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Background: Low birth weight (LBW) is a risk factor for chronic kidney disease (CKD) in later life and is becoming increasingly common in developed countries, including Japan. Furthermore, a serial decrease in birth weight has been associated with an increasing prevalence of CKD stage 2 in male Japanese adolescents. Sex-specific differences affect CKD susceptibility, and the association between birth weight and CKD in women, has not been elucidated. In this study, we investigated the sex-specific effect of LBW on renal function. Methods: Annual cross-sectional data of 2417 Japanese adolescents (males 1736; females 681), aged 15–16 years, were evaluated over 8 years (2007–2014). Results: Over the study period, mean birth weights decreased significantly in males (p < 0.01) and females (p < 0.05). Furthermore, both sexes showed significant decrease in estimated glomerular filtration rates corresponding to the birth weight reduction. The prevalence of CKD stage 2 also increased in males (from 26.0 to 32.4%, p < 0.01) and females (from 6.3 to 18.5%, p < 0.05). The incidence of CKD stage 2 was significantly related to history of LBW (males: odds ratio 1.73; 95% confidence interval 1.06–2.80; p < 0.05; females: odds ratio 3.29; 95% confidence interval 1.25–8.02; p < 0.05). Conclusions: Our data revealed that renal function and birth weight have decreased over time, in healthy Japanese adolescents. In view of the recent declining trend demonstrated by birth weight in Japan, we speculate that the prevalence of CKD might increase in the future. [ABSTRACT FROM AUTHOR]

Aims/Introduction Genetic risk variants for type 2 diabetes; rs391300-G in SRR and rs17584499-T in PTPRD, have been identified by a genome-wide association study using Han Chinese individuals living in Taiwan. In an attempt to know the effects of these two variants in conferring susceptibility to type 2 diabetes in the Japanese, we carried out a replication study for the association of the two single nucleotide polymorphisms ( SNPs) with type 2 diabetes in a Japanese population. Materials and Methods We genotyped 11,530 Japanese individuals (8,552 type 2 diabetes patients and 2,978 controls) for rs391300 and rs17584499, and analyzed the association of these two SNPs with type 2 diabetes by logistic regression analysis. Results Neither of the variants was associated with susceptibility to type 2 diabetes in the Japanese population (rs391300-G: odds ratio [ OR] = 0.97; 95% confidence interval [ CI] 0.91-1.04; P = 0.44; rs17584499-T: OR = 1.04; 95% CI 0.96-1.14; P = 0.34). Adjustment or stratified analysis for age, sex and body mass index ( BMI) did not affect the association of these variants with the disease. We did not observe a significant association of the SNPs with any metabolic traits, BMI, fasting plasma glucose, homeostasis model assessment of β-cell function ( HOMA-β) and HOMA of insulin resistance ( HOMA- IR) ( P > 0.05). Conclusions Neither rs391300 nor rs17584499 had a significant effect on conferring susceptibility to type 2 diabetes in the Japanese population. [ABSTRACT FROM AUTHOR]

Pancreatic cancer shows very poor prognosis and is the fifth leading cause of cancer death in Japan. Previous studies indicated some genetic factors contributing to the development and progression of pancreatic cancer; however, there are limited reports for common genetic variants to be associated with this disease, especially in the Asian population. We have conducted a genome-wide association study (GWAS) using 991 invasive pancreatic ductal adenocarcinoma cases and 5,209 controls, and identified three loci showing significant association (P-value<5×10-7) with susceptibility to pancreatic cancer. The SNPs that showed significant association carried estimated odds ratios of 1.29, 1.32, and 3.73 with 95% confidence intervals of 1.17-1.43, 1.19-1.47, and 2.24-6.21; P-value of 3.30×10-7, 3.30×10-7, and 4.41×10-7; located on chromosomes 6p25.3, 12p11.21 and 7q36.2, respectively. These associated SNPs are located within linkage disequilibrium blocks containing genes that have been implicated some roles in the oncogenesis of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Macrophages uptake oxidized low-density lipoprotein (LDL) via a scavenger receptor such as CD36 from plasma, and then become foam cells. We examined the association of CD36 gene single nucleotide polymorphisms (SNPs) with certain metabolic characteristics in a young male Japanese population ( n = 494). The G allele in a SNP located at +30215 on the 3’-untranslated region (UTR) was significantly correlated with the plasma LDL-cholesterol concentrations ( r = 0.13, p <0.01). The difference in LDL-cholesterol concentrations was 10 mg dl−1 between GG- and AA-genotype carriers ( p <0.05). The CD36 gene SNP is a novel maker of the variation in the LDL-cholesterol levels in young Japanese men. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Association between metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD) was verified and significance of liver function tests, especially alanine aminotransferase/aspartate aminotransferase ratio (ALT/AST) to evaluate the statuses of MetS and/or visceral fat accumulation was examined. Materials and Methods: After excluding subjects with liver diseases other than NAFLD, 1643 male and 1764 female Japanese were cross-sectionally examined. The diagnosis of MetS was done by its clinical criteria for Japanese with some modifications. Results: Levels of AST, ALT, gamma glutamyl transpeptidase and ALT/AST were significantly higher in subjects with MS than in those without it. Stepwise regression analyses indicated that AST, ALT, and ALT/AST in male and ALT/AST in female were significantly associated with waist circumference (WC), a marker of visceral fat accumulation. Among these associations, the association between WC and ALT/AST was always significant even when subjects with normal level of ALT of WC were selectively examined. Conclusions: NAFLD can be considered as one of morbid conditions of MetS, i.e. visceral fat accumulation. Among liver function test items, ALT/AST could be a powerful index reflecting their progression even in their pre-diagnosis/silent phases. [Copyright &y& Elsevier]

We conducted a genome-wide association study using 207,097 SNP markers in Japanese individuals with type 2 diabetes and unrelated controls, and identified KCNQ1 (potassium voltage-gated channel, KQT-like subfamily, member 1) to be a strong candidate for conferring susceptibility to type 2 diabetes. We detected consistent association of a SNP in KCNQ1 (rs2283228) with the disease in several independent case-control studies (additive model P = 3.1 × 10−12; OR = 1.26, 95% CI = 1.18–1.34). Several other SNPs in the same linkage disequilibrium (LD) block were strongly associated with type 2 diabetes (additive model: rs2237895, P = 7.3 × 10−9; OR = 1.32, 95% CI = 1.20–1.45, rs2237897, P = 6.8 × 10−13; OR = 1.41, 95% CI = 1.29–1.55). The association of these SNPs with type 2 diabetes was replicated in samples from Singaporean (additive model: rs2237895, P = 8.5 × 10−3; OR = 1.14, rs2237897, P = 2.4 × 10−4; OR = 1.22) and Danish populations (additive model: rs2237895, P = 3.7 × 10−11; OR = 1.24, rs2237897, P = 1.2 × 10−4; OR = 1.36). [ABSTRACT FROM AUTHOR]

OBJECTIVE--Recently, several genes have been shown to be associated with an increased risk of type 2 diabetes by genomewide association studies in white populations. To further investigate the involvement of these polymorphisms in conferring susceptibility to type 2 diabetes, we examined the association of 14 single nucleotide polymorphisms (SNPs) within 11 candidate loci with type 2 diabetes in a Japanese population. RESEARCH DESIGN AND METHODS--We analyzed 14 SNPs (rs4402960 in IGF2BP2, rs10811661 in CDKN2A/B, rs1111875 and rs7923837 in HHEX, rs13266634 in SLC3OA8, rs1113132 and rs11037909 in EXT2, rs9939609 and rs8050136 in FTO, rs7756992 in CDKAL1, rs1801282 in PPARG Pro12Ara, rs5219 in KCNJ11 Glu23Lys, rs7480010 in LOC387761, and rs9300039 in Ch11) in 1,630 Japanese subjects with type 2 diabetes and in 1,064 control subjects by using an invader assay or a TaqMan assay. RESULTS--Among the 11 loci examined, 6 were significantly associated with type 2 diabetes in our population by a logistic regression analysis, similar to previously reported results (rs4402960, P = 0.00009; rs10811661, P = 0.0024; rs5219, P = 0.0034; rs1111875, P = 0.0064; rs13266634, P = 0.0073; rs7756992, P = 0.0363). In this population, the remaining five loci were not significantly associated with type 2 diabetes. In addition, we identified significant association of the SNPs in FTO gene with BMI in the control subjects. CONCLUSIONS--We have identified 6 of the 11 loci that were identified by genome-wide association studies in white populations, and these loci are considered strong candidates for type 2 diabetes susceptibility across different ethnicities. Diabetes 57: 791-795, 2008 [ABSTRACT FROM AUTHOR]

To search a gene(s) conferring susceptibility to type 2 diabetes mellitus, we genotyped nearly 60,000 gene-based SNPs for Japanese patients and found evidence that the gene at chromosome 6p12 encoding transcription-factor-activating protein 2β ( TFAP2B) was a likely candidate in view of significant association of polymorphism in this gene with type 2 diabetes. Extensive analysis of this region identified that several variations within TFAP2B were significantly associated with type 2 diabetes [a variable number of tandem repeat locus: χ2=10.9, P=0.0009; odds ratio=1.57, 95% CI 1.20–2.06, intron 1+774 (G/T); χ2=11.6, P=0.0006; odds ratio=1.60, 95% CI 1.22–2.09, intron 1+2093 (A/C); χ2=12.2, P=0.0004; odds ratio=1.61, 95% CI 1.23–2.11]. The association of TFAP2B with type 2 diabetes was also observed in the UK population. These results suggest that TFAP2B might be a new candidate for conferring susceptibility to type 2 diabetes and contribute to the pathogenesis of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: The majority of type 1 diabetes is considered to be autoimmune with, for the most part, abrupt development. However, type 1 diabetes with slow onset, or the so-called slowly progressive type 1 diabetes or latent autoimmune diabetes in adults, has been recently recognized and is considered to be autoimmune-related. Although some investigators tried to explain the difference in onset pattern by the genetic background, including HLA type, it has not been established thus far. We hypothesized that the difference in onset pattern may relate to regeneration or differentiation of pancreatic beta-cells, and we therefore focused on the NeuroD/BETA2 gene, which encodes a transcription factor for the insulin gene and beta-cell differentiation.Research Design and Methods: We examined the NeuroD/BETA2 gene polymorphism in 105 Japanese type 1 diabetic patients and in 122 nondiabetic Japanese subjects in a case-control study, and we stratified the patients according to their onset pattern and islet-associated autoantibody positivity.Results: Regardless of the existence of islet-associated autoantibody, we found a significant difference in A allele frequency between type 1 diabetic patients with acute-onset type and control subjects. However, no difference was found between type 1 slow-onset diabetic patients and control subjects.Conclusions: These results support our hypothesis that NeuroD/BETA2 may affect the ability of regeneration of beta-cells, leading to a difference in the onset pattern and clinical course of type 1 diabetes. [ABSTRACT FROM AUTHOR]

Currently, the transcription factor 7-like 2 (TCF7L2) gene was shown to be strongly associated with type 2 diabetes in white populations. To examine the role of TCF7L2 in conferring susceptibility to type 2 diabetes further, we examined the association of TCF7L2 polymorphisms with type 2 diabetes, as well as the correlation between the TCF7L2 polymorphisms and the expression of TCF7L2 in the adipose or plasma GLP-1 concentrations in a Japanese population. The SNPs within TCF7L2 (rs12255372, rs7903146, rs7901695 and rs11196205), which was reported to be associated with type 2 diabetes, were analyzed using the TaqMan assay and microsatellite marker (DG10S478) was analyzed with respect to allele sizes by fragment analysis in 1,630 type 2 diabetes patients and 1,064 control subjects. Total GLP-1 concentration was measured by ELISA and the gene expression in adipose tissue was determined by real-time RT-PCR in 71 volunteers. All SNPs and the microsatellite polymorphisms were significantly associated with type 2 diabetes, and the association of rs12255372 was stronger than those of other SNPs (T vs. G, p = 0.0024, odds ratio = 1.7, 95% CI = 1.20-2.41), although the minor allele frequencies were much less than in white populations (approximately 3.5% vs. 35.0% in subjects with type 2 diabetes). We could not identify a significant correlation between plasma GLP-1 concentrations, or the adipose tissue gene expressions of TCF7L2 and the TCF7L2 polymorphisms. These results indicate that TCF7L2 gene polymorphisms contribute to conferring susceptibility to type 2 diabetes across different ethnicities, although further functional analyses are required to elucidate the role of this gene in the pathogenesis of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Gastric cancer is the third leading cause of cancer mortality in Japan and worldwide. Although previous studies identify various genetic variations associated with gastric cancer, host genetic factors are largely unidentified. To identify novel gastric cancer loci in the Japanese population, herein, we carried out a large-scale genome-wide association study using 6171 cases and 27 178 controls followed by three replication analyses. Analysis using a total of 11 507 cases and 38 904 controls identified two novel loci on 12q24.11-12 (rs6490061, P = 3.20 × 10 -8 with an odds ratio [OR] of 0.905) and 20q11.21 (rs2376549, P = 8.11 × 10 -10 with an OR of 1.109). rs6490061 is located at intron 19 of the CUX2 gene, and its expression was suppressed by Helicobacter pylori infection. rs2376549 is included within the gene cluster of DEFB families that encode antibacterial peptides. We also found a significant association of rs7849280 in the ABO gene locus on 9q34.2 (P = 2.64 × 10 -13 with an OR of 1.148). CUX2 and ABO expression in gastric mucosal tissues was significantly associated with rs6490061 and rs7849280 (P = 0.0153 and 8.00 × 10 -11 ), respectively. Our findings show the crucial roles of genetic variations in the pathogenesis of gastric cancer., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Low birthweight (LBW) is a worldwide public health problem, demonstrating an increasing incidence in developed countries, including Japan. LBW is also a risk factor for later development of chronic kidney disease (CKD). To date, studies have not evaluated the population impacts of increasing LBW rates on renal function., Methods: Estimated glomerular filtration rate (eGFR) was evaluated in 3737 Japanese adolescent males (15-16 years old) using annual cross-sectional data over an 18-year period (1998-2015)., Results: Between the initial (1998-2003) and final (2010-15) periods of the study, the mean birthweight decreased from 3213.4 ± 383.8 to 3116.2 ± 382.3 g and the LBW rate increased from 2.5 to 5.5% (both P ≤ 0.01). Additionally, the mean eGFR decreased from 105.1 ± 15.9 to 97.4 ± 13.8 mL/min/1.73 m2 and the prevalence of mildly reduced renal function (eGFR ≤ 60- <90 mL/min/1.73 m2) increased from 16.4 to 30.0% (both P ≤ 0.01), most evident in the LBW group (from 10.3 to 41.7%, P ≤0.01). The prevalence of proteinuria also increased significantly. Mildly reduced renal function was significantly associated with LBW [odds ratio (LBW 3000-3999 g) 1.51; 95% confidence interval 1.00-2.55; P = 0.047]., Conclusions: In this population of Japanese adolescents, the frequency of mildly reduced renal function increased as the LBW frequency increased. Our findings may have implications for the broader Japanese population as well as for other populations in which the prevalence of LBW is increasing., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.)

Objective . The aim of this study was to evaluate the relationships between the composition of free fatty acids (FFAs) and metabolic parameters, including body fat distribution, in Japanese. Methods . The study subjects were 111 Japanese patients (54 males, 57 females). Metabolic parameters and visceral and subcutaneous fat areas as determined by CT scanning at the umbilical level were measured. Glucose tolerance test (GTT) was performed by administering 75 g glucose orally. Results . The percentage of linoleic acid (C18:2), the greatest constituent among FFAs, was negatively correlated with visceral fat area ( r = -0.411, p < 0.0001), fasting glucose ( r = -0.330, p < 0.0001), HbA1c ( r = -0.231, p = 0.0146), and systolic blood pressure ( r = -0.224, p = 0.0184). Linoleic acid percentage was also significantly negatively correlated with HOMA-IR ( r = -0.416, p < 0.0001) by simple correlation. Based on the findings of OGTT, the 111 subjects were classified into three groups: 33 with normal glucose tolerance, 71 with impaired glucose tolerance (IGT), and 7 diabetic subjects. The percentage of serum linoleic acid in diabetic subjects was significantly lower than that in normal subjects. Conclusion . We conclude that serum linoleic acid level is negatively correlated with the accumulation of visceral fat in relation to a reduction of insulin resistance in Japanese subjects.

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

Genome-wide association studies (GWAS) have identified more than 80 susceptibility loci for type 2 diabetes (T2D), but most of its heritability still remains to be elucidated. In this study, we conducted a meta-analysis of GWAS for T2D in the Japanese population. Combined data from discovery and subsequent validation analyses (23,399 T2D cases and 31,722 controls) identify 7 new loci with genome-wide significance (P<5 × 10(-8)), rs1116357 near CCDC85A, rs147538848 in FAM60A, rs1575972 near DMRTA1, rs9309245 near ASB3, rs67156297 near ATP8B2, rs7107784 near MIR4686 and rs67839313 near INAFM2. Of these, the association of 4 loci with T2D is replicated in multi-ethnic populations other than Japanese (up to 65,936 T2Ds and 158,030 controls, P<0.007). These results indicate that expansion of single ethnic GWAS is still useful to identify novel susceptibility loci to complex traits not only for ethnicity-specific loci but also for common loci across different ethnicities.

Aim: The association between aging and insulin resistance has been unclear. We evaluated the effects of aging on visceral fat area (VFA) and subcutaneous fat area (SFA) measured by computed tomography, homeostasis model assessment of insulin resistance (HOMA-IR), and homeostasis model assessment of β-cell function (HOMA-β) among participants in a comprehensive health checkup., Methods: This study included 1,050 male and 700 female Japanese participants aged 35-84 years in our comprehensive health checkup program during a 2-year period. Participants who were on medication for diabetes mellitus or those who met the pre-determined exclusion criteria were excluded. The participants were divided into five groups according to age., Results: As age increased from Group 1 to Group 5, both VFA and VFA/SFA ratio significantly increased in both male and female participants, whereas log[HOMA-IR] linearly and significantly decreased (p＜0.0001 for each). Body mass index (BMI), waist circumference (WC), and SFA increased with age in female participants but decreased in male participants. Although age was not or only weakly correlated with log[glucose] and log[HbA1c] in both male and female participants, age showed significant negative correlations with log[insulin], log[HOMA-IR], and log[HOMA-β] even after adjusting for BMI and WC (p＜0.0001 for each). Serum high-molecular-weight adiponectin (HMW-ADPN) levels were measured in 114 male and 87 female participants, and log[HMW-ADPN] was negatively correlated with log[HOMA-IR] and positively correlated with age in both male and female participants., Conclusions: In the present study, both male and female participants showed increases in VFA and VFA/SFA ratio and decreases in insulin, HOMA-IR, and HOMA-β with age.

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

Context: Genome-wide association studies (GWASs) have identified over 60 susceptibility loci for type 2 diabetes (T2D). Although the ability of previous genetic information (∼40 loci) to discriminate between susceptible and nonsusceptible individuals is limited, the added benefit of updated genetic information has not been evaluated., Objective: We assessed the clinical utility of GWAS-derived T2D susceptibility variants in a Japanese population., Design and Setting: We conducted a cross-sectional case-control study., Participants: T2D cases (n = 2613) and controls (n = 1786) with complete genotype data for 49 single-nucleotide polymorphisms (SNPs) were selected for analyses., Outcome Measures: We constructed genetic risk scores (GRSs) by summing the susceptibility alleles of 49 SNP loci for T2D (GRS-49) or 10 SNP loci with genome-wide significant association in previous Japanese studies (GRS-10) and examined the association of the GRSs with the disease by receiver operating characteristic analyses using a logistic regression model., Results: The GRS-49 was significantly associated with T2D (P = 8.75 × 10(-45)). The area under the curve (AUC) for GRS-49 alone (model 1) and for age, sex, and body mass index (model 2) was 0.624 and 0.743, respectively. Addition of the GRS-49 to model 2 resulted in a small but significant increase in the AUC (ΔAUC = 0.03, P = 7.99 × 10(-15)). Receiver operating characteristic AUC was greater for GRS-49 than for GRS-10 (0.624 vs 0.603, P = .019), whereas the odds ratio per risk allele was smaller for GRS-49 than for GRS-10 (GRS-49, 1.13, 95% confidence interval 1.11-1.15; GRS-10, 1.26, 95% confidence interval = 1.22-1.31, P = 7.31 × 10(-10)). The GRS-49 was significantly associated with age at diagnosis in 1591 cases (β = -0.199, P = .0069) and with fasting plasma glucose in 804 controls (β = 0.009, P = 0.021)., Conclusions: Updated genetic information slightly improves disease prediction ability but is not sufficiently robust for translation into clinical practice.

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

To identify a novel susceptibility locus for type 2 diabetes, we performed an imputation-based, genome-wide association study (GWAS) in a Japanese population using newly obtained imputed-genotype data for 2 229 890 single-nucleotide polymorphisms (SNPs) estimated from previously reported, directly genotyped GWAS data in the same samples (stage 1: 4470 type 2 diabetes versus 3071 controls). We directly genotyped 43 new SNPs with P-values of <10(-4) in a part of stage-1 samples (2692 type 2 diabetes versus 3071 controls), and the associations of validated SNPs were evaluated in another 11 139 Japanese individuals (stage 2: 7605 type 2 diabetes versus 3534 controls). Combined meta-analysis using directly genotyped data for stages 1 and 2 revealed that rs515071 in ANK1 and rs7656416 near MGC21675 were associated with type 2 diabetes in the Japanese population at the genome-wide significant level (P < 5 × 10(-8)). The association of rs515071 was also observed in European GWAS data (combined P for all populations = 6.14 × 10(-10)). Rs7656416 was in linkage disequilibrium to rs6815464, which had recently been identified as a top signal in a meta-analysis of East Asian GWAS for type 2 diabetes (r(2) = 0.76 in stage 2). The association of rs7656416 with type 2 diabetes disappeared after conditioning on rs6815464. These results indicate that the ANK1 locus is a new, common susceptibility locus for type 2 diabetes across different ethnic groups. The signal of association was weaker in the directly genotyped data, so the improvement in signal indicates the importance of imputation in this particular case.

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

Objective: This study aimed to predict the 6-year incidence of metabolic syndrome (MetS) using an artificial neural network (ANN) system and multiple logistic regression (MLR) analysis based on clinical factors, including the insulin resistance index calculated by homeostasis model assessment (HOMA-IR)., Design: Subjects were recruited from participants in annual health check-ups in both 2000 and 2006. A total of 410 Japanese male teachers and other workers at Keio University, 30-59 years of age at baseline, participated in this retrospective cohort study., Measurements: Clinical parameters were randomly divided into a training dataset and a validation dataset, and the ANN system and MLR analysis were applied to predict individual incidences. The leave some out cross validation method was used for validation., Results: The sensitivity of the prediction was 0.27 for the MLR model and 0.93 for the ANN system, while specificities were 0.95 and 0.91, respectively. Sensitivity analysis employing the ANN system identified BMI, age, diastolic blood pressure, HDL-cholesterol, LDL-cholesterol and HOMA-IR as important predictors, suggesting these factors to be non-linearly related to the outcome., Conclusion: We successfully predicted the 6-year incidence of MetS using an ANN system based on clinical data, including HOMA-IR and serum adiponectin, in Japanese male subjects., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background & Aims: Two major types of gastric cancer, intestinal and diffuse, develop through distinct mechanisms; the diffuse type is considered to be more influenced by genetic factors, although the mechanism is unknown. Our previous genome-wide association study associated 3 single nucleotide polymorphisms (SNPs) with diffuse-type gastric cancer (DGC); 1 was a functional SNP (rs2294008) in prostate stem cell antigen (PSCA), but the loci of the other 2 were not investigated., Methods: We performed high-density mapping to explore a linkage disequilibrium status of the 2 SNPs at chromosome 1q22. A DGC case-control study was conducted using DNA from 606 cases and 1264 controls (all Japanese individuals) and validated using DNA from Japanese (304 cases, 1465 controls) and Korean (452 cases, 372 controls) individuals. The effects of SNPs on function were analyzed by reporter assays and analyses of splice variants., Results: A region of a strong linkage disequilibrium with the 2 SNPs contained mucin 1 (MUC1) and other 4 genes and SNPs significantly associated with DGC (rs2070803: P = 4.33 × 10(-13); odds ratio [OR], 1.71 by meta-analysis of the studies on the 3 panels) but not with intestinal-type gastric cancer. Functional studies demonstrated that rs4072037 (P = 1.43 × 10(-11); OR, 1.66 by meta-analysis) in MUC1 affects promoter activity and determines the major splicing variants of MUC1 in the gastric epithelium. Individuals that carry both SNPs rs2294008 in PSCA and rs4072037 in MUC1 have a high risk for developing DGC (OR, 8.38)., Conclusions: MUC1 is the second major DGC susceptibility gene identified. The SNPs rs2070803 and rs4072037 in MUC1 might be used to identify individuals at risk for this type of gastric cancer., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Several novel susceptibility loci for type 2 diabetes have been identified through genome-wide association studies (GWAS) for type 2 diabetes or quantitative traits related to glucose metabolism in European populations. To investigate the association of the 13 new European GWAS-derived susceptibility loci with type 2 diabetes in the Japanese population, we conducted a replication study using 3 independent Japanese case-control studies., Methodology/principal Findings: We examined the association of single nucleotide polymorphisms (SNPs) within 13 loci (MTNR1B, GCK, IRS1, PROX1, BCL11A, ZBED3, KLF14, TP53INP1, KCNQ1, CENTD2, HMGA2, ZFAND6 and PRC1) with type 2 diabetes using 4,964 participants (2,839 cases and 2,125 controls) from 3 independent Japanese samples. The association of each SNP with type 2 diabetes was analyzed by logistic regression analysis. Further, we performed combined meta-analyses for the 3 studies and previously performed Japanese GWAS data (4,470 cases vs. 3,071 controls). The meta-analysis revealed that rs2943641 in the IRS1 locus was significantly associated with type 2 diabetes, (P = 0.0034, OR = 1.15 95% confidence interval; 1.05-1.26) and 3 SNPs, rs10930963 in the MTNR1B locus, rs972283 in the KLF14 locus, and rs231362 in the KCNQ1 locus, had nominal association with type 2 diabetes in the present Japanese samples (P<0.05)., Conclusions: These results indicate that IRS1 locus may be common locus for type 2 diabetes across different ethnicities.

Aim: We questioned whether the ratio of C-reactive protein to high-molecular-weight adiponectin (C/A ratio), compared to each value alone, is more useful to predict insulin resistance and/or metabolic syndrome., Methods: We measured serum CRP and HMW adiponectin levels in 841 Japanese men who had participated in an annual health checkup. Correlations of the C/A ratio with metabolic parameters were assessed, and its predictive values for insulin resistance and MetS were compared with CRP or HMW adiponectin alone., Results: The C/A ratio was higher in subjects with MetS (n = 114) than in those without MetS (0.46 ± 0.67 vs. 0.23 ± 0.39, p<0.0001). The C/A ratio was correlated with a larger number of metabolic parameters than CRP, but the correlation was comparable to HMW adiponectin. Likewise, the area under the curve of the C/A ratio in receiver operator characteristic analysis for MetS was greater than that of CRP, but comparable to that of HMW adiponectin. However, the AUC of the C/A ratio in ROC analysis for insulin resistance (HOMA-IR >2.5) was greater than that of CRP or HMW adiponectin alone., Conclusion: While the C/A ratio provided little advantage to predict MetS, it might be more useful to predict insulin resistance than CRP or HMW adiponectin alone.

Little is known about the attitudes of doctors and patients to the use of home blood pressure monitoring (HBPM) and its relationship with compliance to exercise, diet, and antihypertensive medication and blood pressure (BP) control. We conducted a cross-sectional internet survey in treated patients with hypertension in Japan. Overall, 500 questionnaires were returned; 292 respondents (58.4%) reported that their doctor had recommended HBPM and among them 106 (36.3%) reported satisfactory adherence to HBPM. Compared to patients with poor adherence to HBPM, patients with satisfactory adherence to HBPM were more likely to have satisfactory compliance with exercise, diet and medication but no significant difference in BP control.

Aims: Cardiovascular diseases are the major cause of mortality in patients with diabetes mellitus. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine and plays an important role in cardiovascular diseases. The objective of this study was to evaluate the relation between the genotypes of the MCP-1 A-2518G polymorphism and the development of carotid atherosclerosis in patients with type 2 diabetes., Methods: The subjects were 303 unrelated patients who were diagnosed with type 2 diabetes mellitus. To evaluate macroangiopathy, we measured carotid artery intima-media thickness (IMT) by ultrasonography. The MCP-1 A-2518G polymorphism was determined by TaqMan PCR method., Results: IMT in patients with the MCP-1 -2518 AG or GG genotype was significantly greater than the AA-genotype (P=0.007). Simple regression analysis showed that age, systolic blood pressure, LDL-cholesterol, the MCP-1 -2518 AG+GG polymorphism, and HbA1c level were correlated with IMT (P<0.0001, <0.0001, 0.006, 0.007, 0.025, respectively). In multiple regression analysis, the MCP-1 -2518 AG+GG polymorphism was the third strongest independent determinant of IMT in patients with type 2 diabetes (P=0.021), subsequent to age and systolic blood pressure., Conclusion: Assessment of the MCP-1 A-2518G polymorphism would be useful in identifying the risk of developing carotid atherosclerosis in patients with type 2 diabetes.

The tumor necrosis factor (TNF)-alpha pathway has a key role in regulating insulin resistance. TNF receptor 2 (TNFR2) is an emerging candidate gene for insulin resistance in essential hypertension. We examined the association of insulin resistance and enhanced TNF pathway with severe hypertension and the association of a microsatellite polymorphism of the TNFR2 gene with severe hypertension. Male severe essential hypertensive patients (HT) with the onset before 60 years of age and with genetic predispositions to hypertension were consecutively enrolled at our outpatient department (N=92). Normotensive men (NT) over 50 years of age were randomly registered from the participants in the annual health check program (N=78). Patients were selected as HT and NT who met stringent criteria for systolic/diastolic blood pressure (SBP/DBP) levels >or=180 and/or 110 mm Hg and <120/80 mm Hg, respectively. HT revealed significantly higher plasma insulin levels, C-reactive protein (CRP) and soluble fraction of TNFR2 concentrations (sTNFR2) than NT. A microsatellite polymorphism of the CA repeat in intron 4 of the TNFR2 gene was analyzed. The allele frequency of CA16 in HT differed significantly from that in NT (66/184 vs. 36/156, P=0.01 by chi(2) analysis). In HT, the CA16 carriers showed significantly higher SBP and plasma insulin levels and a higher tendency of sTNFR2 than did those without this allele. In NT, CA16 carriers revealed significantly higher sTNFR2 and CRP levels than did the CA16 non-carriers. These results suggest that the TNFR2 gene locus has a potential effect on developing severe hypertension through the augmented TNF pathway and insulin resistance.

Aim: Both oxidative stress and inflammation are known to play roles in the pathogenesis of cardiovascular disease. We investigated the relations between reactive oxygen metabolites (ROMs) and various inflammatory and metabolic parameters in a Japanese population., Methods: We analyzed 48 male and 69 female subjects, aged 25 to 65 years, who underwent an annual health checkup in our university. Serum ROM level was assayed using a free radical elective evaluator. We also measured serum concentrations of high-sensitivity C-reactive protein (hsCRP), insulin, and high molecular weight (HMW) adiponectin., Results: Although the serum ROM level in females (347+/-83 Carr U) was slightly higher than in males (333+/-53 Carr U), this was not statistically significant. In the 48 male subjects, the ROM level negatively correlated with age (r=-0.344, p=0.0161), and positively correlated with the hsCRP level (r=0.306, p=0.0338). In the 69 female subjects, the ROM level negatively correlated with serum creatinine (r=-0.293, p=0.0141), and positively correlated with insulin (r=0.278, p=0.0202), the insulin resistance index (r=0.286, p=0.0170) and hsCRP levels (r=0.487, p<0.0001). Stepwise multiple regression analysis revealed that serum hsCRP, creatinine, and age were independently correlated with the serum ROMs level (R2=0.365; F value highest for hsCRP). When the study subjects were divided into tertiles according to the ROM level, serum hsCRP was significantly different among the three groups: its level was highest in the highest tertile of ROMs (p<0.001)., Conclusion: These results suggest that the serum ROM level is closely associated with serum hsCRP in Japanese adult subjects.

Purpose: Some reports have shown that the cause of type 1 diabetes is associated with dysfunction of regulatory T cells (Tregs). The FOXP3/Scurfin gene is known to be a master gene of Tregs. Therefore, we tried to analyze the relation between the gene polymorphism and adult onset type 1 diabetes and its subtype in the Japanese population., Methods: In this study, we recruited 316 Japanese patients with type 1 diabetes (155 male and 161 female, mean onset age 35.4 years) and 432 healthy Japanese controls (263 male and 169 female, mean age 44.4 years). Then we subdivided the patients by onset type, sex, and islet-associated autoantibody positivity., Results: The genotype frequency of (GT)(16)/(GT)(16) in female patients with overall type 1 diabetes was especially lower than that in controls (19.9% vs. 38.5%, p = 0.0002). Moreover, the genotype frequency of (GT)(16)/(GT)(16) in female patients with slowly progressive type 1 diabetes was significantly lower than that in controls (15.4% vs. 38.5%, p = 0.002)., Conclusion: Our data showed that the (GT)n microsatelloite polymorphism in the FOXP3/Scrufin gene was associated with Japanese adult onset type 1 diabetes, especially in females, and slowly progressive type 1 diabetes.

Recent genome wide association (GWA) studies on European and American populations revealed association with lung cancer risk of single-nucleotide polymorphisms (SNPs) in the locus containing two nicotine acetylcholine receptor (CHRNA) genes, whose involvement in tobacco addiction had been indicated. Association with lung cancer risk in smokers was consistently, but that in non-smokers as well as that with smoking behavior was inconsistently, observed in these studies. To obtain further information on the significance of CHRNA SNPs in lung cancer risk, association of seven SNPs in this locus with lung cancer risk as well as smoking status was examined in a Japanese population by a case-control study of 1250 cases (562 adenocarcinoma, 391 squamous cell carcinoma and 297 small cell carcinoma) and 936 controls. The frequency of the haplotype consisting of minor alleles for three SNPs, rs8034190, rs16969968 and rs1051730, which had been defined as a susceptible haplotype in the GWA studies, was much lower in the Japanese population (0.013) than in European and American populations (0.3-0.4). However, this haplotype was significantly associated with lung cancer risk also in Japanese (odds ratio = 2.3, 95% confidence interval = 1.5-3.7, P = 0.00028, respectively). The association was observed both in smokers and non-smokers and in all histological types of lung cancers. Individuals with this haplotype showed higher smoking doses than those without; however, the difference was not statistically significant. These results strongly indicate that CHRNA SNPs confer lung cancer susceptibility in a small subset of Japanese in a smoking-independent manner.

Background & Aims: This study attempts to elucidate a part of the genetic predisposition to the sporadic invasive ductal adenocarcinoma of the pancreas focusing on the genes implicated in the gene-environment interactions in carcinogenesis., Methods: First, 227 single nucleotide polymorphisms (SNPs) of 46 genes were genotyped on 198 cases and 182 controls. The SNPs, which showed a significant association, were further genotyped on additional samples to perform a joint analysis (total 317 cases vs 1232 controls). The gene selected by joint analysis was resequenced for a high-density SNP typing and a haplotype analysis on 702 cases and 785 controls. Function of the risk and wild-type haplotypes was assessed using cells transfected with complementary DNA (cDNA)., Results: The joint analysis with multiple testing adjustment identified 2 SNPs on the methionine synthase reductase (MTRR) gene: rs162049 (intronic SNP), Fisher exact test, P = .0018; OR, 1.33; 95% CI: 1.11-1.60 and rs10380 (His595Tyr), Fisher exact test, P = .0063; OR, 1.45; 95% CI: 1.11-1.88. The SNPs remained significant in the recessive model after the permutation test for multiple testing (rs162049, P = .024; rs10380, P = .023) in the high-density analysis. Stable transfectants of the risk haplotype MTRR cDNA showed significantly elevated homocysteine levels in a culture medium, a lower level of the LINE-1 methylation, and a lower expression of the MTRR protein than did the transfectants with the wild-type haplotype cDNA., Conclusions: Our study suggested a common missense SNP of the MTRR gene as a novel pancreatic cancer susceptibility factor with a functional significance in folate-related metabolism and the genome-wide methylation status.

Gastric cancer is classified into intestinal and diffuse types, the latter including a highly malignant form, linitis plastica. A two-stage genome-wide association study (stage 1: 85,576 SNPs on 188 cases and 752 references; stage 2: 2,753 SNPs on 749 cases and 750 controls) in Japan identified a significant association between an intronic SNP (rs2976392) in PSCA (prostate stem cell antigen) and diffuse-type gastric cancer (allele-specific odds ratio (OR) = 1.62, 95% CI = 1.38-1.89, P = 1.11 x 10(-9)). The association was far less significant in intestinal-type gastric cancer. We found that PSCA is expressed in differentiating gastric epithelial cells, has a cell-proliferation inhibition activity in vitro and is frequently silenced in gastric cancer. Substitution of the C allele with the risk allele T at a SNP in the first exon (rs2294008, which has r(2) = 0.995, D' = 0.999 with rs2976392) reduces transcriptional activity of an upstream fragment of the gene. The same risk allele was also significantly associated with diffuse-type gastric cancer in 457 cases and 390 controls in Korea (allele-specific OR = 1.90, 95% CI = 1.56-2.33, P = 8.01 x 10(-11)). The polymorphism of the PSCA gene, which is possibly involved in regulating gastric epithelial-cell proliferation, influences susceptibility to diffuse-type gastric cancer.

Objective: Serum C-reactive protein (CRP) and adiponectin levels predict atherosclerosis and coronary heart disease. However, the efficacy of the combination of both markers remains unknown. In the present study, we investigated whether the combination of CRP and adiponectin is associated with further metabolic abnormalities compared to each of them alone., Research Design and Methods: Eighty-three Japanese type 2 diabetic outpatients participated in this study. We measured serum high-sensitive CRP and high molecular weight (HMW)-adiponectin, and investigated their relationship with various metabolic parameters., Results: In univariate analysis, CRP was significantly correlated with diastolic blood pressure and HDL-cholesterol. On the other hand, HMW-adiponectin was significantly correlated with systolic (SBP) and diastolic blood pressure, plasma glucose, HDL-cholesterol, triglycerides and HOMA-IR, but not with CRP. We then classified the subjects into three groups: low CRP and high HMW-adiponectin levels (low risk group, 19%), high CRP and low HMW-adiponectin levels (high risk group, 22%), and others. In Spearman rank correlation coefficient analysis, this classification was significantly associated with a larger number of metabolic risk factors: SBP, glucose, HbA1c, LDL-cholesterol, HDL-cholesterol, triglycerides and HOMA-IR, compared with classification by CRP or HMW-adiponectin alone., Conclusion: These results suggest that combination of CRP and HMW-adiponectin reflects further metabolic abnormalities compared with each of them in type 2 diabetic subjects. The combined measurement of both markers may be useful to detect cardiovascular high risk patients.

Adipokines play crucial roles in obesity-related insulin resistance in adults, but little is known in the general adolescent population. This study was designed to investigate the relationships between adipokines and metabolic parameters, the insulin resistance index, and proinflammatory cytokines in the general population of Japanese male adolescents. We studied 662 Japanese male high school students aged 16 to 17 years and 282 healthy Japanese male adults aged 30 to 61 years who received annual health checkups. High-molecular weight (HMW) adiponectin levels were significantly lower in adolescents (4.18 +/- 2.24 microg/mL) than in adults (4.84 +/- 3.20 microg/mL), despite body mass index (BMI) being significantly lower in adolescents. The HMW adiponectin levels correlated negatively with BMI and the homeostasis model assessment of insulin resistance index (HOMA-IR) in adults. In adolescents, HMW adiponectin correlated negatively with BMI and waist circumference, but not with HOMA-IR or other metabolic parameters except high-density lipoprotein cholesterol. Leptin levels correlated positively with HOMA-IR, triglycerides, tumor necrosis factor alpha, interleukin 6, and monocyte chemoattractant protein 1 and negatively with high-density lipoprotein cholesterol even after adjustment for BMI. These findings suggest that serum leptin is a more useful biomarker of fat accumulation-related insulin resistance, inflammation, and metabolic abnormalities than HMW adiponectin in the general population of male adolescents. The inverse correlation between adiponectin and insulin resistance may manifest in the later phase of obesity development.

Aims: Although it has been reported that angiotensin II receptor blocker inhibited the formation and accumulation of advanced glycation endproducts (AGEs) in vitro and in vivo, whether it can do so clinically is unknown. We therefore examined the effect of valsartan on markers of oxidation and glycation., Methods: We started 40mg/day valsartan treatment in 15 type 2 diabetic subjects with hypertension, and metabolic parameters, lipid peroxide, paraoxonase activity, platelet-activating factor acethylhydrolase activity, AGEs and urine 8-isoprostane were measured at baseline and after 3 and 6 months of treatment., Results: Even after valsartan treatment, the blood pressure level of the patients did not change during the study. However, AGEs and urine 8-isoprastane levels had decreased at 6 months (p<0.05 and <0.01) as well as urine microalbumin level (p<0.01), although other oxidative stress markers were unchanged., Conclusion: In this study, low-dose valsartan treatment decreased serum AGEs level, whereas blood pressure level was unchanged. The effect of valsartan on AGEs might be a blood pressure-independent effect in type 2 diabetic subjects.

We examined whether serum gammaGTP activity (gammaGTP) is associated with Breslow's lifestyle index and whether it could be used as a tool to detect subjects with unhealthy lifestyles. To that effect, 724 male Japanese workers excluding patients suffering from hepatitis virus infection, autoimmune liver diseases and apparently active bile duct diseases were cross-sectionally examined. gammaGTP was inversely associated with the total score of Breslow's index for all subjects (lambda=30.643) and in subjects aged 40 or more (lambda=37.073). The association was consistent even after adjustments of subjects' ages and levels of triglycerides, total cholesterol and uric acid (p=0.0001). Among the seven lifestyle factors comprising Breslow's index, improper habits of drinking (p<0.0001), smoking (p=0.0204), exercise (p=0.0189) and body weight control (p<0.0001), were associated with increased gammaGTP. Even in a survey in which subjects who had proper habits of drinking and body weight control were selectively examined, improper habits of smoking and exercise still tended to be associated with increased gammaGTP. Receiver operating characteristic curves indicated that gammaGTP was beneficial for detecting subjects who scored two or less on Breslow's index, at least in subjects aged 40 or more. gammaGTP was associated with insulin resistance level estimated by the homeostasis model assessment (p<0.0001), which was inversely associated with Breslow's index (p=0.0040). gammaGTP could be used as an objective substitute of Breslow's index, allowing us to identify subjects with low scores on Breslow's index, at least after sorting subjects properly. Such screening would enable interventions to correct subjects' unhealthy lifestyles, helping to solve lifestyle-related disease issues.

GPR40 is a member of the G-protein-coupled receptors. Recent studies suggest that GPR40 is highly expressed in pancreatic beta cells and insulin-secreting cell lines, and that fatty acids increase intracellular calcium concentration and amplify glucose-stimulated insulin secretion by activating GPR40. Despite identification of the Arg211His polymorphism in the GPR40 gene, there have been no clinical studies concerning this polymorphism. The present study was performed to investigate the effects of the GPR40 gene Arg211His polymorphism on clinical and metabolic parameters, including serum insulin level, in 327 healthy Japanese men, using the TaqMan polymerase chain reaction method. Serum insulin level, homeostasis model of insulin resistance (HOMA-IR), and beta-cell function (HOMA-beta were significantly different (P = .0075, .0152, and .0039, respectively) and were lowest in Arg/Arg homozygotes and highest in His/His homozygotes, although plasma glucose and serum lipids were not significantly different. Multiple regression analyses showed that serum insulin level, HOMA-IR, and HOMA- beta were significantly correlated with this polymorphism after adjusting for age and body mass index. After Bonferroni's correction for multiple comparisons was made, only HOMA- beta was significantly different among the 3 genotypes. These results suggest that the Arg211His polymorphism in the GPR40 gene may contribute to the variation of insulin secretory capacity in Japanese men.

Leptin plays an important role in the regulation of body weight and is known to circulate in both free and bound forms. One of the leptin receptor isoforms exists in a circulating soluble form that can bind leptin. Clinical studies have shown that soluble leptin receptor (sOB-R) levels are lower in obese individuals. In the present study, we measured the serum sOB-R level in 419 healthy Japanese subjects (198 men and 221 women, aged 30 to 65 years, body mass index [BMI] 21.7 +/- 2.6 [SD] kg/m2) and in 150 type 2 diabetic patients (96 men and 54 women, BMI 24.3 +/- 3.8 kg/m2). We investigated the relationships between serum sOB-R level and BMI, blood pressure, homeostasis model assessment-insulin resistance index (HOMA-IR), serum leptin and adiponectin levels, lipid profile, and leptin receptor (LEPR) gene Lys109Arg and Gln223Arg polymorphisms. Serum leptin and sOB-R levels were measured by radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA), respectively. The serum sOB-R level in men was significantly higher than that in women. The serum sOB-R level was negatively correlated with BMI, fasting insulin, HOMA-IR, and serum leptin level and positively correlated with high-density lipoprotein (HDL)-cholesterol and serum adiponectin levels. The correlations between serum sOB-R level and fasting insulin, HOMA-IR, serum leptin, adiponectin, and HDL-cholesterol levels were significant even after adjustment for age, sex, and BMI in healthy subjects. There was no association between serum sOB-R level and the LEPR polymorphisms examined. These findings suggest that the serum sOB-R level is negatively correlated with HOMA-IR and serum leptin level and positively correlated with HDL-cholesterol level and serum adiponectin level, independent of age, sex, and BMI, in the Japanese population.

Background/aims: Since a novel polypeptide named adiponectin was shown to prevent the development of steatosis and steatohepatitis in animal models, we studied whether it was also possible in a clinical situation., Methods: Associations between serum adiponectin levels and serum transaminase activities were studied in 791 Japanese males who were not heavy drinkers, and had no autoimmune or HBV- or HCV-induced liver diseases., Results: Various markers of metabolic diseases including levels of body mass index (BMI), serum triglyceride, total cholesterol, and insulin resistance assessed by the homeostasis model were significantly higher in subjects with increased transaminase activities when compared to those with normal activities. Single regression analyses demonstrated that the logarithmic serum adiponectin level was inversely correlated with the levels of logarithmic serum AST (r=-0.229, P<0.0001), ALT (r=-0.305, P<0.0001), and gammaGTP (r=-0.278, P<0.0001). Even in multiple regression analyses in which subjects' age and levels of BMI, serum triglyceride, total cholesterol, and insulin resistance were adjusted, the inverse correlations were significant (P=0.0426, 0.0332, and 0.0011, respectively)., Conclusions: Hypoadiponectinemia may worsen liver diseases associated with metabolic diseases in clinical cases. In addition to aggravation of insulin resistance and hyperlipidemia, some hypoadiponectinemia specific mechanisms may stand behind the association.

We investigated the effects of leptin receptor gene 3'-untranslated region (3'-UTR) polymorphism on clinical and metabolic parameters in 221 young Japanese men aged 21 to 28 years. The polymerase chain reaction-restriction fragment length polymorphism method was used to identify a pentanucleotide (CTTTA) insertion in 3'-UTR of the leptin receptor gene. Body mass index, blood pressure, plasma glucose, insulin, leptin, total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, triglycerides, free fatty acids, uric acid, apolipoprotein A-I (apoA-I), and cholesteryl-ester transfer protein levels were measured. There was only 1 homozygote and 38 heterozygotes for the 3'-UTR insertion allele among the 221 subjects. The insertion allele frequency was 0.090. Plasma HDL-cholesterol and apoA-I levels were significantly lower (p = 0.015 and p = 0.032 by Mann-Whitney U test, respectively) in homozygous or heterozygous carriers of the insertion allele than in subjects homozygous for the normal allele. There were no differences in other parameters measured. Furthermore, when the subjects were divided into three groups according to HDL-cholesterol level, the percentage of insertion allele-positive subjects was significantly lower in the highest HDL-cholesterol group (chi(2) = 8.42, p = 0.015). These findings suggest that serum HDL-cholesterol and apoA-I levels are influenced by the leptin receptor gene 3'-UTR polymorphism in young Japanese men.

It has been reported that the serum adiponectin level was negatively correlated with body mass index (BMI), insulin resistance index, and triglycerides and was positively correlated with high-density lipoprotein cholesterol in several cross-sectional studies. However, the causal relationship has not been elucidated. We investigated whether the baseline adiponectin level could predict subsequent changes in insulin resistance, lipid profile, or body weight in a 2-yr longitudinal study. This study included 590 male Japanese subjects, aged 30-65 yr, who received annual health checkups in both 2000 and 2002. Blood pressure, heart rate, and anthropometric and metabolic parameters, including serum insulin and adiponectin levels, were determined. The insulin resistance index was calculated based on homeostasis model assessment. Baseline adiponectin level was not correlated with the subsequent change in lipid profile or BMI in 2 yr after adjustment for each baseline value. However, the baseline adiponectin level was negatively correlated with subsequent changes in insulin and insulin resistance index based on homeostasis model assessment, even after adjustment for change in BMI (r = -0.162 and r = -0.140, respectively). These findings suggest that the serum adiponectin concentration predicts subsequent changes in insulin resistance, but not in lipid profile or body weight.

Recent studies have reported an association between systolic blood pressure (BP) and rhinitis. The prevalence of allergic rhinitis is 20% to 30% in Japan. The present cross-sectional study was performed to assess the relation between BP and allergic rhinitis in a sample of 2,292 male adolescent high school students who attended the annual school health examination. Of the 2,292 students (mean age, 16 years), 26.6% were considered to have allergic rhinitis based on their responses to a questionnaire, 25.1% were diagnosed with allergic rhinitis by an otolaryngologist, and 12.6% were consistently diagnosed with allergic rhinitis by both questionnaire and an otolaryngologist. There was no difference in systolic BP between subjects with and without allergic rhinitis. Diastolic BP, however, was higher in subjects without allergic rhinitis than in those with allergic rhinitis as diagnosed by questionnaire alone or by both questionnaire and an otolaryngologist. When the subjects were divided into three BP categories (normal, high normal, and hypertension) according to the criteria in the JSH 2000, the rates of allergic rhinitis were similar in the three BP categories. These findings do not confirm a relation between allergic rhinitis and systolic BP.

Type 1 diabetes is characterized by cell-mediated autoimmune destruction of pancreatic beta cells. Although the disease shows a strong association with HLA class II alleles, other genes may influence the initiation or the rate of progression of the autoimmune process. Recently, it was reported that a polymorphism of the stromal cell-derived factor-1 (SDF-1) (a kind of chemokine) gene was associated with early onset of type 1 diabetes in Caucasians. Therefore, we examined SDF-1 gene polymorphism in Japanese type 1 diabetes in this study. We examined the SDF-1 gene polymorphism (801G-->A) in 298 unrelated Japanese type 1 diabetic patients and 270 healthy subjects by the TaqMan PCR method. Allelic and genotypic frequencies of the SDF-1 A variants were similar in overall type 1 diabetic patients and healthy subjects. We then stratified the patients by their onset pattern (acute vs. slow onset) and islet-associated autoantibody positivity. However, no significant difference was found among each group of type 1 diabetes. Furthermore, unlike the previous report in "Caucasian" type 1 diabetics, the SDF-1 A variant was not associated with early onset of the disease in Japanese type 1 diabetics. The SDF-1 gene polymorphism was not associated with onset age (or onset pattern) of type 1 diabetes in Japanese. Further study is necessary to conclude whether SDF-1 gene polymorphism affects the onset age in type 1 diabetes in general.

Only a few longitudinal studies in Asians have shown a close association between hyperinsulinemia and the incidence of hypertension. In the present study, we used the insulin resistance index, HOMA-IR [fasting plasma glucose (FPG) (mmol/l) X insulin (microUl/ml) / 22.5], and tried to elucidate longitudinally the relationship among insulin resistance, blood pressure, body mass index (BMI), FPG, and lipid profile in middle-aged Japanese men. Three hundred and ten male non-hypertensive subjects aged 30 to 58 years in 1993 (44.5 +/- 7.8 (SD) years; BMI, 22.6 +/- 2.5 kg/m2) were divided into three groups according to HOMA-IR (A: lowest; B: middle; and C: highest). Their BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, FPG and lipid profile were followed up for 7 years. The percentage of high normal blood pressure in 1993 and 2000 did not differ among the three groups. However, in 2000 hypertensive subjects made up 11.7% of group A (12/103), 15.4% of group B (16/104), and 29.1% of group C (30/103) (chi2 = 11.50, p = 0.003). SBP, DBP, and many other metabolic parameters in 2000 were significantly higher in group C than in the other groups. Furthermore, both SBP and DBP in 2000 were positively correlated with HOMA-IR in 1993 (r = 0.17 and p < 0.01 for both). The correlation between HOMA-IR in 1993 and DBP in 2000 was significant, even after adjustment for age and BMI in 1993. These findings suggest an important role of insulin resistance in predicting the future incidence of hypertension in middle-aged Japanese men.

Hypertension is often accompanied by type 2 diabetes mellitus. Recently, the American Diabetes Association (ADA) published guidelines on the treatment of hypertension in adult patients with diabetes mellitus. However, the views of general physicians on how to control blood pressure (BP) in diabetic patients and the impact of the ADA guidelines in Japan are still not known. We conducted an internet survey in May 2002: Questionnaires were e-mailed to a total of 3,616 medical doctors, of whom 441 (12.2%) properly responded. About half of the respondents (48.3%) had already read the ADA guidelines. Before being given an outline of the guidelines, the respondents' average BP level for starting medication was 152/94 mmHg, and the BP goal 133/83 mmHg; after reading the outline, these values were 149/92 and 132/82 mmHg, respectively. The goal BP decreased more after reading the guidelines in doctors who had not previously read the ADA guidelines than in those who had already read. After being given an outline of the ADA guidelines, 40.3% of respondents reported that they would select, as a first-line agent, an angiotensin II receptor antagonist (ARB), 35.6% an angiotensin-converting enzyme inhibitor (ACEI), and 18.6% a calcium channel blocker (CCB); as a second-line medication, 39.7% of the respondents would select a CCB. Seventy percent of doctors reported having at least one patient receiving CCB monotherapy; after reading the guidelines, 41.5% of these doctors said they would continue CCB monotherapy, 36.6% said they would add an ACEI or ARB, and 29.7% planned to change to an ACEI or ARB. In conclusion, our data suggest the impact of the ADA guidelines on the target BP and the first choice of antihypertensive medication in diabetic patients. ARBs and ACEIs became first-line medications, and CCBs became second-line medications to achieve the BP goal and prevent organ damage.

Type 1 diabetes mellitus is recognized as a T-cell-mediated autoimmune disease. Vitamin D compounds are known to suppress T-cell activation by binding to the vitamin D receptor (VDR); and thus, VDR gene polymorphisms may be related to T-cell-mediated autoimmune diseases. We, therefore, investigated a VDR gene polymorphism in type 1 diabetes. We examined the VDR gene Bsm I polymorphism in 203 type 1 diabetic patients and 222 controls, and the association between the VDR gene polymorphism and type 1 diabetes and their onset pattern. We found a significantly higher frequency of B allele in type 1 diabetics overall, compared with controls (P = 0.0010). Moreover, there was a significant difference in B-allele frequency between acute-onset type 1 diabetics and controls (P = 0.0002), whereas this difference was not observed between slow-onset type 1 diabetics and controls. Regardless of the existence of islet-associated autoantibody, we found a significant difference in B-allele frequency between acute-onset type 1 diabetics and controls. In conclusion, we found an association between a VDR gene polymorphism and acute-onset type 1 diabetes. Assessment of this VDR gene polymorphism may contribute to prediction of the onset pattern in individuals with a high risk of type 1 diabetes.

Adiponectin is an adipocyte-derived protein, which possesses an anti-atherosclerotic action and improves insulin sensitivity. Peroxisome proliferator-activated receptor gamma (PPAR(gamma)) regulates the transcription of many adipocyte-specific genes. A Pro12Ala polymorphism has been detected in the PPAR(gamma)2 gene, and this substitution has been reported to reduce transactivation activity in vitro. We hypothesized that individuals possessing this Ala12 allele may have a lower serum adiponectin level, because of the observation that PPAR(gamma) agonists increase the plasma adiponectin level in humans. To test this hypothesis, we investigated the effects of the PPAR(gamma)2 Pro12Ala polymorphism on anthropometric and metabolic parameters, including serum adiponectin level, in 478 Japanese men and 117 women aged 30 to 65 years. There were no homozygous subjects for the Ala12 allele of the PPAR(gamma)2 gene in this study. Plasma adiponectin levels were significantly lower in subjects with the Ala12 allele in the Japanese population of both sexes, although body mass index (BMI), plasma glucose, serum lipids, and insulin resistance index were not significantly different between subjects with and without this polymorphism. It is suggested that the Pro12Ala polymorphism of the PPAR(gamma)2 gene may reduce serum adiponectin level in the Japanese population., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Adiponectin, which is secreted specifically by adipose tissue, has been shown to act as an anti-atherosclerotic protein by direct effects on endothelial cells. Clinical studies have shown that adiponectin levels are lower in individuals with obesity, diabetes and coronary artery disease. The present study investigated relationships between serum adiponectin levels and body mass index (BMI), blood pressure, insulin resistance index, lipid profile, uric acid and high-sensitivity C-reactive protein levels in a large number of Japanese subjects not taking any medication for metabolic disease and without severe illness (705 men and 262 women; age 30-65 years; BMI 22.5+/-2.9 kg/m(2)). The serum adiponectin concentration was measured by ELISA, without a protein-denaturing step. The insulin resistance index was assessed by homoeostasis model assessment (HOMA-IR). The serum concentration of adiponectin in women (13.5+/-7.9 microg/ml) was significantly higher than that in men (7.2+/-4.6 microg/ml). The serum adiponectin level was negatively correlated with BMI, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, insulin, HOMA-IR, total cholesterol, triacylglycerols, low-density lipoprotein (LDL)-cholesterol and uric acid, and positively correlated with high-density lipoprotein (HDL)-cholesterol. The correlations between serum adiponectin level and insulin, HOMA-IR, triacylglycerols, HDL-cholesterol, LDL-cholesterol and uric acid were significant even after adjustment for age, sex and BMI. Stepwise multiple regression analysis revealed that HDL-cholesterol, sex, BMI and HOMA-IR were independently correlated with the serum adiponectin level (R(2)=0.377). These findings suggest that the serum adiponectin level is negatively correlated with HOMA-IR and positively correlated with HDL-cholesterol, independent of age, sex and BMI, in the Japanese population.

To understand the significance of elevated serum gamma-GTP levels, factors relevant to the serum gamma-GTP level were studied using data of health check-ups for the employees of a Japanese corporation. The gamma-GTP level was positively correlated with levels of various liver function tests including aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Except for them, the gamma-GTP level was positively correlated with levels of insulin resistance, uric acid, total cholesterol, triglyceride, and body mass index. The correlation between the gamma-GTP level and LDL cholesterol was also observed only when subjects who drank more than 5 times a week were selectively studied. When non-drinkers and opportunity drinkers were selectively studied, 63.6% of subjects whose gamma-GTP level was more than 120 IU/liter showed elevated insulin resistance levels. Multiple factors including insulin resistance may affect serum gamma-GTP activity in clinical subjects.