Population-Based Impact of Smoking, Drinking, and Genetic Factors on HDL-cholesterol Levels in J-MICC Study Participants.

BACKGROUND: Environmental and genetic factors are suggested to exhibit factor-based association with HDL-cholesterol (HDL-C) levels. However, the population-based effects of environmental and genetic factors have not been compared clearly. We conducted a cross-sectional study using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study to evaluate the population-based impact of smoking, drinking, and genetic factors on low HDL-C. METHODS: Data from 11,498 men and women aged 35-69 years were collected for a genome-wide association study (GWAS). Sixty-five HDL-C-related SNPs with genome-wide significance (P < 5 × 10-8) were selected from the GWAS catalog, of which seven representative SNPs were defined, and the population-based impact was estimated using population attributable fraction (PAF). RESULTS: We found that smoking, drinking, daily activity, habitual exercise, egg intake, BMI, age, sex, and the SNPs CETP rs3764261, APOA5 rs662799, LIPC rs1800588, LPL rs328, ABCA1 rs2575876, LIPG rs3786247, and APOE rs429358 were associated with HDL-C levels. The gene-environmental interactions on smoking and drinking were not statistically significant. The PAF for low HDL-C was the highest in men (63.2%) and in rs3764261 (31.5%) of the genetic factors, and the PAFs of smoking and drinking were 23.1% and 41.8%, respectively. CONCLUSION: The present study showed that the population-based impact of genomic factor CETP rs3764261 for low HDL-C was higher than that of smoking and lower than that of drinking.

Effect of Garcinia mangostana pericarp extract on glial NF-κB levels and expression of serum inflammation markers in an obese-type 2 diabetes mellitus animal model.

Type 2 diabetes mellitus (T2DM) is an age-related disease associated with cerebral inflammation and Alzheimer's disease. Garcinia mangostana pericarp (GMP) possesses antihyperglycemic, antidiabetic and anti-inflammatory effects. The aim of the present study was to evaluate the effect of GMP extract on cerebral inflammation in Wistar rats with T2DM by examining the expression levels of glial nuclear factor-κB (NF-κB), interleukin (IL)-6, tumor necrosis factor-α (TNF-α) and superoxide dismutase (SOD). A total of 36 8-10-week-old male Wistar rats were randomly divided into six groups and provided a standard diet (normal control; C1), high-fat diet (HFD) with 200 g/kg GMP extract BW/day (GMP control; C2), HFD with streptozotocin-nicotinamide (diabetic control; C3), and HFD with 100 (M1), 200 (M2) or 400 g/kg body weight (BW)/day (M3) GMP extract for Wistar rats with diabetes. GMP extract was administered for 8 weeks after induction of T2DM was confirmed. Glial NF-κB activity was assessed by immunohistochemical staining, and by measuring IL-6 levels, TNF-α levels and SOD activity in the serum using ELISA. BW significantly increased following HFD treatment. After 7 weeks, the BW remained significantly higher compared with the normal control and GMP extract-treated groups, but decreased continuously in the T2DM groups. Glial NF-κB immunoreaction in the hippocampal region was significantly higher in the diabetic Wistar rats compared with the normal control Wistar rats, and 200 g/kg BW/day GMP significantly reduced its activity. The T2DM Wistar rats showed significantly higher expression levels of serum IL-6 and TNF-α and lower activity of SOD compared with the normal control Wistar rats. Meanwhile, rats in GMP groups M1, M2 and M3 exhibited significant reductions in the levels of IL-6 and TNF-α expression, and increases in SOD activity. GMP extract treatment effectively reduced hippocampal NF-κB, IL-6 and TNF-α levels and increased antioxidant SOD activity. These results suggest that GMP extract prevents cerebral inflammation in T2DM Wistar rats.

Genomewide Association Study of Leisure-Time Exercise Behavior in Japanese Adults.

PURPOSE: Although several genetic factors may play a role in leisure-time exercise behavior, there is currently no evidence of a significant genomewide association, and candidate gene replication studies have produced inconsistent results. METHODS: We conducted a two-stage genomewide association study and candidate single-nucleotide polymorphisms (SNP) association study on leisure-time exercise behavior using 13,980 discovery samples from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study, and 2036 replication samples from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center-2 study. Leisure-time physical activity was measured using a self-administered questionnaire that inquired about the type, frequency and duration of exercise. Participants with ≥4 MET·h·wk of leisure-time physical activity were defined as exhibiting leisure-time exercise behavior. Association testing using mixed linear regression models was performed on the discovery and replication samples, after which the results were combined in a meta-analysis. In addition, we tested six candidate genetic variants derived from previous genomewide association study. RESULTS: We found that one novel SNP (rs10252228) located in the intergenic region between NPSR1 and DPY19L1 was significantly associated with leisure-time exercise behavior in discovery samples. This association was also significant in replication samples (combined P value by meta-analysis = 2.2 × 10). Several SNP linked with rs10252228 were significantly associated with gene expression of DPY19L1 and DP19L2P1 in skeletal muscle, heart, whole blood, and the nervous system. Among the candidate SNP, rs12612420 in DNAPTP6 demonstrated nominal significance in discovery samples but not in replication samples. CONCLUSIONS: We identified a novel genetic variant associated with regular leisure-time exercise behavior. Further functional studies are required to validate the role of these variants in exercise behavior.

A genome-wide association study in the Japanese population identifies the 12q24 locus for habitual coffee consumption: The J-MICC Study.

Coffee is one of the most widely consumed beverages worldwide, and its role in human health has received much attention. Although genome-wide association studies (GWASs) have investigated genetic variants associated with coffee consumption in European populations, no such study has yet been conducted in an Asian population. Here, we conducted a GWAS to identify common genetic variations that affected coffee consumption in a Japanese population of 11,261 participants recruited as a part of the Japan Multi-Institutional Collaborative Cohort (J-MICC) study. Coffee consumption was collected using a self-administered questionnaire, and converted from categories to cups/day. In the discovery stage (n = 6,312), we found 2 independent loci (12q24.12-13 and 5q33.3) that met suggestive significance (P < 1 × 10-6). In the replication stage (n = 4,949), the lead variant for the 12q24.12-13 locus (rs2074356) was significantly associated with habitual coffee consumption (P = 2.2 × 10-6), whereas the lead variant for the 5q33.3 locus (rs1957553) was not (P = 0.53). A meta-analysis of the discovery and replication populations, and the combined analysis using all subjects, revealed that rs2074356 achieved genome-wide significance (P = 2.2 × 10-16 for a meta-analysis). These findings indicate that the 12q24.12-13 locus is associated with coffee consumption among a Japanese population.

Modification of the Associations of Alcohol Intake With Serum Low-Density Lipoprotein Cholesterol and Triglycerides by ALDH2 and ADH1B Polymorphisms in Japanese Men.

BACKGROUND: Although beneficial associations have been reported between moderate alcohol intake and the serum lipid profile, it is unclear whether polymorphisms in alcohol-metabolizing enzymes can modify these associations. Here, we assessed the effects of ADH1B His48Arg (rs1229984), ALDH2 Glu504Lys (rs671), and their combination on these associations. Furthermore, we examined if the findings for ALDH2 could be replicated. METHODS: We categorized 889 male participants in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study into two groups based on presence or absence of minor allele(s) or four groups based on genotype combinations. We performed regression analyses of serum lipid concentrations on alcohol intake, with multivariable adjustment. The replication study was conducted among 2,562 men in the Shizuoka part of the J-MICC Study. RESULTS: The ALDH2 Glu/Lys or Lys/Lys groups showed significant decreases in serum low-density lipoprotein (LDL) cholesterol with increasing alcohol consumption; the coefficient per intake increase of 10 g/day was -2.49 mg/dL (95% confidence interval [CI], -3.85 to -1.13), and a significant interaction with the polymorphism was confirmed (P for interaction = 0.006). This inverse correlation was more evident among the ADH1B His/His + ALDH2 Glu/Lys or Lys/Lys groups (-3.24 mg/dL, 95% CI, -5.03 to -1.45). Serum triglycerides were positively associated with alcohol consumption in the ADH1B His/His group (P for interaction = 0.020). The stronger association between serum LDL cholesterol and alcohol consumption in the ALDH2 Glu/Lys or Lys/Lys groups was replicated. CONCLUSIONS: The ALDH2 Glu504Lys polymorphism can modify the association between alcohol intake and serum LDL cholesterol in Japanese men.

Interactions between inflammatory gene polymorphisms and HTLV-I infection for total death, incidence of cancer, and atherosclerosis-related diseases among the Japanese population.

BACKGROUND: An increased risk of total death owing to human T-lymphotropic virus type-I (HTLV-I) infection has been reported. However, its etiology and protective factors are unclear. Various studies reported fluctuations in immune-inflammatory status among HTLV-I carriers. We conducted a matched cohort study among the general population in an HTLV-I-endemic region of Japan to investigate the interaction between inflammatory gene polymorphisms and HTLV-I infection for total death, incidence of cancer, and atherosclerosis-related diseases. METHOD: We selected 2180 sub-cohort subjects aged 35-69 years from the cohort population, after matching for age, sex, and region with HTLV-I seropositives. They were followed up for a maximum of 10 years. Inflammatory gene polymorphisms were selected from TNF-α, IL-10, and NF-κB1. A Cox proportional hazard model was used to estimate the hazard ratio (HR) and the interaction between gene polymorphisms and HTLV-I for risk of total death and incidence of cancer and atherosclerosis-related diseases. RESULTS: HTLV-I seropositivity rate was 6.4% in the cohort population. The interaction between TNF-α 1031T/C and HTLV-I for atherosclerosis-related disease incidence was statistically significant (p = 0.020). No significant interaction was observed between IL-10 819T/C or NF-κB1 94ATTG ins/del and HTLV-I. An increased HR for total death was observed in the Amami island region, after adjustment of various factors with gene polymorphisms (HR 3.03; 95% confidence interval, 1.18-7.77). CONCLUSION: The present study found the interaction between TNF-α 1031T/C and HTLV-I to be a risk factor for atherosclerosis-related disease. Further follow-up is warranted to investigate protective factors against developing diseases among susceptible HTLV-I carriers.

Associations between Dietary Patterns, ADRß2 Gln27Glu and ADRß3 Trp64Arg with Regard to Serum Triglyceride Levels: J-MICC Study.

Interactions between dietary patterns and 2 ß-adrenergic receptor (ADRß) gene polymorphisms (ADRß2 Gln27Glu and ADRß3 Trp64Arg) were examined with regard to the effects on serum triglyceride levels. The cross-sectional study comprised 1720 men and women (aged 35-69 years) enrolled in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. Genotyping was conducted using a multiplex polymerase chain reaction-based invader assay. We used 46 items from a validated short food frequency questionnaire and examined major dietary patterns by factor analysis. We identified four dietary patterns: healthy, Western, seafood and bread patterns. There was no significant association between any dietary pattern and serum triglyceride levels. After a separate genotype-based analysis, significant interactions between ADRß3 Trp64Arg genotype and the bread pattern (p for interaction = 0.01) were associated with serum triglyceride levels; specifically, after adjusting for confounding factors, Arg allele carriers with the bread pattern had lower serum triglycerides (p for trend = 0.01). However, the Trp/Trp homozygous subjects with the bread pattern showed no association with serum triglycerides (p for trend = 0.55). Interactions between other dietary patterns and ADRß polymorphisms were not significant for serum triglyceride levels. Our findings suggest that ADRß3 polymorphism modifies the effects of the bread pattern on triglyceride levels.

Positive Association of Plasma Homocysteine Levels with Cardio-Ankle Vascular Index in a Prospective Study of Japanese Men from the General Population.

AIM: Observational studies have reported that elevated homocysteine (Hcy) levels are associated with the risk of cardiovascular disease (CVD). However, interventions that lower Hcy do not provide a corresponding risk reduction. Therefore, the causal role of Hcy in CVD remains unclear. This 5-year prospective study investigated the associations of Hcy levels, folate intake, and host factors with arterial stiffness among the general Japanese population. METHODS: We prospectively recruited 658 participants (40-69 years old) from the general population during regular health checkup examinations. Arterial stiffness was evaluated using the cardio-ankle vascular index (CAVI) at baseline and the 5-year follow-up. Folate intake was estimated using a structured questionnaire. Genotyping was used to evaluate the MTHFR C677T and MS A2756G gene polymorphisms. Ultrafast liquid chromatography was used to measure total plasma Hcy levels. Association between these variables and CAVI values was evaluated using general linear regression and logistic regression models that were adjusted for atherosclerosis-related factors. RESULTS: Men had higher Hcy levels and CAVI values and lower folate intake than women (all, p＜0.001). At baseline, Hcy, folate intake, and the two genotypes were not associated with CAVI values for both sexes. Among men, Hcy levels were positively associated with CAVI values at the 5-year follow-up (p=0.033). Folate intake and the two genotypes were not associated with the 5-year CAVI values. CONCLUSION: Plasma Hcy may be involved in arterial stiffness progression, as monitored using CAVI, among men.

Effect of losartan and benzbromarone on the level of human urate transporter 1 mRNA.

Both an angiotensin II receptor blocker, losartan (CAS 124750-99-8) and a serum urate lowering agent, benzbromarone (CAS 3562-84-3) exert a uricosuric action by inhibiting urate transporter 1 (URAT1). A recent clinical trial indicated that losartan could reduce the level of serum urate in hypertensive patients treated with urate lowering agents, suggesting the different mode of action of losartan from benzbromarone. In the present study, the effect of losartan and benzbromarone on the level of URAT1 mRNA was determined in transfected HEK293 cells. Losartan caused a significant reduction of its mRNA level, whereas it was not affected by benzbromarone. These results indicate that losartan decreases the level of human URAT1 mRNA, which may underlie the uricosuric action of losartan in hypertensive patients treated with serum urate lowering agents.