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Background: Thioredoxin-interacting protein (TXNIP) controls the cellular redox balance by binding to and inhibiting the expression and function of thioredoxin. DNA methylation of the TXNIP gene is involved in the regulation of TXNIP mRNA expression. Changes in TXNIP DNA methylation levels are associated with the development of various diseases such as type 2 diabetes mellitus (T2DM). However, few studies have focused on the influence of lifestyle factors such as alcohol intake on TXNIP DNA methylation. Objectives: This research examines the association of drinking behaviors with TXNIP DNA methylation levels in the general Japanese population. Methods: We conducted a cross-sectional study of 404 subjects (176 males and 228 females) who were divided into non-, moderate and heavy drinkers based on self-reported drinking behaviors. TXNIP DNA methylation levels in leukocytes were determined using a pyrosequencing assay. Results: The mean TXNIP DNA methylation level in heavy drinkers (74.2%) was significantly lower than that in non- and moderate drinkers (non: 77.7%, p <.001; moderate: 76.6%, p =.011). Multivariable linear regression analysis showed that log-transformed values of daily (b = −1.34; p <.001) and cumulative (b = −1.06; p =.001) alcohol consumption were associated with decreased TXNIP DNA methylation levels. Conclusion: TXNIP DNA methylation levels in heavy drinkers was lower than in non- and- moderate drinkers. Decreased TXNIP DNA methylation level increases the expression of TXNIP and elevates the risk of developing of diseases such as T2DM. Therefore, decreasing alcohol use in heavy drinkers may lessen the likelihood of some alcohol-related illnesses moderated through TXNIP DNA methylation. [ABSTRACT FROM AUTHOR]

Background Thioredoxin-interacting protein (TXNIP) inhibits the activity of thioredoxin (TXN), leading to increased oxidative stress. Expression of the TXNIP gene is regulated by DNA methylation. However, no study has reported the influence of lifestyle factors on TXNIP DNA methylation. Our goal was to determine the association between drinking habits and TXNIP DNA methylation levels in the general Japanese population. Methods We conducted a cross-sectional study of 404 subjects (176 males and 228 females) participating in a health examination. Subjects were divided into non-, moderate (male: 1-39g; female: 1-19g ethanol/day) and heavy (male: ≥40g; female: ≥20g ethanol/day) drinkers based on self-reported drinking habits. We used a pyrosequencing assay to determine TXNIP DNA methylation levels in leukocytes. Results Among men, the mean TXNIP DNA methylation level in heavy drinkers (73.2%) was significantly lower than that in non- and moderate drinkers (non: 76.7%, p <0.001; moderate: 75.8%, p =0.024). In multiple linear regression analysis adjusted for confounding factors, TXNIP DNA methylation levels showed significant negative association with alcohol consumption per day and cumulative alcohol consumption in male current drinkers. Conclusions We found that heavy drinkers had TXNIP DNA hypomethylation compared to non- and moderate drinkers in men. Moreover, alcohol consumptions were also negatively associated with TXNIP DNA methylation levels in male current drinkers. Key messages Heavy drinkers had decreased levels of TXNIP DNA methylation compared to non- and moderate drinkers in men. [ABSTRACT FROM AUTHOR]

Hearing impairment is one of the most common sensory disorders that affect ~1 in 1000 children, and half of them are considered to be hereditary. Information about the carrier frequencies of mutations that underlie autosomal recessive disorders is indispensable for accurate genetic counseling to predict the probability of patients' children's disease. However, there have been few reports specific to the Japanese population. GJB2 mutations are reported to be the most frequent cause of hereditary hearing loss, and the mutation spectrum and frequency of GJB2 mutations were reported to vary among different ethnic groups. In this study, we investigated the carrier frequency of GJB2 mutations and the mutation spectrum in 509 individuals randomly selected from the general Japanese population. We show that the carrier frequencies of the two most common pathogenic mutations are 1.57% (8/509) for c.235delC and 1.77% (9/509) for p.Val37Ile. In addition to these mutations, we found two pathogenic variants (p.[Gly45Glu;Tyr136*] and p.Arg143Trp), and the total carrier frequency was estimated to be around 3.73% (19/509). We also detected six unclassified variants, including two novel variants (p.Cys60Tyr and p.Phe106Leu), with the former predicted to be pathogenic. These findings will provide indispensable information for genetic counseling in the Japanese population. [ABSTRACT FROM AUTHOR]

Background/Objective: Gene-gene interactions in the reverse cholesterol transport system for high-density lipoprotein-cholesterol (HDL-C) are poorly understood. The present study observed gene-gene combination effect and interactions between single nucleotide polymorphisms (SNPs) in ABCA1, APOA1, SR-B1, and CETP in serum HDL-C from a cross-sectional study in the Japanese population. Methods: The study population comprised 1,535 men and 1,515 women aged 35–69 years who were enrolled in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. We selected 13 SNPs in the ABCA1, APOA1, CETP, and SR-B1 genes in the reverse cholesterol transport system. The effects of genetic and environmental factors were assessed using general linear and logistic regression models after adjusting for age, sex, and region. Principal Findings: Alcohol consumption and daily activity were positively associated with HDL-C levels, whereas smoking had a negative relationship. The T allele of CETP, rs3764261, was correlated with higher HDL-C levels and had the highest coefficient (2.93 mg/dL/allele) among the 13 SNPs, which was statistically significant after applying the Bonferroni correction (p<0.001). Gene-gene combination analysis revealed that CETP rs3764261 was associated with high HDL-C levels with any combination of SNPs from ABCA1, APOA1, and SR-B1, although no gene-gene interaction was apparent. An increasing trend for serum HDL-C was also observed with an increasing number of alleles (p<0.001). Conclusions: The present study identified a multiplier effect from a polymorphism in CETP with ABCA1, APOA1, and SR-B1, as well as a dose-dependence according to the number of alleles present. [ABSTRACT FROM AUTHOR]

Abstract: A genome-wide association study identified that LRP2 rs2544390 in intron 1 was associated with serum uric acid (SUA) levels among Japanese, as well as polymorphisms of SLC22A12, ABCG2, and SLC2A9. This study aimed to confirm the association of rs2544390 C/T with SUA, as well as another LRP2 polymorphism (rs3755166 G/A) in the promoter. Subjects were 5016 health checkup examinees (3409 males and 1607 females) aged 35 to 69years with creatinine<2.0mg/dL. The subjects with SLC22A12 258WW, SLC2A9 rs11722228C allele, ABCG2 126QQ and 141Q allele (2546 males and 1199 females) were selected for analysis. Mean SUA was 6.03mg/dL for CC, 6.18mg/dL for CT, and 6.19mg/dL for TT among males (p=0.012), and 4.49mg/dL, 4.45mg/dL, and 4.42mg/dL among females (not significant), respectively. No association was observed for rs3755166. The association with rs2544390 was stronger among male drinkers. The odds ratio of drinking ≥5/week relative to no drinking for hyperuricemia (SUA≥7mg/dL and/or under medication for hyperuricemia) was 1.11 (95% confidence interval, 0.67–1.84) among CC males, 1.75 (1.22–2.51) among CT males, and 3.13 (1.80–5.43) among TT males. The interaction terms with drinking ≥5/week were 1.56 (p=0.156) for CT and 2.87 (p=0.005) for TT. This was the first report on the interaction between LRP2 genotype and alcohol drinking for SUA. Since the low density lipoprotein-related protein 2 (megalin) encoded by LRP2 is a multi-ligand endocytic receptor expressed in many tissues including the kidney proximal tubules, the association/interaction remained to be confirmed both epidemiologically and biologically. [Copyright &y& Elsevier]

Uncovering population structure is important for properly conducting association studies and for examining the demographic history of a population. Here, we examined the Japanese population substructure using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC), which covers all but the northern region of Japan. Using 222 autosomal loci from 4502 subjects, we investigated population substructure by estimating FST among populations, testing population differentiation, and performing principal component analysis (PCA) and correspondence analysis (CA). All analyses revealed a low but significant differentiation between the Amami Islanders and the mainland Japanese population. Furthermore, we examined the genetic differentiation between the mainland population, Amami Islanders and Okinawa Islanders using six loci included in both the Pan-Asian SNP (PASNP) consortium data and the J-MICC data. This analysis revealed that the Amami and Okinawa Islanders were differentiated from the mainland population. In conclusion, we revealed a low but significant level of genetic differentiation between the mainland population and populations in or to the south of the Amami Islands, although genetic variation between both populations might be clinal. Therefore, the possibility of population stratification must be considered when enrolling the islander population of this area, such as in the J-MICC study. [ABSTRACT FROM AUTHOR]

Background: A G/C polymorphism in miRNA-146a (rs2910164) was shown to be associated with the risk of hepatocellular carcinoma.Objective: This study aimed to examine the associations of the miR-146a G/C (rs2910164) and TLR4 +3725 G/C (rs11536889) polymorphisms with the risk of Helicobacter pylori (H. pylori) infection, gastric atrophy, and gastric cancer in a Japanese population.Methods: Subjects for this study were 583 histologically diagnosed gastric cancer patients and age- and sex-frequency-matched 1,742 control outpatients (1,637 subjects were eligible for the analyses), who visited Aichi Cancer Center Hospital from the year 2001 to 2005. Serum pepsinogens were measured to evaluate gastric atrophy.Results: When H. pylori-seropositive subjects or subjects with gastric atrophy were defined as H. pylori-infected subjects, the age- and sex-adjusted odds ratio (aOR) of severe gastric atrophy among the H. pylori infected was 1.44 (95% confidence interval [95% CI]=0.89-2.34, p=0.133) in G/G genotype of miR-146a polymorphism. When combined with TLR4 G/C polymorphism, the OR in those with miR-146a G/G and TLR4 G/C+C/C genotypes was significantly increased relative to those with miR-146a C/C+G/C and TLR4 G/G among the H. pylori-infected subjects: aOR=2.04 (95% CI=1.10-3.82, p=0.025).Conclusions: This study revealed the combined effect of miR-146a rs2910164 G/G and TLR4 +3725 C allele on the increased risk of severe gastric atrophy among the H. pylori-infected Japanese subjects. [ABSTRACT FROM AUTHOR]

Background: Although SLC22A12 258X allele was found among those with hypouricemia, it was unknown that serum uric acid distribution among those with SLC22A12 258X allele. This study examined serum uric acid (SUA) distribution according to SLC22A12 W258X genotype in a general Japanese population. Methods: Subjects were 5,023 health checkup examinees (3,413 males and 1,610 females) aged 35 to 69 years with creatinine < 2.0 mg/dL, who were participants of a cohort study belonging to the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study). SLC22A12 W258X was genotyped with a polymerase chain reaction with confronting two-pair primers. Results: The genotype frequency was 4,793 for WW, 225 for WX, and 5 for XX, which was in Hardy-Weinberg equilibrium (p = 0.164) with X allele 0.023 (95% confidence interval [0.021-0.027]). Mean (range) SUA was 6.2 (2.1- 11.4) mg/dL for WW, 3.9 (0.8-7.8) mg/dL for WX, and 0.8 (0.7-0.9) mg/dL for XX among males, and 4.5 (1.9-8.9) mg/ dL, 3.3 (2.0-6.5) mg/dL, and 0.60 (0.5-0.7) mg/dL among females, respectively. Six individuals with SUA less than 1.0 mg/dL included two males with XX genotype, one male with WX genotype, and three females with XX genotype. Subjects with WX genotype were 14 (77.8%) of 18 males with a SUA of 1.0-2.9 mg/dL, and 28 (34.6%) of 81 females with the same range of SUA. The corresponding values were 131 (25.1%) of 522 males and 37 (3.5%) of 1,073 females for SUA 3.0-4.9 mg/dL, and 8 (0.4%) of 2,069 males and 5 (1.1%) of 429 females for SUA 5.0-6.9 mg/ dL. The X allele effect for SUA less than 3 mg/dL was significantly (p < 0.001) higher in males (OR = 102.5, [33.9- 309.8]) than in females (OR = 25.6 [14.4-45.3]). Conclusions: Although SLC22A12 W258X was a determining genetic factor on SUA, SUA of those with WX genotype distributed widely from 0.8 mg/dL to 7.8 mg/dL. It indicated that other genetic traits and/or lifestyle affected SUA of those with WX genotype, as well as those with WW genotype. [ABSTRACT FROM AUTHOR]

This study aimed to examine the associations of a RUNX3 T/A polymorphism at exon 1 (Asn18Ile) (rs6672420) and another RUNX3 intronic T/A polymorphism (rs760805) with the risk of gastric cancer together with the risk of H. pylori seropositivity and gastric atrophy in Japanese people. Study subjects were 583 histologically diagnosed gastric cancer patients and age- and sex-frequency-matched 1,742 control outpatients (among whom 1,637 subjects were eligible for the analyses), who visited Aichi Cancer Center Hospital from 2001 to 2005. Serum pepsinogens were measured to evaluate gastric atrophy. There was no significant association between the RUNX3 polymorphisms and the seropositivity. Among H. pylori seropositive subjects, we found a significant association between RUNX3 rs760805 polymorphism and the risk of gastric atrophy with the age- and sex-adjusted OR of 1.51 (95% CI 1.11–2.05, P = 0.008) in T/A, 1.59 (95% CI 1.08–2.33, P = 0.019) in A/A, and 1.53 (95% CI 1.14–2.05, P = 0.004) in T/A + A/A, compared with T/T genotype. We found no statistically significant associations between RUNX3 rs6672420 polymorphism and risk of gastric atrophy, nor between these two RUNX3 polymorphisms and the risk of gastric cancer relative to the subjects with gastric atrophy. Our study results revealed that the RUNX3 intronic T/A polymorphism (rs760805) might modulate the risk of gastric atrophy among H. pylori seropositive subjects, and the RUNX3 T/A polymorphism at exon 1 (rs6672420) had little influence on the risks of H. pylori infection, gastric atrophy or gastric cancer in Japanese people. Further investigation is required to verify our findings. [ABSTRACT FROM AUTHOR]

In postmenopausal women, extraovarian sex hormone production plays an important role in hormone-related diseases, such as breast and endometrial cancers. Aromatase, an enzyme encoded by CYP19A1, is a key enzyme involved in estrogen biosynthesis. The impact of CYP19A1 polymorphisms on serum sex hormone levels in the Japanese population has never been investigated. This study enrolled 100 postmenopausal Japanese women found to be without cancer. Twenty-five CYP19A1 loci were identified, and measurements were conducted on serum levels of sex hormones; lifestyle data were collected, namely estrone (E1), estradiol (E2), testosterone and sex hormone-binding globulin (SHBG). We conducted a cross-sectional analysis to evaluate the impact of CYP19A1 haplotype on serum sex hormone levels. We found that subjects with BMI25 kg/m2 showed a significant difference in circulating testosterone levels (0.29±0.19, P=0.050). Neither age nor the amount of physical exercise or drinking habits showed any effect on hormone levels. We identified seven haplotype blocks in CYP19A1 by LD analysis. Estrone levels differed in rs12148604 (SNP 1) and rs11632903 (SNP14). No significant locus for estradiol was observed. SHBG levels were associated with rs4441215 (SNP11). Testosterone levels were strongly associated with rs752760 (SNP24) and rs2445768 (SNP25) and weakly associated with SNP 1, SNP11 and SNP14 as well. We found that polymorphisms in CYP19A1 influence sex hormone levels in Japanese postmenopausal women.Journal of Human Genetics (2009) 54, 78–85; doi:10.1038/jhg.2008.11; published online 16 January 2009 [ABSTRACT FROM AUTHOR]

Helicobacter pylori, especially the cytotoxin-associated antigen A ( cagA)-positive strains, plays a crucial role in the development of gastric atrophy and gastric cancer. CagA delivered into gastric epithelial cells combines with src homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2), possibly leading to atrophy/cancer. Our previous study found that a single-nucleotide polymorphism (SNP; IMS-JST057927) of the PTPN11 gene encoding SHP-2, was associated with gastric atrophy among H. pylori-seropositive subjects. This study aimed to examine the reproducibility of the association among Japanese residing in a different circumstance. The subjects were 918 healthy adult Japanese Brazilians from four different areas in Brazil. Blood was sampled from March to May 2001. The target SNP in intron 3 of PTPN11 was genotyped by polymerase chain reaction with confronting two-pair primers (PCR-CTPP). Gastric atrophy was evaluated with serum pepsinogens (PGs); PG I, less than 70 ng/dl and PG I/II ratio, less than 3. The genotype frequency of PTPN11 was in Hardy-Weinberg equilibrium: 65.5% for G/ G, 30.4% for G/ A, and 4.1% for A/ A. The PTPN11 polymorphism had no significant association with H. pylori seropositivity. Among the H. pylori-seropositive subjects, the odds ratios (ORs) of gastric atrophy were 0.93 (95% confidence interval [CI], 0.59–1.47) for the G/ A genotype and 0.31 (95% CI, 0.10–0.95) for the A/ A genotype, compared with the G/ G genotype. The present study reproduced the significant association between the A/ A genotype and reduced risk of gastric atrophy among Japanese outside Japan. According to the Japan Single Nucleotide Polymorphisms (JSNP) database (db)SNP data, the G allele is very frequent among Japanese and rare in Caucasians. This fact may partly explain the distribution of gastric atrophy/cancer in the world. [ABSTRACT FROM AUTHOR]

The peroxisome proliferator-activated receptor gamma ( PPARγ) gene plays important roles in energy homeostasis. To examine interactions between consumption of foods and fatty acids and the Pro12Ala and C161T ( His447His) polymorphisms for colorectal cancer, we performed two case-control studies in Japanese. In study 1, there were 128 colorectal cancer cases and 238 non-cancer controls, and in study 2 there were 257 cases and 771 (age- and sex-matched) non-cancer controls. Assessment of food and nutrients consumption in study 1 was via a nine-item questionnaire, while in study 2 assessment of consumption was according to a more detailed semiquantitative food frequency questionnaire. Consumption of foods and fatty acids was divided into low, moderate and high groups. The overall frequency of the Ala allele was <4%, and the frequencies of the Pro/Pro +  C/C and Pro/Pro + ( C/T + T/T) genotypes were 70–73% and 20–26%, respectively. Compared with subjects with low meat intake and the Pro/Pro +  C/C genotype, those with high meat consumption and the same genotype had a stronger increased risk in study 1 [OR, 2.88; 95% CI, 1.14–7.30; P for trend = 0.02], but a positive association with processed meat consumption was greatest in those with the Pro/Pro + ( C/T + T/T) genotype ( P for trend = 0.05) in study 2. Likewise, high consumption of saturated fatty acids and milk appeared to confer marginal increased risk and stronger decreased risk, respectively, in those with the Pro/Pro and Pro/Pro +  C/C genotypes (OR, 1.35 and 0.65; 95% CI, 0.93–1.96 and 0.43–1.00; P for trend = 0.10 and 0.06). Further large-scale studies are needed to determine colorectal cancer risk according to relationships between the PPARγ gene polymorphisms and dietary intakes of meat, processed meat, milk and saturated fatty acids in Japanese with very low frequency of the Ala allele. ( Cancer Sci 2006; 97: 1226–1235) [ABSTRACT FROM AUTHOR]

Abstract: A previous study showed expression of CD36, recently reported to play important roles in metabolism of oxidized low-density lipoprotein and long-chain fatty acids and to be positively correlated with colon cancer prognosis. To examine relationships between colorectal cancer and the CD36 gene A52C polymorphism according to meat consumption as a surrogate for saturated fatty acid intake, we conducted the present hospital-based, case-control study of 128 cases and 238 non-cancer controls. Consumption of meat and vegetables/fruit was divided into three (low, moderate, and high) and two (low and high) groups, respectively. Regarding the risk of colorectal cancer on cross-classifying subjects for the CD36 genotype and meat consumption, the odds ratio (OR) for the C/C genotype with moderate meat consumption relative to the A/A genotype with low meat consumption was 8.30 (95% confidence interval, CI = 2.15–32.00). None of individuals with the C/C genotype was in the high meat consumption group. In the low vegetables/fruit consumption group, the OR for the C/C genotype relative to the A/A genotype was 3.03 (95% CI = 1.12–7.90). Our findings suggest that interactions between moderate-high meat consumption and the CD36 gene A52C polymorphism may increase the risk of colorectal cancer. [ABSTRACT FROM AUTHOR]

To examine the possible association between cervical cancer and p73 G4C14-to-A4T14 in exon 2 and p53 Arg72Pro polymorphisms, an incident case-control study was conducted in Japanese. The cases were 112 cervical cancer patients. Controls were 320 healthy women and 122 non-cancer female outpatients. Risk estimation for each genotype by an unconditional logistic model demonstrated a possible association between the p73 A4T14 variant and the risk of cervical cancer in our Japanese population (OR=1.57; 95%CI, 0.99–2.48, P=0.053). There was no significant difference in the p53 Arg72Pro genotype frequency between the controls and cases. [Copyright &y& Elsevier]

Background Methods. The subjects were 291 seropositive individuals (129 males and 162 females; age, 30 to 69 years) out of 656 Japanese-Brazilian volunteers in SÃo Paulo city. Information on lifestyle factors was obtained using a self-administered questionnaire. Atrophic gastritis was defined as a PG1 serum level less than 70 ng/ml and PG1/PG2 ratio less than 3. Results. The prevalence of atrophic gastritis was 31.9% (95% confidence intervals, 26.6%–37.6%). The proportion of subjects with atrophic gastritis increased with age, but there were no significantly marked differences in the proportions of subjects with atrophic gastritis among the three generations studied (first generation [Issei], second generation [Nisei], and third generation [Sansei]) for any 10-year age group. The associations with smoking and alcohol drinking were not significant. Length of education was inversely associated with gastric atrophy, while infrequent rice intake was preventive; the odds ratio relative to everyday rice intake was 0.13 (95% confidence intervals, 0.39–0.46) on multivariate analysis. Conclusions. The present study demonstrated that frequent rice intake was a risk factor for atrophic gastritis among the H. pylori-infected Japanese-Brazilians, suggesting that diet including rice plays a role in the step from H. pylori infection to gastric atrophy. Studies of lifestyle factors related to gastric atrophy development in Helicobacter pylori-infected individuals are limited. The present cross-sectional study aimed to examine the associations between lifestyle factors and serum pepsinogens (PGs) among anti-H. pylori antibody-seropositive Japanese in Brazil, where gastric cancer mortality was reported to be as high as in Japanese in Japan, and seropositive individuals were still frequently detected. [ABSTRACT FROM AUTHOR]

Background DNA methylation plays an important role in progression of cardiovascular disease (CVD). The methylation status of long interspersed nuclear element-1 (LINE-1) reflects the global DNA methylation level and is associated with lipid profiles and glycemia. We conducted a longitudinal study to examine the association between LINE-1 DNA methylation and CVD mortality in a Japanese elderly population. Methods We targeted for 357 subjects (143 men and 214 women) who were more than 60 years, participated in the health checkup in 1990, and had no clinical history of cancer, stroke, or ischemic heart disease. During 29 years of follow-up period, total 69 subjects were died from CVD, and died of cerebrovascular disease (CBD) and ischemic heart disease (IHD) were 25 and 13, respectively. LINE-1 DNA methylation was measured using PBMCs. We defined the hypermethylation group as greater than median of the LINE-1 DNA methylation levels and hypomethylation group as others. Multivariable Hazard ratios (HRs) for each disease mortality were calculated by the Cox proportional hazard model. We adjusted for age, sex, smoking habits, and alcohol consumption. Results Significantly higher HRs for CVD and CBD mortality were observed in the hypermethylation group compared to the hypomethylation group (CVD: HR 1.67 [95%CI 1.02-2.73], CBD: HR 3.29 [95%CI 1.29-8.40]). However, IHD mortality did not associated with LINE-1 DNA methylation. Conclusions We found that LINE-1 DNA hypermethylation in PBMCs was associated with high CVD mortality, especially CBD mortality. Key messages Higher levels of LINE-1 methylation in PBMCs can be a predictive marker for CBD risk [ABSTRACT FROM AUTHOR]

Objectives: This study sought to develop a Japanese version of the General Oral Health Assessment Index (GOHAI) and validate its use in an elderly Japanese population.Methods: The GOHAI scale was translated in a standardized way consisting of forward translation, pilot study, and backward translation. Psychometric properties of the final version were assessed on 175 participants (mean age: 70.0 years, SD 6.4).Results: The response rate was more than 98% for each item. The reliability in terms of a Cronbach's alpha value was 0.89. The mean GOHAI scores were significantly lower for participants with poor perceived oral health (P<0. 001) or poor perceived general health (P<0.01). Significant correlations were observed between the GOHAI scores and the general health or physical functioning scores of the Medical Outcome Study Short Form 36 (P<0.01).Conclusions: The present study showed that the Japanese version of the GOHAI was psychometrically valid in an elderly sample population. [ABSTRACT FROM AUTHOR]

• We compared nine different eGFR formula in a Japanese population. • Japanese creatinine-based eGFR was lower than eGFR values from other formulas. • Japanese creatinine-based eGFR had a V-shaped difference with eGFR CKD- EPI 2021. • Choice of the estimation method needs caution, especially at a higher eGFR range. Previous studies have proposed different formulas of estimating glomerular filtration rate (eGFR) among clinical patients. The comprehensive comparison of eGFR formulas is not well established in a Japanese population. We compared eGFR values and chronic kidney disease (CKD) classification of nine different eGFR in a Japanese general population sample. We analyzed 469 Japanese community-dwelling adults (184 men) without any self-reported kidney disease. GFR estimated using the 4- and 6-parameter Modification of Diet in Renal Disease (MDRD) formulas (MDRD4 and MDRD6); the CKD-EPI formulas based on creatinine with (CKD-EPI-2009) and without race coefficient (CKD-EPI-2021), on cystatin C (CKD-EPI-Cys), on both (CKD-EPI-CreCys); the Japanese creatinine-based formula (JPN-Cre), cystatin C-based formula (JPN-Cys), and modified CKD-EPI formula (JPN-CKD-EPI). CKD stages were defined by KDIGO guidelines (eGFR < 60 ml/min/1.73 m2). eGFR JPN-Cre (mean = 71.2; SD = 14.3) were much lower than eGFR CKD- EPI -2021 (mean = 94.2; SD = 12.7), while eGFR JPN-Cys (mean = 102.8; SD = 24.2) was comparable to the MDRD and CKD-EPI formulas. The difference between eGFR CKD- EPI -2021 and eGFR JPN-Cre showed a V-shaped distribution across eGFR levels, indicating complex errors between these formulas. We observed very low agreement in CKD classification between eGFR JPN-Cre and the eGFR CKD- EPI -2021 (kappa = 0.13; 95% confidence interval: 0.06, 0.23). JPN-Cre was substantially different from the CKD-EPI formula without race term (CKD-EPI-2021), which means that it is impossible to recalibrate those with a simple coefficient. Although a comparison with measured GFR should be necessary, choice of the estimation method needs caution in clinical decision-making and academic research. [ABSTRACT FROM AUTHOR]

Erythrocyte count and volume are the commonly used hematological indices for anemia that change in various diseases. To date, however, only one study ever exists that addressed erythrocyte trait-associated single nucleotide polymorphisms (SNPs) in a Japanese population. Because that study was performed in patients with various diseases, we confirmed the reported associations in a general population. Participants in the current study were from the Shizuoka component of the Japan Multi-Institutional Collaborative Cohort Study, which included 4971 men and women aged 35 to 69 years who were recruited between 2006 and 2007. We analyzed the association of seven selected SNPs with the following erythrocyte traits: red blood cell count, hemoglobin (Hb) and hematocrit (Ht) levels, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration. The erythrocyte traits were regressed on a number of minor alleles of selected SNPs. Then we compared our findings with those from a genome-wide association study performed in a Japanese population. We replicated the association of ABO rs495828, PDGFRA-KIT rs218237, USP49-MED20-BSYL-CCND3 rs3218097, C6orf182-CD164 rs11966072, TERT rs2736100, and TMPRSS6 rs5756504 with erythrocyte traits in our independent Japanese population. In addition, we found a significant interaction between TERT rs2736100 and smoking habit that affected Hb and Ht levels. [ABSTRACT FROM AUTHOR]

Aims: Brain-muscle-Arnt-like protein-1 (BMAL1) and BMAL2 genes are essential components of the circadian clock, and are considered to be involved in glucose homeostasis. We examined whether single nucleotide polymorphisms (SNPs) of BMAL1 and BMAL2 were associated with the prevalence of type 2 diabetes (T2DM) in the general Japanese population.Methods: We studied 2467 subjects (1232 men and 1235 women, 35-69 years old), including 105 men and 57 women with T2DM, from the participants of the Japan Multi-institutional Collaborative Cohort Study. The association between SNPs in the BMAL1 (rs11022775 and rs2290035) and BMAL2 (rs7958822) genes and T2DM were analyzed by multiple logistic regression after adjustment for potential confounders. Analysis was also performed after stratification by body mass index (≥25 kg/m(2) and <25 kg/m(2)) to investigate an interaction between genotypes and obesity.Results: The A/G and A/A genotypes of BMAL2 rs7958822 showed significantly higher adjusted odds ratios (OR) for T2DM than the G/G genotype among obese men (OR=2.2, 95% confidence intervals [CI] 1.1, 4.6, P for interaction=0.0495) and obese women (OR=2.7, 95% CI 1.1, 6.7, P for interaction=0.199). There were no significant associations between BMAL1 rs11022775 or rs2290035 genotypes and T2DM.Conclusions: To the best of our knowledge, this is the first study to show the significant association between BMAL2 rs7958822 genotype and T2DM among obese subjects. [ABSTRACT FROM AUTHOR]

Cytokines, including interleukin-6 (IL-6), play an important role in the liver. The aim of this study was to investigate associations between common polymorphisms in potential functional promoters of cytokine genes and liver damage markers among enrollees of a large Japanese cohort study. Subjects included 3257 Japanese individuals (1608 men and 1649 women, aged 35–69 years). Six single nucleotide polymorphisms (SNPs) in the promoter regions of five cytokine genes, IL1B (T-31C), IL6 (C-634G), IL8 (T-251A), IL10 (T-819C), tumor necrosis factor-A ( TNFA ) (T-1031C), and TNFA (C-857T), were genotyped by polymerase chain reaction. Information regarding alcohol intake, smoking habits, height, and weight was collected by a self-administered questionnaire. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured during a routine health check-up. Of the six SNPs genotyped, an IL6 polymorphism (rs1800796, C-634G) was most strongly associated with a liver damage marker, AST. Mean serum AST was significantly different among the three genotypes (mean ± SD, 22.7 ± 7.3 IU/L for CC, 22.8 ± 7.7 IU/L for CG, and 24.3 ± 8.6 IU/L for GG, p = 0.011 by analysis of variance). The differences remained significant after adjustment for potential confounders by general linear models. The variations in mean serum AST and ALT levels were marked especially among men. Thus, the functional polymorphism IL6 C-634G may affect serum AST and ALT levels, possibly through different IL-6 production. [ABSTRACT FROM AUTHOR]

Abstract: Urokinase plasminogen activator (uPA) plays important physiological and pathological roles in fibrinolysis, cancer metastasis, and atherosclerosis. One study suggested that uPA also has a major role in cholesterol biosynthesis in humans via its receptor uPAR. Thus, we investigated the associations of functional uPA polymorphism (plasminogen activator, urokinase; PLAU Pro141Leu, rs2227564) with serum lipid profiles in a Japanese cohort. The study included 5152 participants (1465 male, 3687 female; age range, 35–69years) of the Daiko Study, a part of the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study). Subjects were enrolled at the Daiko Medical Center from June 2008 to May 2010. Low-density lipoprotein cholesterol (LDL-C) and non-HDL-C (subtraction of high-density lipoprotein cholesterol from total cholesterol) in fasting blood of participants were each classified into two groups, < or ≥140mg/dL, and < or ≥170mg/dL, respectively. Genotype frequencies of PLAU Pro141Leu (rs2227564) were 59.1% for ProPro, 35.6% for ProLeu, and 5.3% for LeuLeu, and were in Hardy–Weinberg equilibrium (p =0.789). The allele frequencies were 0.769 for Pro and 0.231 for Leu. The multivariate-adjusted odd ratios (ORs) and 95% confidence intervals (CIs) for high LDL-C and non-HDL-C were 1.11 (95%CI; 1.00–1.23) and 1.16 (95%CI; 1.03–1.30) for those with Leu allele relative to ProPro. This study suggested that PLAU Pro141Leu (rs2227564) is significantly associated with serum lipid levels in a Japanese population. [Copyright &y& Elsevier]

Abstract: Objectives: Timing of menopause affects postmenopausal health risks. The objective of this study was to evaluate the associations of the single nucleotide polymorphisms (SNPs) in peroxisome proliferator-activated receptor (PPAR)-related genes (PPARD, PPARG, and PPARGC1A) and environmental factors with timing of natural menopause among the general Japanese population. Study design: We analyzed cross-sectional data from 1758 women aged 40–69 years who were enrolled in the baseline surveys of the Japan Multi-institutional Collaborative Cohort (J-MICC) Study. Main outcome measures: Associations of timing of natural menopause with its probable covariates and with target gene variants were evaluated by univariate and multivariate Cox proportional hazards models. Results: Lower body mass index and later age at menarche were significantly associated with earlier natural menopause. Women with minor alleles at T-48444C in PPARD showed a significantly higher adjusted hazard ratio of 1.57 (95% confidence interval: 1.18–2.10) for earlier natural menopause. In contrast, women with minor alleles at Thr394Thr in PPARGC1A showed a significantly lower adjusted hazard ratio of 0.86 (0.76–0.97) for earlier natural menopause. These associations did not substantially alter when re-analyzed after excluding the subjects who self-reported a history of diabetes or the subjects whose age was more than 65 years. Conclusions: Gene variants in PPARD and PPARGC1A might be associated with timing of natural menopause, probably through direct actions on the ovaries, among the general Japanese population. [Copyright &y& Elsevier]

Abstract: Background: Several studies have reported that serum concentrations of carotenoids and adiponectin are inversely associated with the risk for cardiovascular disease (CVD). However, no studies have investigated the association between serum concentrations of adiponectin and carotenoids in the general population. Methods: We investigated cross-sectionally whether serum carotenoids are associated with serum high molecular weight (HMW) adiponectin and some inflammatory markers in 437 Japanese subjects (116 men and 321 women) who attended a health examination. Results: In multiple linear regression analysis adjusted for confounding factors, serum β-carotene concentrations were significantly associated with serum HMW adiponectin concentrations in both sexes (standardized β coefficient=0.197, p =0.036 for men; standardized β coefficient=0.146, p =0.012 for women). Serum α-carotene and β-carotene concentrations were significantly associated with serum C-reactive protein (CRP) concentrations in men. In women, there were significant negative associations between serum carotenoids concentrations and serum interleukin-6 (IL-6) concentrations. Additional adjustment for serum concentrations of IL-6 or CRP did not significantly affect the association between carotenoids and HMW adiponectin in non-smoking men as well as in women. Conclusion: Serum β-carotene concentrations were positively associated with serum HMW adiponectin concentrations even after adjustment for possible confounding factors including inflammatory markers. [Copyright &y& Elsevier]

Abstract: Objectives: It is well-known that smoking causes many diseases including cancers. Informing smokers of their genotypes associated with the vulnerability to the harms of smoking may be effective measures for smoking cessation. The present study examined the effects of genotype notification of an oncogene (L-myc) genotype to smokers on their behavior to quit smoking. Methods: Subjects were 562 employees of a bank who answered to be a smoker for a questionnaire used at annual health checkup at workplace from July to December 2002. Those enrolled on August, October, and December were allocated into the genotype notification group (intervention group), and the rest into the controls. Among 286 smokers allocated into the intervention group, 257 participants (89.9%) agreed to genotype testing. One year after the enrollment, a follow-up questionnaire survey was conducted for all smokers including controls. Results: Those who stated to have quitted smoking were 22 (8.0%) among the 276 controls and 15 (5.8%) among the 257 genotype notified participants, providing that the odds ratio (OR) of cessation for the intervention was 0.64 (95% confidence interval, 0.32–1.28). No psychological problems associated with genotype notification were observed. Conclusion: The present study did not show positive effects of genotype notification on smoking cessation rate. To elevate the cessation rate, methods to explain and notify genotypes should be improved. [Copyright &y& Elsevier]

Abstract: It is well known that high serum uric acid (SUA) is the cause of gout and a risk factor of cardiovascular diseases. Although SUA is thought to have an association with folate metabolism through elevated production and/or damaged renal excretion, studies on functional polymorphisms of folate metabolizing are still limited, showing inconsistent findings. We hypothesized that hyperuricemia would be associated with methylenetetrahydrofolate reductase (MTHFR) C677T and thymidylate synthase (TS) 28-bp tandem repeat polymorphism. Subjects were 793 healthy health checkup examinees (272 male and 521 female Japanese) aged 39 years or older. There was no clear difference in SUA means among those with different genotypes of MTHFR and TS, but a significant association between hyperuricemia (SUA ≥7mg/dL) and MTHFR 677T allele carriers was observed. The odds ratio of harboring 677T allele adjusted for sex, age, body mass index, serum creatinine, systolic blood pressure, currents habits of smoking and drinking, and TS genotype was 2.77 (95% confidence interval, 1.38-5.56). The TS genotype was not significantly associated with hyperuricemia; the corresponding adjusted odds ratio was 1.36 (95% confidence interval, 0.75-2.48) for non–33 genotype relative to 33 genotype. Because MTHFR 677CC was rarer both in <4 mg/dL group and ≥7 mg/dL group, the comparisons of SUA means were not useful to elucidate the roles of the polymorphism. This new view may partly explain the inconsistent results on the association of the MTHFR polymorphism with SUA. [Copyright &y& Elsevier]

Abstract: Resistin, which appears to be related to insulin resistance, is secreted mainly from macrophages in human and some of its polymorphisms have been reported. Based on recent in vitro studies, resistin may be associated with atherosclerosis by mediating endothelial hyperactivity. We investigated whether resistin polymorphism at −420C>G is associated with serum resistin levels and diabetic macroangiopathy (coronary heart disease, arteriosclerosis obliterans, and stroke) in 349 Japanese type 2 diabetic patients (DM) and 286 non-diabetic controls (non-DM). Serum resistin levels in DM with a history of stroke were significantly higher than those without, 19.6±2.1 and 12.4±0.5ng/ml (P <0.001), respectively. Furthermore, the levels were significantly increased in a genotype-dependent manner (CC, CG, GG) based on the polymorphism at −420C>G (P <0.001) in both DM and non-DM. The prevalence of stroke in DM significantly increased according to the presence of mutations (P <0.035). In multivariate logistic-regression analysis, individuals with the CG or GG genotypes were significantly more likely to have had a stroke than individuals with the CC genotype (vs. CG; OR 2.99, P =0.024, vs. GG; OR 4.49, P =0.010). These data suggested that the genotyping of resistin polymorphism at −420(C>G) can be a risk marker for stroke susceptibility in Japanese type 2 diabetic patients. [Copyright &y& Elsevier]