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We investigated changes in blood pressure (BP) and metabolic adverse effects, especially elevation of uric acid (UA), after treatment with a thiazide-like diuretic (TD) in patients with essential hypertension. Furthermore, the role of genetic factors in the elevation of UA by TD was assessed by a 500 K SNP DNA microarray. The subjects included 126 hypertensive patients (57 women and 69 men, mean age 59 ± 12 years) who registered for the GEANE (Gene Evaluation for ANtihypertensive Effects) study. After one month of the nontreatment period, TD, indapamide, angiotensin II receptor antagonist valsartan, and Ca channel blocker amlodipine were administered to all patients for 3 months each in a randomized crossover manner. BP, renal function, serum UA level, and electrolytes were measured at baseline and at the end of each treatment period. Single nucleotide polymorphisms (SNPs) associated with UA elevation after treatment with indapamide were investigated by a genome-wide association study (GWAS). Indapamide significantly decreased both office and home BP levels. Treatment with indapamide also significantly reduced the estimated glomerular filtration rate and serum potassium and increased serum UA. Patients whose UA level increased more than 1 mg/dl showed significantly higher baseline office SBP and plasma glucose and showed greater decline in renal function compared with those who showed less UA increase (

We previously reported that single nucleotide polymorphism (SNP)-420 CG (rs1862513) in the promoter region of RETN was associated with type 2 diabetes. Plasma resistin was tightly correlated with SNP-420 genotypes. SNP-420 is a CpG-SNP affecting the sequence of cytosine-phosphate-guanine dinucleotides.To examine whether methylation at SNP-420 affects plasma resistin, we analyzed plasma resistin and methylation at RETN SNP-420.Genomic DNA was extracted from peripheral white blood cells in 2078 Japanese subjects. Quantification of the methylation was performed by pyrosequencing after DNA bisulfite conversion.Methylation at SNP-420 was highest in the C/C genotype (36.9 ± 5.7%), followed by C/G (21.4 ± 3.5%) and G/G (2.9 ± 1.4%; P0.001). When assessed in each genotype, methylation at SNP-420 was inversely associated with plasma resistin in the C/C (β = -0.134, P0.001) or C/G (β = -0.227, P0.001) genotype. In THP-1 human monocytes intrinsically having the C/C genotype, a demethylating reagent, 5-aza-dC, decreased the methylation at SNP-420 and increased RETN messenger RNA. SNP+1263 (rs3745369), located in the 3' untranslated region of RETN, was also associated with methylation at SNP-420. In addition, highly sensitive C-reactive protein was inversely associated with methylation at SNP-420 in the C/C genotype, whereas body mass index was positively associated.Plasma resistin was inversely associated with the extent of methylation at SNP-420 mainly dependent on the SNP-420 genotype. The association can also be explained partially independent of SNP-420 genotypes. SNP-420 could have dual, genetic and epigenetic effects on plasma resistin.

While alcohol consumption is known to increase plasma high-density lipoprotein (HDL) cholesterol levels, its relationship with low-density lipoprotein (LDL) cholesterol levels is unclear. Aldehyde dehydrogenase 2 (ALDH2) is a rate-controlling enzyme in alcohol metabolism, but a large number of Japanese people have the inactive allele. Here, we conducted a Mendelian randomization analysis using the ALDH2 genotype to clarify a causal role of alcohol on circulating cholesterol levels and lipoprotein particle numbers.This study was conducted in three independent general Japanese populations (men, n = 2289; women, n = 1940; mean age 63.3 ± 11.2 years). Alcohol consumption was assessed using a questionnaire. Lipoprotein particle numbers were determined by nuclear magnetic resonance spectroscopy.Alcohol consumption increased linearly in proportion to the number of subjects carrying the enzymatically active *1 allele in men (p 0.001). The *1 allele was also positively associated with HDL cholesterol level (adjusted mean ± standard error, *1*1: 60 ± 0.5, *1*2: 56 ± 0.6, *2*2: 55 ± 1.3 mg/dl, p 0.001) and inversely associated with LDL cholesterol level (116 ± 0.9, 124 ± 1.1, 130 ± 2.6 mg/dl, p 0.001). The *1 allele was also positively associated with HDL particle numbers (per-allele: 2.60 ± 0.32 μmol/l, p 0.001) and inversely associated with LDL particle numbers (-67.8 ± 19.6 nmol/l, p = 0.001). Additional Mendelian randomization analysis failed to clarify the involvement of cholesteryl ester transfer protein in alcohol-related changes in lipoprotein cholesterol levels. No significant association was observed in women, presumably due to their small amount of alcohol intake.Alcohol consumption has a causal role in not only increasing HDL cholesterol levels but also decreasing LDL cholesterol levels and particle numbers.

IntroductionNordic walking, characterized by the use of two walking poles, is becoming increasingly popular. The aim of this study was to analyze the effects produced by a 12-week Nordic walking training program on functional abilities and metabolic profiles, specifically walk distance and insulin resistance, among elderly women.MethodsThe present study included 74 women (68 ± 7 years). The Nordic walking training program of 120 minutes per week was performed for 12 weeks. Before and at the end of the 12-week intervention, 6-minute walking distance (6MWD) and the homeostasis of the model assessment of insulin resistance (HOMA-IR) were measured.Results and conclusionsAfter the 12-week Nordic walking training program, 6MWD increased significantly (p

Background Sarcopenic obesity, age-related muscle loss, which is compensated by an increase in fat mass, impairs quality of life in elderly people. Although the increase in intramuscular fat is associated with decreased insulin sensitivity and increased metabolic risk factors, the origin of diabetes-associated intramuscular fat has not been elucidated. Here, we investigated intramuscular fat deposition using a muscle injury model in type 2 diabetic mice. Methods Male 8-week-old C57BL/6 and 8-week-old and 26-week-old KKAy underwent intramuscular injection of cardiotoxin (Ctx) (100 μL/10 μM) into the tibialis anterior (TA) muscles. After 2 weeks, the muscles were removed and evaluated. Results KKAy exhibited impaired muscle regeneration and ectopic fat deposition. Such impairment was more marked in older KKAy. These changes were also observed in another diabetic mouse model, db/db and diet-induced obese mice but not in streptozocin-induced diabetic mice. Deposited fat was platelet-derived growth factor (PDGF) receptor alpha positive and its cytoskeleton was stained with Masson's trichrome, indicating it to be of fibro-adipocyte progenitor cell origin. Expression of a myogenic marker, myoD, was lower and that of PDGF receptor alpha and CCAAT/enhancer binding protein (CEBP) alpha was higher in Ctx-injured TA of KKAy compared with that of C57BL/6. Peroxisome proliferator-activated receptor γ (PPARγ) was highly expressed in fat-forming lesions in older KKAy. Treatment with all-trans retinoic acid prevented the formation of intramuscular fat; however, treatment with GW9662, a PPARγ antagonist, increased the fibrotic change in muscle. Conclusions Diabetic mice showed impaired muscle regeneration with fat deposition, suggesting that diabetes may enhance sarcopenic obesity through a mechanism involving anomalous fibro-adipocyte progenitor cell differentiation.

Background/purpose Perceived age may be a better predictor of mortality rate than chronological age. We have demonstrated that perceived age was a significant biomarker for carotid atherosclerosis in Japanese. However, it remains to be determined which skin parameter is associated with atherosclerosis. The purpose of this study is to analyze the relationship between 10 facial skin-aging parameters and atherosclerosis in 169 middle-aged to elderly Japanese women who participated. Methods Facial photographs were taken under a shadowless lamp from three directions using a high-resolution digital camera. The digital images of each subject were analyzed using computer software and various parameters of skin aging such as pigmentation, wrinkles, and skin color were quantified. Carotid intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) were measured as indices for atherosclerosis. Results Facial pigmentation showed a significant correlation with carotid IMT, even after correction for age (r = 0.13, P = 0.03), and with visceral fat area. Stepwise regression analysis indicated that facial pigmentation was associated with carotid IMT via visceral fat area. Conclusion Facial pigmentation may be a useful biomarker for carotid atherosclerosis in Japanese women.

No long-term exercise training regimen with high adherence and effectiveness in middle-aged and older people is broadly available in the field. We assessed the adherence to, and effects of, our long-term training program comprising an interval walking training (IWT) and an information technology network system and the factors affecting adherence. Middle-aged and older men and women [ n = 696, aged 65 ± 7(SD) yr] underwent IWT. The subjects were instructed to repeat five or more sets of fast and slow walking for 3 min each at ≥70 and 40% peak aerobic capacity for walking (V̇o2peak), respectively, per day ≥4 days/wk for 22 mo. Adherence was assessed as training days accomplished relative to the target of 4 days/wk over 22 mo. The effects on the V̇o2peak and lifestyle-related disease score were evaluated every 6 mo. The independent factors affecting adherence were assessed by multiple-regression analysis after adjustment for baseline physical characteristics and other possible covariates, including vasopressin V1a receptor polymorphisms. The adherence over 22 mo averaged 70% and was highly correlated with a 13% reduction in the lifestyle-related disease score ( R2 = 0.94, P = 0.006) and with a 12% increase in V̇o2peak ( R2 = 0.94, P = 0.006). The major determinant of higher adherence was lower baseline body mass index (BMI) ( P < 0.0001) and male sex ( P < 0.0001). For men, in addition to BMI, nonsmokers ( P = 0.031) and V1a receptor polymorphisms ( P = 0.033) were independent determinants of higher adherence. Thus the long-term IWT program is an effective regimen. Moreover, baseline BMI and sex for all subjects, and smoking and V1a receptor polymorphisms for men, were associated with adherence.

We recently reported that thigh muscle sarcopenia measured by computed tomography is related to arterial stiffness, pressure wave reflection, and central pulse pressure (PP). However, it remains to be determined whether more straightforward and simple techniques such as hand grip strength and the bio-impedance method are also useful for the clinical evaluation of sarcopenia.A total of 1593 middle-aged to older patients participated in this cross-sectional study. Brachial-to-ankle pulse wave velocity (baPWV) was measured as an index of arterial stiffness. Second PP (PP2) at the second peak of radial SBP was used to estimate central PP. Radial augmentation index was calculated as PP2/PP. Thigh muscle cross-sectional area and abdominal visceral fat area were quantified by computed tomography. Patients were classified as sarcopenic if their hand grip strength or skeletal muscle mass (measured by bioelectrical impedance) was more than 1 SD lower than the mean of those in a reference group aged below 50 years, or in the lowest 20% of the studied population. Visceral obesity was defined as visceral fat area greater than 100 cm.Antidyslipidemia drug and antidiabetic drug were significantly associated with lower hand grip strength. Both sarcopenic indices were significantly and independently associated with baPWV, radial augmentation index, and PP2. Sarcopenia defined by either criterion was significantly associated with higher baPWV, radial augmentation index, and PP2. Visceral obesity was significantly associated only with baPWV.These findings indicate the clinical usefulness of noninvasive methods for assessment of sarcopenia, which is a risk factor for cardiovascular disease.

The subjects comprised 230 men aged 77 ± 10 (range: 50–100) years and 279 women aged 81 ± 10 (50–101) years that visited the medical department. We examined the relationship between increased serum bilirubin and renal function evaluated by estimated glomerular filtration rate (eGFR) using CKD-EPI equations modified by a Japanese coefficient. Compared with the fourth quartile in serum bilirubin (1.01–1.97 mg/dL), the nonadjusted, age and gender-adjusted, and multivariate-adjusted odds ratios{95% confidence interval (CI)}of eGFR 2for the first quartile in serum bilirubin (0.13–0.50 mg/dL) were 2.08 (1.25–3.44), 1.82 (1.07–3.09), and 1.53 (0.83–2.81), respectively. Moreover, compared with the fourth quartile, nonadjusted, age and gender-adjusted, and multivariate-adjusted odds ratios (95% CI) of eGFR 2for the first quartile were 3.50 (1.95–6.23), 3.12 (1.72–5.65), and 3.53 (1.71–7.26), respectively. The data were further stratified by gender, age, medication (antihypertensive, antidyslipidemic, and antidiabetic agents), and prevalence of cardiovascular disease (CVD). The standardized coefficients for eGFR were significant in all the subgroups other than the prevalence of CVD, and there were significant interactions between the two groups regarding CVD. Our data demonstrated an independent positive association between serum bilirubin and eGFR among diabetic patients.

Background and Purpose— Arterial stiffness, a risk factor of brain small vessel diseases (SVD), causes hemodynamic changes. Mechanical stresses, circumferential wall tension (WT), and shear stress (SS) may change with arterial stiffness and be related to SVD. We investigated the associations between mechanical stresses and arterial stiffness and SVD. Methods— A total of 1296 subjects without apparent cardiovascular diseases were recruited. Brachial-to-ankle pulse wave velocity (baPWV) was measured as an arterial stiffness index. Silent lacunar infarction and deep subcortical white matter hyperintensity were evaluated as SVD indices. Circumferential WT and SS at peak systole and end diastole were measured at the common carotid artery. Second peak of systolic blood pressure was obtained from the radial waveform and used as a central systolic blood pressure substitute. Results— baPWV was associated positively with WT ( P P =0.0007) even after correction for confounding parameters including baPWV. SVD was associated with significantly higher WT ( P P P =0.0017) and end diastolic WT (odds ratio, 1.60; P =0.0038) were related to presence of silent lacunar infarction, whereas peak systolic (odds ratio, 0.95; P =0.014) and end diastolic SS (odds ratio, 0.94; P =0.014) were associated with presence of deep subcortical white matter hyperintensity grade >3. Regression lines between blood pressure and WT were significantly steeper in subjects with SVD than without SVD (β=0.02; P Conclusions— These findings indicate that SVD is phenotype-specifically associated with alterations in WT and SS independently of arterial stiffness.

Objective Osteoporosis and atherosclerosis are the two most common diseases in postmenopausal women. In most cases, they are simultaneously present in the same individual and commonly lead to bone fracture or cardiovascular disease (CVD). Bisphosphonates (BPs) are frequently used in the treatment of osteoporosis and have the ability to increase lumbar spine bone mineral density (L-BMD). BPs may also protect against CVD. A single monthly 50-mg dose of minodronate (monthly minodronate) is now common practice and is highly anticipated to reduce the incidence of both bone fracture and CVD. A useful approach to independently predicting CVD is brachial-ankle pulse wave velocity (baPWV). Here, we directly compared the effects of monthly minodronate with those of a standard single weekly 35-mg dose of alendronate (weekly alendronate) on L-BMD and baPWV in postmenopausal women with osteoporosis across a 12-month period. Methods Thirty-eight postmenopausal women with osteoporosis were randomized into two treatment groups (group 1, weekly alendronate, n = 19; group 2, monthly minodronate, n = 19). L-BMD and baPWV were assessed at baseline and 12-month follow-up. Results At the end of the 12-month period, increases in L-BMD were similar between group 1 (7.6%) and group 2 (8.5%), but baPWV was significantly reduced in group 2 compared with group 1. The change in baPWV during the study period showed a significant negative correlation with the change in L-BMD. Conclusions Changes in L-BMD in the monthly minodronate and weekly alendronate groups are generally comparable. Good control of changes in L-BMD in the postmenopausal phase might be associated with regression of CVD. Monthly minodronate is a promising new BP and potential first-line drug for the treatment of osteoporosis in postmenopausal women.

Objective The relationship between plasma levels of adiponectin and cardiovascular events is inconclusive. We evaluated the clinical characteristics of people with high plasma adiponectin and high plasma leptin levels. Methods Thousand seven hundred participants recruited from visitors to the Anti-Aging Doc were divided into four groups by combining the bipartiles of plasma adiponectin and leptin levels in men and women separately: AL, high adiponectin and high leptin; Al, high adiponectin and low leptin; al, low adiponectin and low leptin; aL, low adiponectin and high leptin. Body composition, including visceral fat area and thigh muscle cross-sectional area (CSA), brachial-ankle pulse wave velocity (baPWV), periventricular hyperintensity, and urinary albumin excretion, were determined. Results Twenty percent of the studied population fell within the AL group. This group had a significantly higher visceral fat area than the Al group. Thigh muscle CSA was lowest in the AL group among groups. baPWV, brain white matter lesions, and albuminuria findings in the AL group were significantly higher than those of the Al group. Multiple and logistic regression analyses with confounding parameters further confirmed that plasma adiponectin was not an independent determinant for brain and renal small vessel-related disease. Conclusion These findings suggest that the plasma level of adiponectin alone is not enough for the risk stratification of cardiovascular disease. Leptin resistance associated with skeletal muscle loss in addition to obesity may need to be addressed to identify high risk people with high plasma adiponectin levels.

The electrocardiogram has several advantages in detecting cardiac arrhythmia-it is readily available, noninvasive and cost-efficient. Recent genome-wide association studies have identified single-nucleotide polymorphisms that are associated with electrocardiogram measures. We performed a genome-wide association study using Korea Association Resource data for the discovery phase (Phase 1, n = 6805) and two consecutive replication studies in Japanese populations (Phase 2, n = 2285; Phase 3, n = 5010) for QRS duration and PR interval. Three novel loci were identified: rs2483280 (PRDM16 locus) and rs335206 (PRDM6 locus) were associated with QRS duration, and rs17026156 (SLC8A1 locus) correlated with PR interval. PRDM16 was recently identified as a causative gene of left ventricular non-compaction and dilated cardiomyopathy in 1p36 deletion syndrome, which is characterized by heart failure, arrhythmia and sudden cardiac death. Thus, our finding that a PRDM16 SNP is linked to QRS duration strongly implicates PRDM16 in cardiac function. In addition, C allele of rs17026156 increases PR interval (beta ± SE, 2.39 ± 0.40 ms) and exists far more frequently in East Asians (0.46) than in Europeans and Africans (0.05 and 0.08, respectively).

In the 'Millennium Genome Project', we identified ATP2B1 as a gene responsible for hypertension through single-nucleotide polymorphism analysis. The ATP2B1 gene encodes the plasma membrane calcium ATPase isoform 1, which contributes to the maintenance of intracellular calcium homeostasis by removing calcium ions.Since ATP2B1 knockout mice are reported to be embryo-lethal, we generated systemic heterozygous ATP2B1 null (ATP2B1(+/-)) mice, and evaluated the implication of ATP2B1 in blood pressure.ATP2B1(+/-) mice revealed significantly higher SBP as measured by a radiotelemetric method. Phenylephrine-induced vasoconstriction was significantly increased in vascular rings from ATP2B1(+/-) mice, and the difference in this contraction disappeared in the presence of a nitric oxide synthase (NOS) inhibitor. Vasorelaxation to acetylcholine was significantly attenuated in vascular rings from ATP2B1(+/-) mice. In addition, cultured endothelial cells of ATP2B1(+/-) mice showed that the phosphorylation (Ser-1177) level of endothelial NOS protein was significantly lower, and nitric oxide production in endothelial cells and aorta was lower compared with those in control mice. In contrast, neural NOS expression in vascular smooth muscle cells from ATP2B1(+/-) mice and control mice were not significantly different.These results suggest that decreased ATP2B1 gene expression is associated with impaired endothelial NOS activity and nitric oxide production, and the ATP2B1 gene plays a crucial role in the regulation of blood pressure.

Central blood pressure (BP) has been shown to strongly associate with cardiovascular disease and outcome. Recent studies have demonstrated a relationship between changes in body size by exercise training and peripheral BP; however, the effect on changes in central BP is unknown. The aim of this study was to assess whether changes in body size are independently related to changes in central BP in the elderly. The subjects were 11 men (mean age, 68±6 years) and 84 women (68±7 years) from a rural village. Before and at the end of the 12-week training program, metabolic variables, and first peak radial systolic BP (SBP1) and second peak radial SBP (SBP2) as estimates of central SBP, were obtained. Radial augmentation index (AI) was calculated as follows: ((SBP2-diastolic BP (DBP))/(SBP1-DBP)) × 100 (%) and we used AI corrected at heart rate 75 per min (AI@75). After the 12-week training program, weight loss correlated strongly with reduction in brachial mean arterial pressure (MAP), radial SBP1, SBP2 and AI@75. After adjusting for confounding factors, weight loss was significantly and independently associated with each reduction in brachial MAP (β=0.34, P=0.001), radial SBP1 (β=0.31, P=0.002), SBP2 (β=0.37, P

Glycated hemoglobin A1c(HbA1c) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes. To discover novel loci harboring common variants associated with HbA1cin East Asians, we conducted a meta-analysis of 13 genome-wide association studies (GWAS; N = 21,026). We replicated our findings in three additional studies comprising 11,576 individuals of East Asian ancestry. Ten variants showed associations that reached genome-wide significance in the discovery data set, of which nine (four novel variants at TMEM79 [ P value = 1.3 × 10-23], HBS1L/MYB [8.5 × 10-15], MYO9B [9.0 × 10-12], and CYBA [1.1 × 10-8] as well as five variants at loci that had been previously identified [CDKAL1, G6PC2/ ABCB11, GCK, ANK1, and FN3KI]) showed consistent evidence of association in replication data sets. These variants explained 1.76% of the variance in HbA1c. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Among individuals with nondiabetic levels of fasting glucose (

[Objective]: Increasing blood pressure (BP) variability is reported to be a cardiovascular risk factor. However, the clinical implications of postprandial hypotension (PHYPO), a commonly observed BP variability in elderly persons, are poorly understood. Here, we investigated the possible associations between postprandial BP decline and asymptomatic cerebral damage in community residents. [Methods]: Study participants consisted of 1308 general community residents (65 ± 9 years old). Postprandial BP change was calculated from SBP measured just before and 30 min after lunch. PHYPO was defined as a decline in SBP of more than 20 mmHg. The presence of asymptomatic cerebrovascular damage was evaluated by brain MRI. [Results]: Prevalence of lacunar infarction was significantly higher in participants with PHYPO (P = 0.004). A postprandial decline in SBP was linearly increased with the number of lacunar lesions (none, n = 1200, −3.4± 11.3 mmHg; one lesion, n = 82, −5.2 ± 11.8; two lesions, n = 18, −6.9 ± 11.5; three lesions, n = 7, −13.4 ± 11.3; and four lesions, n = 1, −27; P = 0.012). Although participants with PHYPO were older (P

Variants in the CDH13 gene have been identified as determinants of blood levels of adiponectin, an insulin-sensitizing adipokine. However, their association with other metabolic risk factors remains unclear. We examined variants at CDH13 in relation to total and high-molecular-weight (HMW) adiponectin using data from a genome-wide association study performed in 2,434 Singaporean Chinese with replication in up to 3,290 Japanese and 1,610 Koreans. The top signal rs4783244 in CDH13 showed strong associations with total adiponectin (standardized β [β] = −0.34, 95% CI −0.38 to −0.30, P = 2.0 × 10−70), HMW adiponectin (β = −0.40, 95% CI −0.43 to −0.36, P = 1.1 × 10−117), and the HMW-to-total adiponectin ratio (β = −0.44, 95% CI −0.49 to −0.40, P = 3.2 × 10−83). In the replication study, this single nucleotide polymorphism explained 4.1% of total and 6.5% of HMW adiponectin levels. No association was observed between rs4783244 and metabolic traits associated with insulin resistance before adjustment for HMW adiponectin levels. After adjustment for HMW adiponectin levels, the minor allele was associated with lower BMI (β = −0.15, 95% CI −0.19 to −0.11, P = 3.5 × 10−14), homeostasis model assessment-insulin resistance index (β = −0.16, 95% CI −0.20 to −0.12, P = 9.2 × 10−16), and triglycerides (β = −0.16, 95% CI −0.19 to −0.12, P = 1.3 × 10−16) and with higher HDL (β = 0.16, 95% CI 0.12 to 0.19, P = 2.1 × 10−17). CDH13 variants strongly influence plasma total and HMW adiponectin levels in East Asian populations but appear to alter adiponectin sensitivity, resulting in better metabolic health than expected based on circulating adiponectin levels.

Background: Patients with mild-to-moderate essential hypertension in the HOMED-BP trial were randomly allocated to first-line treatment with a calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB). Methods: We recruited 265 (93 for CCB, 71 for ACEI and 101 for ARB) patients who completed the genomic study. Home blood pressure was measured for 5 days off-treatment before randomization and for 5 days after 2-4 weeks of randomized drug treatment. Genotyping was performed by 500K DNA microarray chips. The blood pressure responses to the three drugs were analyzed separately as a quantitative trait. For replication of SNPs with p < 10(-4), we used the multicenter GEANE study, in which patients were randomized to valsartan or amlodipine. Results: SNPs in PICALM, TANC2, NUMA1 and APCDD1 were found to be associated with CCB responses and those in ABCC9 and YIPF1 were found to be associated with ARB response with replication. Conclusion: Our approach, the first based on high-fidelity phenotyping by home blood pressure measurement, might be a step in moving towards the personalized treatment of hypertension. Original submitted 29 April 2013; Revision submitted 14 August 2013. ispartof: Pharmacogenomics vol:14 issue:14 pages:1709-21 ispartof: location:England status: published

There are few data available on the association between serum uric acid (SUA) levels and blood pressure (BP) categories earlier in the disease continuum, when efforts for its prevention may be applicable. We performed a cross-sectional study to examine the association between SUA and prehypertension in a community-dwelling sample of Japanese adults. Study participants without hypertension aged 19 to 90 years [567 men aged 56 ± 15 (mean ± standard deviation) years and 808 women aged 58 ± 13 years] were recruited for a survey at the community based annual medical check-up. The main outcome was the presence of prehypertension [systolic BP (SBP) 120-139 mmHg and/or diastolic BP (DBP) 80-89 mmHg]. After adjustments by gender and age, both SBP (p

Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P = 3.0 × 10(-14)) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P = 1.2 × 10(-7)). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P = 6.8 × 10(-165)), ADIPOQ (P = 1.8 × 10(-22)), PEPD (P = 3.6 × 10(-12)), CMIP (P = 2.1 × 10(-10)), ZNF664 (P = 2.3 × 10(-7)) and GPR109A (P = 7.4 × 10(-6)). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (Pinitial = 0.020; Pconditional = 7.0 × 10(-7)). We further confirmed the independence of two pairs of closely located loci (

Impaired fasting glucose (IFG) in diabetes is a risk factor for arterial stiffness and cardiovascular disease (CVD), but the impact of a slightly high-normal glucose level remains controversial. We investigated whether slightly high-normal fasting plasma glucose (FPG) was independently associated with arterial stiffness in non-diabetic community-dwelling persons. We recruited 114 men aged 69 ± 9 years (range 40–89) and 208 women aged 68 ± 7 years (range 36–84) during their annual health examination in a single community. Arterial stiffness was evaluated by the mean of the right and left brachial–ankle pulse wave velocity (ba-PWV). Age-adjusted ba-PWV increased significantly from the lowest to the highest FPG group ( p < 0.001). Multiple linear regression analyses for ba-PWV revealed that FPG levels (β=0.154, p < 0.001) were independently and significantly associated with ba-PWV. The multivariate-adjusted ba-PWV value of the high-normal glucose group (Group 3: 95–100 mg/dL) was significantly higher than that of the lowest normal glucose group (Group 1: 52–89 mg/dL) ( p=0.021), and the ba-PWV value in the IFG group (Group 4: 101–125 mg/dL) was significantly higher than those of the normal glucose groups (Group 1

Metabolic syndrome (MetS) is associated with an increased risk of major cardiovascular events. In women, increased uric acid (UA) levels are associated with MetS and its components. High-sensitivity C-reactive protein (hsCRP) levels are also associated with MetS, and hsCRP levels could be modulated by UA. We investigated whether combining UA and hsCRP levels are independently associated with MetS and insulin resistance in Japanese community-dwelling women. From a single community, we recruited 1,097 women (63 ± 12 years) during their annual health examination, and examined the cross-sectional relationship between UA, hsCRP, and MetS and insulin resistance, which was evaluated by homeostasis of minimal assessment of insulin resistance. Of these subjects, 218 women (19.9 %) had MetS. Multiple linear regression analysis was performed to evaluate the contribution of each confounding factor for MetS and insulin resistance, both UA and hsCRP as well as age and alcohol consumption, were independently and significantly associated with MetS and insulin resistance. The adjusted-odds ratios (95 % confidence interval) for MetS across tertiles of UA and hsCRP were 1.00, 1.45 (0.95–2.22), and 2.61 (1.74–3.93), and 1.00, 1.80 (1.18–2.74), and 3.23 (2.15–4.85), respectively. In addition, the combination increased UA, and hsCRP was also a significant and independent determinant for MetS and insulin resistance. In direction associations, we also observed a synergistic effect between these two molecules (F = 2.76, P = 0.027). These results suggested that combined assessment of UA and hsCRP levels provides incremental information for risk stratification of patients with MetS, independent of other confounding factors in community-dwelling women.

Serum uric acid (SUA) levels are strongly correlated with aging, gender, renal function, obesity, and metabolic abnormality; however, whether SUA has a causative role in elevated blood pressure (BP) is still a matter of debate. From a single community, we recruited 1177 eligible women (mean age, 61±13 years) during their annual health examination. All subjects were divided into two groups according to their age (participants aged ≥55 years and those aged

Resistin is an adipokine secreted from adipocytes in mice. We previously reported that a single nucleotide polymorphism (SNP) –420 (rs1862513) in the human resistin gene (RETN), is correlated with plasma resistin. Decorin is a multifunctional proteoglycan, and its isoform, lacking 14 amino acids from the N terminal region of mature core decorin, recently was identified as a resistin receptor in mice. To examine whether SNPs in the vicinity of the human decorin gene (DCN) are associated with plasma resistin, we cross-sectionally analyzed six tag SNPs selected around DCN in the same linkage disequilibrium block in 2,078 community-dwelling Japanese subjects. Plasma resistin was associated with the rs7139228, rs7956537, rs516115, and rs3138167 genotypes in DCN. A multiple regression analysis revealed that the genotype of rs7308752 (G/G) or rs516115 (C/C) was associated with decreased plasma resistin after adjusted for age, sex, BMI, and the RETN SNP rs1862513. The effect of rs7139228 and rs1862513 seemed to be additive without synergistic interaction. Therefore, plasma resistin was associated with some tag SNPs around DCN in the general Japanese population. The possibility that human decorin is a human resistin receptor should be pursued.

BACKGROUND: Elevated hematocrit levels have been suggested to be an independent determinant of insulin resistance and type 2 diabetes. To clarify the diagnostic significance of hematocrit level, we investigated the association with hemodynamic profiles, insulin resistance and insulin sensitivity, arterial properties, and asymptomatic cerebrovascular damage in a general Japanese population. METHODS: This study included 1, 978 participants from two independent cohorts. Insulin sensitivity was assessed by the oral 75 g glucose tolerance test. Carotid ultrasonography was performed to evaluate atherosclerosis and wall shear stress. Periventricular hyperintensity and lacunar infarction were assessed by brain magnetic resonance imaging. RESULTS: Hematocrit quartile showed a stepwise association with insulin sensitivity (Q1: 2.2 ± 0.7, Q2: 2.0 ± 0.7, Q3: 1.9 ± 0.7, Q4: 1.8 ± 0.6, p < 0.001) and insulin resistance (1.0 ± 0.6, 1.2 ± 0.7, 1.3 ± 0.8, 1.5 ± 1.0, p < 0.001). Multiple linear regression analysis adjusted for possible covariates identified hematocrit as an independent determinant of insulin sensitivity (β = −0.074, p = 0.019) and insulin resistance (β = 0.115, p < 0.001). However, this association was lost after further adjustment for visceral fat area and plasma alanine aminotransferase level. Further, no significant association was observed between hematocrit and carotid intima-media thickness (p = 0.306) where as wall shear stress was inversely associated with the carotid atherosclerosis (r = −0.250, p < 0.001). In contrast, a low hematocrit level was independently associated with periventricular hyperintensity (odds ratio 0.87 (95% CI 0.80–0.95), p = 0.001). CONCLUSION: Hematocrit was positively associated with insulin resistance and insulin sensitivity. This association was epiphenomenon of visceral and hepatic adiposity. Conversely, low hematocrit was a significant risk factor for periventricular hyperintensity independent of insulin resistance.

OBJECTIVE Loss of the nocturnal blood pressure (BP) drop is a risk factor for cardiovascular outcomes. However, clinical parameters that predispose to changes in nocturnal BP are currently uncertain. Given the possible involvement of salt sensitivity in nocturnal BP levels, we investigated a hypothesized association between plasma B-type natriuretic peptide (BNP) levels - a marker of body fluid retention - and nocturnal BP in a general population. METHODS Study participants were 1020 general individuals. Participants were divided into four groups (riser, nondipper, dipper, and extreme dipper) by their percentage changes in nocturnal SBP measured using an ambulatory BP monitor. RESULTS Plasma BNP levels were positively associated with circadian BP change (β = 0.162, P

Resistin is a cytokine inducing insulin resistance in mice. We previously identified single nucleotide polymorphisms (SNPs) at −420 (rs1862513) and −358 (rs3219175) located in the human resistin gene ( RETN) promoter as strong determinants for circulating resistin in the Japanese population. The objective was to identify additional functional variants for circulating resistin. We conducted a genome-wide association study in 448 Japanese subjects. A peak association signal was found on chromosome 19 where RETN is located. The top-hit SNP was SNP −358 G>A, followed by rs1423096 C>T, SNP −420 C>G, and rs10401670 C>T ( P = 5.39×10−47, 1.81×10−22, 2.09×10−16, and 9.25×10−15, respectively). Meta-analysis including another two independent general Japanese populations showed that circulating resistin was most strongly associated with SNP-358, followed by SNP-420, rs1423096, and rs10401670. Rs1423096 and rs10401670 were located in the 3′-region of RETN and were in strong linkage disequilibrium. Although these SNPs were also in linkage disequilibrium with the promoter SNPs, conditional and haplotype association analyses identified rs1423096 and rs10401670 as independent determinants for circulating resistin. Functionally, nuclear proteins specifically recognized T but not C at rs10401670 as evidenced by an electrophoretic mobility shift assay. The promoter activity of a luciferase reporter with T at either rs1423096 or rs10401670 was lower than that with C in THP-1 human monocytes. Therefore, rs1423096 and rs10401670, in addition to SNP-420 and SNP-358, were identified as possible functional variants affecting circulating resistin by the genome-wide search in the Japanese population.

Several large-scale studies have shed light on the primary preventive efficacy of statins against atherosclerotic diseases in the course of treatment of dyslipidemia. However, this efficacy in the management of dyslipidemia in relatively low-risk patients, particularly in women, has not been clarified. Here, we investigated the efficacy of dyslipidemia treatment with a statin on three indices that are widely used to assess atherosclerosis in postmenopausal women: carotid intima-media thickness (CIMT), arterial stiffness index β of the common carotid artery (carotid stiffness β), and brachial artery pulse wave velocity (baPWV).The study enrolled 51 postmenopausal women aged 55 years or older with dyslipidemia. The participants were randomly divided into two treatment groups and received a single daily administration of 2.5 mg of rosuvastatin or no statin therapy as control.At baseline, the groups did not significantly differ with regard to the three indices. At the third and 12th months of treatment, both carotid stiffness β and baPWV values were significantly lower than those of the control group. As for CIMT, the value was significantly lower in the statin group than in the control group at 12 months of treatment. These changes were in conjunction with a significant decrease in low-density lipoprotein cholesterol. Interestingly, changes in CIMT during the 12-month period were significantly correlated with changes in high-sensitivity C-reactive protein during the 3-month period independently of lipid profile.The potent statin improves baPWV and carotid stiffness β, in addition to CIMT (surrogate markers of coronary artery disease), in postmenopausal women with low-risk dyslipidemia. Further studies to clarify the common mechanisms underlying the link between cholesterol-lowering therapy and atherosclerosis in postmenopausal women are required.

Accumulation of visceral fat increases cardiovascular mortality in industrialized societies. However, during the evolution of the modern human, visceral fat may have acted as energy storage facility to survive in times of famine. Therefore, past natural selection might contribute to shaping the variation of visceral fat accumulation in present populations. Here, we report that the gene encoding tribbles homolog 2 (TRIB2) influenced visceral fat accumulation and was operated by recent positive natural selection in East Asians. Our candidate gene association analysis on 11 metabolic traits of 5,810 East Asians revealed that rs1057001, a T/A transversion polymorphism in 3'untranslated region (UTR) of TRIB2, was strongly associated with visceral fat area (VFA) and waist circumference adjusted for body mass index (P = 2.7 × 10(-6) and P = 9.0 × 10(-6), respectively). rs1057001 was in absolute linkage disequilibrium with a conserved insertion-deletion polymorphism in the 3'UTR and was associated with allelic imbalance of TRIB2 transcript levels in adipose tissues. rs1057001 showed high degree of interpopulation variation of the allele frequency; the low-VFA-associated A allele was found with high frequencies in East Asians. Haplotypes containing the rs1057001 A allele exhibited a signature of a selective sweep, which may have occurred 16,546-27,827 years ago in East Asians. Given the predominance of the thrifty gene hypothesis, it is surprising that the apparently non-thrifty allele was selectively favored in the evolution of modern humans. Environmental/physiological factors other than famine would be needed to explain the non-neutral evolution of TRIB2 in East Asians.

The role of resistin in the pathophysiology of insulin resistance in human is controversial and different in men and women. Thus, the discrepancy among previous reports may be resolved by gender-specific analysis of a large number of participants.From a single community, we recruited 746 men (mean age, 60±14 years) and 1033 women (63±12 years) during their annual health examination. We investigated whether plasma resistin levels are associated with insulin resistance evaluated by homeostasis of model assessment of insulin resistance (HOMA-IR) according to gender.Resistin levels were significantly correlated with HOMA-IR in men, but not in women. Analysis of covariance showed that two regression lines were significantly different (F=9.941, P=0.002). Multiple linear regression analyses for resistin showed that the resistin levels (β=0.124, P0.001) were independently and significantly associated with HOMA-IR as well as body mass index (BMI), alcohol consumption, smoking status, uric acid, γ-glutamyltransferase (GGT), and high molecular weight (HMW) adiponectin only in men and not in women. The interaction between gender and resistin level (F=11.50, P0.001) was also a significant and independent determinant for HOMA-IR as well as gender, BMI, alcohol consumption, smoking status, uric acid, GGT, HMW adiponectin, and resistin.These results suggest that plasma resistin levels are associated with insulin resistance in older Japanese men.

Background: HMG-CoA-reductase (statin) therapy to reduce low-density lipoprotein cholesterol (LDL-C) levels in patients with coronary heart disease can substantially improve outcomes; however, the benefits of statins in stroke patients, particularly for secondary stroke prevention, remain poorly under stood. Moreover, the degree of decrease in LDL-C that is required to prevent the recurrence of stroke is unknown. Objective: To determine whether the on-treatment LDL-C/high-density lipoprotein cholesterol ratio (LDL-C/HDL-C) is a predictive marker of stroke recurrence in patients with acute ischaemic stroke, and whether medical management of the LDL-C/HDL-C ratio would be of strategic significance for stroke prevention. Methods: A total of 137 dyslipidaemic patients who had suffered acute ischaemic stroke were enrolled and treated with rosuvastatin 2.5 mg within 24 hours of onset. Blood pressure and serum lipids were assessed at baseline and after 1 month of treatment with rosuvastatin. Fatal and non-fatal stroke events were recorded during a follow-up period of 36 months. We used univariate and multivariate analyses, as well as Kaplan-Meier analysis, to assess the predictive value of various parameters and to identify factors independently associated with stroke recurrence. Results: During a mean follow-up of 34.9 ± 0.8 months, there were ten cases of stroke recurrence. Age, chronic kidney disease (CKD) at baseline, and an on-treatment LDL-C/HDL-C ratio >2 after 1 month of rosuvastatin treatment were predictors of stroke recurrence in univariate analyses. Stepwise regression analysis showed that CKD (standardized adjusted odds ratio [OR] 6.55; 95% confidence interval [CI] 1.12, 36.43; p = 0.030) and on-treatment LDL-C/HDL-C ratio >2 (standardized adjusted OR 9.70; 95% CI 1.70, 55.33; p = 0.011) were independent risk factors for stroke recurrence. Post hoc analysis indicated that more intensive lipid control, to an LDL-C/HDL-C ratio ≤1.5, may reduce the risk of stroke recurrence. Conclusion: These results suggest that the use of statin therapy to achieve an on-treatment LDL-C/HDL-C ratio ≤2 is a suitable treatment strategy in patients having suffered acute ischaemic stroke. Further studies are required to confirm the clinical benefits of reducing the on-treatment LDL-C/HDL-C ratio to ≤1.5.

Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins (α, β, γ) that share identical localization and function to the amyloid-β protein precursor (AβPP) in the brain. Alcs are proteolyzed in neurons through successive cleavages via secretases, resulting in non-aggregative p3-Alc, where p3 corresponds to the AβPP-fragment. We found p3-Alcα detected in human plasma reflected the pathological process of amyloid-β accumulation in Alzheimer's disease (AD) patients and therefore investigated the utility of p3-Alcα as a plasma biomarker in AD. We measured p3-Alcα plasma levels in 83 sporadic-AD, 18 mild cognitive impaired (MCI), and 24 control subjects using the sandwich-ELISA system. Pooled samples with previously published data (171 AD and 45 controls) were also analyzed. The plasma p3-Alcα concentrations in patients with AD and MCI were significantly higher compared with control subjects (224.7 ± 40.4, 223.3 ± 53.9, and 189.1 ± 32.9 pg/ml, respectively; p = 0.0012). In AD patients, the plasma p3-Alcα concentration significantly correlated with age (r = 0.23, p = 0.037) and serum creatinine levels (r = 0.23, p = 0.0012). Even after adjusting for confounding factors of age, gender, renal function, and ApoE-ε4, high plasma p3-Alcα levels were correlated with significant AD risk, with an odds ratio 1.47 (95% confidence interval: 1.18-1.93, p = 0.0019) for every 10 pg/ml increase. Pooled analysis further confirmed these findings. Increased plasma p3-Alcα, evident in the early stages of cognitive impairment, suggests that Alc metabolites are useful plasma biomarkers of AD.

Aim: Werner syndrome (WS) is an autosomal recessive disorder of progeroid symptoms and signs. It is caused by mutations in the WRN gene, which encodes a RecQ DNA helicase. The aim of this study was to revise the diagnostic criteria for Japanese Werner syndrome. Methods: A nationwide epidemiological study was carried out from 2009 to 2011, involving 6921 surveys sent to hospitals with more than 200 beds to assess existing WS diagnostic criteria, as well as additional signs of high incidence on the basis of clinical experience with WS. Results: The existing diagnostic criteria were reviewed, and signs with >90% incidence were listed as cardinal signs. Several criteria were added, including genetic testing and calcification of the Achilles tendon, whereas criteria that are practically difficult to obtain, such as measurement of urinary hyaluronic acid, were omitted. Conclusion: The 26-year-old diagnostic criteria for WS were revised on the basis of the results of a nationwide epidemiological study. The proposed revised criteria will facilitate simpler, faster and more robust diagnosis of WS in the Japanese population. Geriatr Gerontol Int 2013; 13: 475–481.

The Millennium Genome Project for Hypertension was started in 2000 to identify genetic variants conferring susceptibility to hypertension, with the aim of furthering the understanding of the pathogenesis of this condition and realizing genome-based personalized medical care. Two different approaches were launched, genome-wide association analysis using single-nucleotide polymorphisms (SNPs) and microsatellite markers, and systematic candidate gene analysis, under the hypothesis that common variants have an important role in the etiology of common diseases. These multilateral approaches identified ATP2B1 as a gene responsible for hypertension in not only Japanese but also Caucasians. The high blood pressure susceptibility conferred by certain alleles of ATP2B1 has been widely replicated in various populations. Ex vivo mRNA expression analysis in umbilical artery smooth muscle cells indicated that reduced expression of this gene associated with the risk allele may be an underlying mechanism relating the ATP2B1 variant to hypertension. However, the effect size of a SNP was too small to clarify the entire picture of the genetic basis of hypertension. Further, dense genome analysis with accurate phenotype data may be required.

We reported previously that ATP2B1 was one of the genes for hypertension receptivity in a large-scale Japanese population, which has been replicated recently in Europeans and Koreans. ATP2B1 encodes the plasma membrane calcium ATPase isoform 1, which plays a critical role in intracellular calcium homeostasis. In addition, it is suggested that ATP2B1 plays a major role in vascular smooth muscle contraction. Because the ATP2B1 knockout (KO) mouse is embryo-lethal, we generated mice with vascular smooth muscle cell-specific KO of ATP2B1 using the Cre-loxP system to clarify the relationship between ATP2B1 and hypertension. The KO mice expressed significantly lower levels of ATP2B1 mRNA and protein in the aorta compared with control mice. KO mice showed significantly higher systolic blood pressure as measured by tail-cuff method and radiotelemetric method. Similar to ATP2B1, the expression of the Na + -Ca 2+ exchanger isoform 1 mRNA was decreased in vascular smooth muscle cells of KO mice. However, ATP2B4 expression was increased in KO mice. The cultured vascular smooth muscle cells of KO mice showed increased intracellular calcium concentration not only in basal condition but also in phenylephrine-stimulated condition. Furthermore, phenylephrine-induced vasoconstriction was significantly increased in vascular rings of the femoral artery of KO mice. These results suggest that ATP2B1 plays important roles in the regulation of blood pressure through alteration of calcium handling and vasoconstriction in vascular smooth muscle cells.

The aim of this article was that high-density lipoprotein cholesterol (HDL-C) reduces blood vessel injury through its antioxidant and anti-inflammatory functions. However, the effect of HDL-C on blood pressure may be controversial. Therefore, the aim of this study was to address whether HDL-C level is associated with blood pressure, and we examined cross-sectional data from community-dwelling persons. A total of 859 men [58 ± 15 (mean ± standard deviation); 20-89 (range) (years) and 1,169 women (61 ± 13; 19-88 years)] participants not on medication for hypertension were recruited from a single community at the time of their annual health examination. We examined the relationship between cardiovascular risk factors and blood pressure status. Multiple linear regression analysis using systolic blood pressure (SBP) and diastolic blood pressure (DBP) as an objective variable showed that HDL-C was significantly and independently associated with both SBP (β = 0.138), and DBP (β = 0.144). Compared to normotensive participants with the lowest quartile of HDL-C, multivariate-adjusted odds ratio (OR) for pre-hypertension was 1.72 (1.22-2.45) for the second quartile, 1.51 (1.07-2.15) for the third quartile, and 1.52 (1.04-2.22) for the highest quartile. Moreover, compared with normotensive participants with the lowest quartile, the multivariate-adjusted ORs for hypertension were 2.37 (1.63-3.45), 2.24 (1.54-3.28), 3.15 (2.10-4.74), respectively. There were no interactions between the two groups stratified by gender, age, BMI, drinking status, TG, FPG, and medication. Therefore, we concluded that HDL-C levels were positively associated with blood pressure in Japanese dwelling-community persons.

Aim: Vascular aging is known to be a major determinant of life expectancy. Recently, perceived age was reported to be a better predictor for mortality than chronological age. Based on these findings, we investigated whether or not perceived age was related to atherosclerosis in a general population. Methods: The participants were 273 individuals aged ≥50 years who participated in the Skin-doc in Anti-Aging Doc program. Facial photos were taken under a shadowless lamp from three directions (antero-posterior, and 60° right and left oblique projection) using a high-resolution digital camera. Perceived age was assessed either by 19 professional nurses in the geriatric ward or using facial identification program software. Carotid intima-media thickness (IMT), radial augmentation index (AI) and brachial-ankle pulse wave velocity (baPWV) were measured as indices for atherosclerosis. Results: The perceived age difference (expressed as the difference between perceived age and chronological age), when estimated either by nurses or software, was significantly and negatively associated with chronological age. Subjects who were evaluated by nurses to be younger than their chronological age had significantly lower carotid IMT after adjustment for chronological age. Conversely, carotid IMT was an independent and negative determinant of looking young, as perceived by nurses. Similar observations were also made between perceived age using facial identification software and carotid IMT. Radial AI and baPWV were not associated with perceived age. Conclusion: These findings show that carotid atherosclerosis is related to perceived age. This association might underlie previous findings showing that perceived age predicts life expectancy. Geriatr Gerontol Int 2012; ••: ••–••.

AIM Alanine aminotransferase (ALT) and γ-glutamyltransferase (GGT) are associated with insulin resistance and arteriosclerotic disease. Since adiposity raises liver enzyme levels and causes insulin resistance, adipocytokines are thought to underlie the relationship between liver enzymes and insulin resistance. To clarify this hypothesis, we conducted a cross-sectional epidemiological study in a Japanese general population. METHODS The study subjects were 903 middle-aged to elderly persons. Plasma levels of adiponectin and leptin were measured, while other clinical parameters were obtained from personal health records of medical check-ups. Insulin resistance was assessed by a homeostasis model assessment index (HOMA-IR). RESULTS Plasma levels of ALT (r=0.379, p

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.