Conclusion: Despite a significant finding in rs1877724, which concurs with an earlier study, overall, genetic variants in EPHX1 do not have a clinically significant impact on warfarin dose requirements in our population.

Background: Recent research shows that polycystic ovary syndrome (PCOS) may have an association with low-grade chronic inflammation, and that PCOS may induce an increase in serum interleukin-18 (IL-18) levels., Methods: To investigate the polymorphisms of the IL-18 gene promoters with PCOS, two single nucleotide polymorphisms (SNPs) in the promoter of the IL-18 gene (at positions -607C/A and -137G/C) in 118 Chinese women with PCOS and 79 controls were evaluated using polymerase chain reaction (PCR)., Results: No significant differences were found in the genotype distribution, allele frequency and haplotype frequency between the PCOS and control groups. Further analysis demonstrated a relationship between IL-18 gene promoter polymorphisms and PCOS insulin resistance (IR). Regarding the -137 allele frequency, G and C allele frequencies were 93.5% and 6.5%, respectively, in the PCOS with IR patients; G and C allele frequencies were 85.4% and 14.6%, respectively, in PCOS patients without IR (chi2 = 3.601, P = 0.048)., Conclusions: The presence of a polymorphism in the IL-18 gene was found to have no correlation with the occurrence of PCOS. Carriage of the C allele at position -137 in the promoter of the IL-18 gene may play a protective role from the development of PCOS IR.

Associations between the TAQIB and I405V polymorphisms and obesity risk were studied for a single locus as well as in combination. A total of 934 obese subjects and 924 normal controls were included in the study. TAQIB was associated with high-density lipoprotein (HDL) levels (P < 0.001), while I405V was associated with levels of low-density lipoprotein (P = 0.03) and total cholesterol (P = 0.007). Less common alleles of TAQIB and I405V were associated with decreased obesity risk and further drops in odds ratio (OR) were observed in carriers with rare homozygous alleles on both loci (OR = 0.659, P = 0.02). The TAQIB B2 allele was associated with reductions in both hip circumference (P = 0.034) and triceps skinfold thickness (TST) (P = 0.045), although this effect was completely abolished after controlling for HDL levels. The 405V variant was associated with reductions in hip circumference (P = 0.031), body fat composition (P = 0.039) and TST (P = 0.036); these effects were weakened (P < 0.1) after controlling for HDL levels. In conclusion, less common alleles of TAQIB and I405V appear to be modestly associated with obesity risk in an adult Chinese population. Adjustments for HDL levels completely (TAQIB) or partially (I405V) abolished the observed association.

We performed a genome-wide association study of esophageal squamous cell carcinoma (ESCC) by genotyping 1,077 individuals with ESCC and 1,733 control subjects of Chinese Han descent. We selected 18 promising SNPs for replication in an additional 7,673 cases of ESCC and 11,013 control subjects of Chinese Han descent and 303 cases of ESCC and 537 control subjects of Chinese Uygur-Kazakh descent. We identified two previously unknown susceptibility loci for ESCC: PLCE1 at 10q23 (P(Han combined for ESCC) = 7.46 x 10(-56), odds ratio (OR) = 1.43; P(Uygur-Kazakh for ESCC) = 5.70 x 10(-4), OR = 1.53) and C20orf54 at 20p13 (P(Han combined for ESCC) = 1.21 x 10(-11), OR = 0.86; P(Uygur-Kazakh for ESCC) = 7.88 x 10(-3), OR = 0.66). We also confirmed association in 2,766 cases of gastric cardia adenocarcinoma cases and the same 11,013 control subjects (PLCE1, P(Han for GCA) = 1.74 x 10(-39), OR = 1.55 and C20orf54, P(Han for GCA) = 3.02 x 10(-3), OR = 0.91). PLCE1 and C20orf54 have important biological implications for both ESCC and GCA. PLCE1 might regulate cell growth, differentiation, apoptosis and angiogenesis. C20orf54 is responsible for transporting riboflavin, and deficiency of riboflavin has been documented as a risk factor for ESCC and GCA.

hOGG1 protein excises the 8-hydroxy-2'-deoxyguanine (8-OHdG) which is associated with type 2 diabetes mellitus (T2DM). Our aim of this work is to explore whether the polymorphisms of hOGG1 gene are associated with T2DM. We screened the polymorphisms in the 5'-UTR (c.-18G>T, c.-23A>G, c.-45G>A and c.-53G>C) and c.977C>G (Ser326Cys) in exon 7 of hOGG1 gene. A case-control study indicated that c.-23A/G heterozygote was markedly associated with diabetes (P=0.004, OR=2.648, 95%CI=1.355-5.176) and with an increased level of C-peptide (705.00 versus 545.91 pmol/L, P=0.044). Furthermore, a significantly increased risk of T2DM was observed in the subjects carrying heterozygous variant of c.-23A>G and homozygous mutation of Ser326Cys (OR=3.684, 95%CI=1.400-9.697). The promoter activity of the variant allele c.-23G decreased 30-40% in Hela and HEK293 cell lines. In conclusion, the variant c.-23A>G of hOGG1 gene could decrease the gene promoter activity and was a risk factor for T2DM., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: The present study investigated whether single nucleotide polymorphisms (SNPs) in the human urate transporter 1 (hURAT1) gene are associated with primary hyperuricaemia (HUA) in Han Chinese people., Methods: A total of 538 subjects (215 cases and 323 control subjects) were recruited from Qingdao, China. SNPs in potentially functional regions of the gene were identified and genotypes determined by direct sequencing. Association analyses were conducted using Fisher's exact test and logistic regression assuming a genotype model., Results: By sequencing the promoter, 10 exons, and the exon-intron junctions of the hURAT1 gene, 14 SNPs were identified. Two of the SNPs identified were associated with susceptibility to HUA. The first was a rare intron 3 (11 G-->A) SNP (p=0.0005), where carriers of the 'A' allele had a 3.4-fold (95% CI 1.67 to 6.93) increased risk of HUA. The second was a common exon 8 (T1309C) SNP (rs7932775), where carriers of one and two 'C' alleles had respective fold increased risks of 1.64 (95% CI 1.07 to 2.52) and 2.32 (95% CI 1.37 to 3.95). These SNPs had a joint additive effect of risk of HUA, with those individuals carrying at least one 'A' allele at the intron 3 SNP and two 'C' alleles at rs7932775 having a 5.88-fold (95% CI 1.25 to 15.57) increased risk of HUA in comparison to those with no risk alleles., Conclusion: In conjunction with other studies, our results suggest that there are multiple genetic variants within or near hURAT1 that are associated with susceptibility to HUA in Han Chinese, including a novel SNP located in intron 3.

Context: Novel type 2 diabetes mellitus (T2DM) susceptibility loci, identified through genome-wide association studies (GWAS), have been replicated in many European and Japanese populations. However, the association in other East Asian populations is less well characterized., Objective: To examine the effects of SNPs in CDKAL1, CDKN2A/B, IGF2BP2, HHEX, SLC30A8, PKN2, LOC387761, and KCNQ1 on risk of T2DM in Chinese, Malays, and Asian-Indians in Singapore., Design: We genotyped these candidate single-nucleotide polymorphisms (SNPs) in subjects from three major ethnic groups in Asia, namely, the Chinese (2196 controls and 1541 cases), Malays (2257 controls and 1076 cases), and Asian-Indians (364 controls and 246 cases). We also performed a metaanalysis of our results with published studies in East Asians., Results: In Chinese, SNPs in CDKAL1 [odds ratio (OR) = 1.19; P = 2 x 10(-4)], HHEX (OR = 1.15; P = 0.013), and KCNQ1 (OR = 1.21; P = 3 x 10(-4)) were significantly associated with T2DM. Among Malays, SNPs in CDKN2A/B (OR = 1.22; P = 3.7 x 10(-4)), HHEX (OR = 1.12; P = 0.044), SLC30A8 (OR = 1.12; P = 0.037), and KCNQ1 (OR = 1.19-1.25; P = 0.003-2.5 x 10(-4)) showed significant association with T2DM. The combined analysis of the three ethnic groups revealed significant associations between SNPs in CDKAL1 (OR = 1.13; P = 3 x 10(-4)), CDKN2A/B (OR = 1.16; P = 9 x 10(-5)), HHEX (OR = 1.14; P = 6 x 10(-4)), and KCNQ1 (OR = 1.16-1.20; P = 3 x 10(-4) to 3 x 10(-6)) with T2DM. SLC30A8 (OR = 1.06; P = 0.039) showed association only after adjustment for gender and body mass index. Metaanalysis with data from other East Asian populations showed similar effect sizes to those observed in populations of European ancestry., Conclusions: SNPs at T2DM susceptibility loci identified through GWAS in populations of European ancestry show similar effects in Asian populations. Failure to detect these effects across different populations may be due to issues of power owing to limited sample size, lower minor allele frequency, or differences in genetic effect sizes.

Several lines of evidence, including genome-wide linkage scans and postmortem brain studies of patients with schizophrenia or bipolar disorder, have suggested that DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa), a key regulatory molecule in the dopaminergic signaling pathway, is involved in these disorders. After evaluating the linkage disequilibrium pattern of the gene encoding DARPP-32 (PPP1R1B; located on 17q12), we conducted association analyses of this gene with schizophrenia and bipolar disorder. Single-marker and haplotypic analyses of four single nucleotide polymorphisms (SNPs; rs879606, rs12601930, rs907094, and rs3764352) in a sample set (subjects with schizophrenia=384, subjects with bipolar disorder=318, control subjects=384) showed that PPP1R1B polymorphisms were not significantly associated with schizophrenia, whereas, even after Bonferroni corrections, significant associations with bipolar disorder were observed for rs12601930 (corrected genotypic p=0.00059) and rs907094 (corrected allelic p=0.040). We, however, could not confirm these results in a second independent sample set (subjects with bipolar disorder=366, control subjects=370). We now believe that the significant association observed with the first sample set was a result of copy number aberrations in the region surrounding these SNPs. Our findings suggest that PPP1R1B SNPs are unlikely to be related to the development of schizophrenia and bipolar disorder in the Japanese population.

Objective: To investigate whether the common variants 45T/G and 276G/T in APM1 gene were associated with hypertension combined with obesity (HO) and related clinical features in Chinese Han population., Methods: A case-control study design was applied. Common polymorphisms of 45T/G and 276G/T were genotyped by PCR product sequencing in 484 cases with HO and 502 controls with normal blood presure and BMI < 25., Results: The genotype and allele frequencies of 45T/G, 276G/T, and haplotype defined by the two variants in cases did not differ from those in controls. The means of blood pressure, BMI and waist-hip ratio did not differ among genotypes of the two polymorphisms and haplotypes. Among lipid profiles, only serum high-density lipoprotein cholesterol (HDL-C) levels were significantly lower in T allele carriers than that in non-T carriers after adjusting possible confounding factors (1.21 vs 1.32 mmol/L, P=0.0001)., Conclusion: Polymorphisms of 45T/G and 276G/T in APM1 gene are not associated with hypertension or obesity, or their clinical features in Chinese Han population. Common polymorphism of 45T/G might be associated with serum HDL-C levels in Chinese.