GWAS of folate metabolism with gene-environment interaction analysis revealed the possible role of lifestyles in the control of blood folate metabolites in Japanese - the J-MICC Study.


Dietary carbohydrate and fat intakes and risk of mortality in the Japanese population: the Japan Multi-Institutional Collaborative Cohort Study.

An unfavorable association with mortality was observed for low carbohydrate intake in men and for high carbohydrate intake in women. High fat intake could be associated with a lower mortality risk in women among Japanese adults with a relatively high carbohydrate intake.


Association of kidney function with cancer incidence and its influence on cancer risk of smoking: The Japan Multi-Institutional Collaborative Cohort Study.


Investigating the association between glycaemic traits and colorectal cancer in the Japanese population using Mendelian randomisation.


質問紙で調査した成人の身体活動:日本多施設共同コーホート研究(J-MICC Study)


Coffee and Metabolic Phenotypes: A Cross-sectional Analysis of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study

To date, the relationship between coffee consumption and metabolic phenotypes has hardly been investigated and remains controversial. Therefore, the aim of this cross-sectional study is to examine the associations between coffee consumption and metabolic phenotypes in a Japanese population. We analyzed the data of 26,363 subjects (aged 35-69 years) in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. Coffee consumption was assessed using a questionnaire. Metabolic Syndrome (MetS) was defined according to the Joint Interim Statement Criteria of 2009, using body mass index (BMI) instead of waist circumference. Subjects stratified by the presence or absence of obesity (normal weight: BMI <25 kg/m; obesity: BMI ≥25 kg/m) were classified by the number of MetS components (metabolically healthy: no components; metabolically unhealthy: one or more components) other than BMI. In multiple logistic regression analyses adjusted for sex, age, and other potential confounders, high coffee consumption (≥3 cups/day) was associated with a lower prevalence of MetS and metabolically unhealthy phenotypes both in normal weight (OR 0.83, 95% CI 0.76-0.90) and obese subjects (OR 0.83, 95% CI 0.69-0.99). Filtered/instant coffee consumption was inversely associated with the prevalence of MetS and metabolically unhealthy phenotypes, whereas canned/bottled/packed coffee consumption was not. The present results suggest that high coffee consumption, particularly filtered/instant coffee, is inversely associated with the prevalence of metabolically unhealthy phenotypes in both normal weight and obese Japanese adults.

Nutrition, Metabolism, and Cardiovascular Diseases : NMCD


Association between dietary patterns and serum low density lipoprotein cholesterol in Japanese women and men: The Japan Multi-Institutional Collaborative Cohort (J-MICC) Study

The association between dietary patterns and serum low density lipoprotein (LDL) cholesterol would be changing in recent dietary habits in Japan. We investigated the relationship between dietary patterns and serum LDL cholesterol in a large general population. From the baseline survey of Japan Multi-Institutional Collaborative Cohort Study between 2005 and 2013, 27,237 participants (13,994 were women) aged 35-69 years were cross-sectionally analyzed. Using a semi-quantitative food frequency questionnaire, five major sex-specific dietary patterns were identified using factor analysis. We assessed serum LDL cholesterol by quintiles of dietary pattern factor score. We identified dietary patterns; "vegetable rich pattern" , "meat and fried food rich pattern" and "high bread and low rice pattern" in women and men; "fish and shellfish rich pattern" and "high confectioneries and low alcohol pattern" in men; "healthy Japanese diet pattern" and "high alcohol and low rice pattern" in women. Serum LDL cholesterol in men was associated with "high bread and low rice pattern" score (Q5 was 4.2 mg/dL higher than Q1, p for trend <0.001) and "high confectioneries and low alcohol pattern" scores (Q5 was 9.5 mg/dL higher than Q1, p for trend <0.001). In women, serum LDL cholesterol was associated with "high bread and low rice pattern" score (Q5 was 7.1 mg/dL higher than Q1, p for trend <0.001). Some recent dietary patterns in Japan were associated with serum LDL cholesterol. Serum LDL cholesterol was associated with high bread and low rice pattern in both sex, and high confectioneries and low alcohol pattern in men.

Journal of Atherosclerosis and Thrombosis


Effects of gene-lifestyle interactions on obesity based on a multi-locus risk score: a cross-sectional analysis

The relationship between lifestyle and obesity is a major focus of research. Personalized nutrition, which utilizes evidence from nutrigenomics, such as gene-environment interactions, has been attracting attention in recent years. However, evidence for gene-environment interactions that can inform treatment strategies is lacking, despite some reported interactions involving dietary intake or physical activity. Utilizing gene-lifestyle interactions in practice could aid in optimizing interventions according to genetic risk. This study aimed to elucidate the effects of gene-lifestyle interactions on body mass index (BMI). Cross-sectional data from the Japan Multi-Institutional Collaborative Cohort Study were used. Interactions between a multi-locus genetic risk score (GRS), calculated from 76 ancestry-specific single nucleotide polymorphisms, and nutritional intake or physical activity were assessed using a linear mixed-effect model. The mean (standard deviation) BMI and GRS for all participants (n = 12,918) were 22.9 (3.0) kg/m2 and -0.07 (0.16), respectively. The correlation between GRS and BMI was r(12,916) = 0.13 (95% confidence interval [CI] 0.11-0.15, P < 0.001). An interaction between GRS and saturated fatty acid intake was observed (β = -0.11, 95% CI -0.21 to -0.02). An interaction between GRS and n-3 polyunsaturated fatty acids was also observed in the females with normal-weight subgroup (β = -0.12, 95% CI -0.22 to -0.03). Our results provide evidence of an interaction effect between GRS and nutritional intake and physical activity. This gene-lifestyle interaction provides a basis for developing prevention or treatment interventions for obesity according to individual genetic predisposition.


Comparison of the loci associated with HbA1c and blood glucose levels identified by a genome-wide association study in the Japanese population

Hemoglobin A1c (HbA1c) levels are widely employed to diagnose diabetes. However, estimates of the heritability of HbA1c and glucose levels are different. Therefore, we explored HbA1c- and blood glucose-associated loci in a non-diabetic Japanese population. We conducted a two-stage genome-wide association study (GWAS) on variants associated with HbA1c and blood glucose levels in a Japanese population. In the initial stage, data of 4911 participants of the Japan Multi-Institutional Collaborative Cohort (J-MICC) were subjected to discovery analysis. In the second stage, two datasets from the Tohoku Medical Megabank project, with 8175 and 40,519 participants, were used for the replication study. Association of the imputed variants with HbA1c and blood glucose levels was determined via linear regression analyses adjusted for age, sex, body mass index (BMI), smoking, and genetic principal components (PC1-PC10). Moreover, we performed a BMI-stratified GWAS on HbA1c levels in the J-MICC. The discovery analysis and BMI-stratified GWAS results were validated with re-analyses of normalized HbA1c levels adjusted for site in addition to the above, and blood glucose adjusted for fasting time as an additional covariate. Genetic variants associated with HbA1c levels were identified in and . None of the genetic variants associated with blood glucose levels in the discovery analysis were replicated. Association of rs2299620 in with HbA1c levels showed heterogeneity between individuals with BMI ≥ 25 kg/m and BMI < 25 kg/m. The variant rs2299620 in might affect HbA1c levels differentially based on BMI grouping in the Japanese population. The online version contains supplementary material available at 10.1007/s13340-023-00618-0.


BMI and cardiometabolic traits in Japanese: a Mendelian randomization study

Although many observational studies have demonstrated significant relationships between obesity and cardiometabolic traits, the causality of these relationships in East Asians remains to be elucidated. We conducted individual-level Mendelian randomization (MR) analyses targeting 14,083 participants in the Japan Multi-Institutional Collaborative Cohort Study, and two-sample MR analyses using summary statistics based on genome-wide association study data from 173,430 Japanese. Using 83 body mass index-related loci, genetic risk scores (GRS) for BMI were calculated, and the effects of BMI on cardiometabolic traits were examined for individual-level MR analyses by the two-stage least squares estimator method. The β-coefficients and standard errors for the per-allele association of each single-nucleotide polymorphism as well as all outcomes, or odds ratios with 95% confidence intervals were calculated in the two-sample MR analyses. In individual-level MR analyses, the GRS of BMI was not significantly associated with any cardiometabolic traits. In two-sample MR analyses, higher BMI was associated with higher risks of higher blood pressure, triglycerides, uric acid, lower high-density-lipoprotein cholesterol and eGFR. The associations of BMI with type 2 diabetes in two-sample MR analyses were inconsistent by different methods, including the directions. The results of this study suggest that, even among the Japanese, an East Asian population with low levels of obesity, higher BMI could be causally associated with the development of a variety of cardiometabolic traits. Causality in those associations should be clarified in future studies with larger populations, especially those of BMI with type 2 diabetes.


Irregular sleep and all-cause mortality: a large prospective cohort study

Previous studies using objective parameters have shown that irregular sleep is associated with the disease incidence, progression, or mortality. This study aimed to determine the association between subjective sleep duration and sleep regularity, with mortality in a large population. Participants were from the Japan Multi-Institutional Collaborative Cohort study. We obtained information from each participant on sleep duration, sleep regularity, and demographics and overall lifestyle using self-administered questionnaires. We defined sleep regularity according to participants' subjective assessment of sleep/wake time regularity. Participants (n = 81,382, mean age: 58.1 ± 9.1years, males: 44.2%) were classified into 6 groups according to sleep duration and sleep regularity. Hazard ratios (HR) for time-to-event of death were calculated using the Cox proportional hazards model. The mean follow-up period was 9.1 years and the mean sleep duration was 6.6 h/day. Irregular sleep significantly increased the risk of all-cause mortality in all models compared with regular sleep (HR 1.30, 95% confidence interval; CI, 1.18-1.44), regardless of sleep duration. Multivariable analysis of the 6 groups by sleep pattern (sleep regularity and duration) showed irregular sleep and sleep durations of <6 h/day, 6 to <8 h/day, or 8 h/day were associated with a 1.2-1.5-fold increases in mortality, compared to regular sleep and sleep duration of 6 to <8 h/day. Our study shows an association between sleep irregularity and all-cause mortality in a large Japanese population. Our findings provide further confirmation of the need to consider not only sleep duration, but also the regularity aspect of sleep schedules.


Genetic polymorphism of pleiotrophin is associated with pain experience in Japanese adults: case-control study

Genetic factors play a role in individual differences in pain experience. Here, we performed a genome-wide association study (GWAS) to identify novel loci regulating pain processing. We conducted a 2-stage GWAS and the candidate single-nucleotide polymorphisms (SNPs) association study on pain experience using an exploratory cohort of patients with cancer pain. The confirmatory cohort comprised of participants from the general population with and without habitual use of analgesic medication. In the exploratory cohort, we evaluated pain intensity using a numerical rating scale, recorded daily opioid dosages, and calculated pain reduction rate. In the confirmatory cohort, pain experience was defined as habitual nonsteroidal anti-inflammatory drug usage. Using linear regression models, we identified candidate SNP in the exploratory samples, and tested the association between phenotype and experienced pain in the confirmatory samples. We found 1 novel SNP (rs11764598)-located on the gene encoding for pleiotrophin on chromosome 7-that passed the genome-wide suggestive significance at 20% false discovery rate (FDR) correction in the exploratory samples of patients with cancer pain (P = 1.31 × 10-7, FDR = 0.101). We confirmed its significant association with daily analgesic usage in the confirmatory cohort (P = .028), although the minor allele affected pain experience in an opposite manner. We identified a novel genetic variant associated with pain experience. Further studies are required to validate the role of pleiotrophin in pain processing.


Associations of metabolic syndrome and metabolically unhealthy obesity with cancer mortality: The Japan Multi-Institutional Collaborative Cohort (J-MICC) Study

The association between metabolic syndrome (MetS) and the risk of death from cancer is still a controversial issue. The purpose of this study was to examine the associations of MetS and metabolically unhealthy obesity (MUHO) with cancer mortality in a Japanese population. We used data from the Japan Multi-Institutional Collaborative Cohort Study. The study population consisted of 28,554 eligible subjects (14,103 men and 14,451 women) aged 35-69 years. MetS was diagnosed based on the criteria of the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) and the Japan Society for the Study of Obesity (JASSO), using the body mass index instead of waist circumference. The Cox proportional hazards analysis was used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for total cancer mortality in relation to MetS and its components. Additionally, the associations of obesity and the metabolic health status with cancer mortality were examined. During an average 6.9-year follow-up, there were 192 deaths from cancer. The presence of MetS was significantly correlated with increased total cancer mortality when the JASSO criteria were used (HR = 1.51, 95% CI 1.04-2.21), but not when the NCEP-ATP III criteria were used (HR = 1.09, 95% CI 0.78-1.53). Metabolic risk factors, elevated fasting blood glucose, and MUHO were positively associated with cancer mortality (P <0.05). MetS diagnosed using the JASSO criteria and MUHO were associated with an increased risk of total cancer mortality in the Japanese population.


One-year follow-up ultrasonographic study of the subchondral bone surface of the distal femoral epiphysis in children aged 9-11 years.

Subchondral bone surface irregularity of the distal femoral epiphysis was more common on US in growing children aged 9-11 years, and transition from an irregular to a smooth outline accelerated after age 10 years. US is a reliable method for assessing the morphology of the distal femoral epiphysis and could be a useful screening tool for detecting OCD.

Journal of Pediatric Orthopaedics. Part B


A genome-wide association study on adherence to low-carbohydrate diets in Japanese


Association of perceived stress and coping strategies with the renal function in middleaged and older Japanese men and women

Elucidating the risk factors for chronic kidney disease is important for preventing end-stage renal disease and reducing mortality. However, little is known about the roles of psychosocial stress and stress coping behaviors in deterioration of the renal function, as measured by the estimated glomerular filtration rate (eGFR). This cross-sectional study of middle-aged and older Japanese men (n = 31,703) and women (n = 38,939) investigated whether perceived stress and coping strategies (emotional expression, emotional support seeking, positive reappraisal, problem solving, and disengagement) were related to the eGFR, with mutual interactions. In multiple linear regression analyses adjusted for age, area, lifestyle factors, and psychosocial variables, we found a significant inverse association between perceived stress and the eGFR in men (P = 0.02), but not women. This male-specific inverse association was slightly attenuated after adjustment for the history of hypertension and diabetes and was more evident in lower levels of emotional expression (P = 0.003). Unexpectedly, problem solving in men (P < 0.001) and positive reappraisal in women (P = 0.002) also showed an inverse association with the eGFR. Perceived stress may affect the eGFR, partly through the development of hypertension and diabetes. The unexpected findings regarding coping strategies require the clarification of the underlying mechanisms, including the hormonal and immunological aspects.


Associations of breastfeeding history with metabolic syndrome and cardiovascular risk factors in community-dwelling parous women: The Japan Multi-Institutional Collaborative Cohort Study

The aim of the present study was to investigate the associations between breastfeeding and the prevalence of metabolic syndrome in community-dwelling parous women and to clarify whether the associations depend on age. The present cross-sectional study included 11,118 women, aged 35-69 years. Participants' longest breastfeeding duration for one child and their number of breastfed children were assessed using a self-administered questionnaire, and their total breastfeeding duration was approximated as a product of the number of breastfed children and the longest breastfeeding duration. The longest and the total breastfeeding durations were categorized into none and tertiles above 0 months. Metabolic syndrome and cardiovascular risk factors (obesity, hypertension, dyslipidemia, and hyperglycemia) were defined as primary and secondary outcomes, respectively. Associations between breastfeeding history and metabolic syndrome or each cardiovascular risk factor were assessed using multivariable unconditional logistic regression analysis. Among a total of 11,118 women, 10,432 (93.8%) had ever breastfed, and 1,236 (11.1%) had metabolic syndrome. In participants aged <55 years, an inverse dose-response relationship was found between the number of breastfed children and the prevalence of metabolic syndrome; multivariable-adjusted odds ratios for 1, 2, 3, and ≥4 breastfed children were 0.60 (95% confidence interval [CI]: 0.31 to 1.17), 0.50 (95% CI: 0.29 to 0.87), 0.44 (95% CI: 0.24 to 0.84), and 0.35 (95% CI: 0.14 to 0.89), respectively. The longest and total breastfeeding durations of longer than 0 months were also associated with lower odds of metabolic syndrome relative to no breastfeeding history in participants aged <55 years. In contrast, all measures of breastfeeding history were not significantly associated with metabolic syndrome and cardiovascular risk factors in participants aged ≥55 years old. Breastfeeding history may be related to lower prevalence of metabolic syndrome in middle-aged parous women.


Effect of the interaction between physical activity and estimated macronutrient intake on HbA1c: population-based cross-sectional and longitudinal studies

Healthy diet and physical activity (PA) are essential for preventing type 2 diabetes, particularly, a combination of diet and PA. However, reports on interaction between PA and diet, especially from large epidemiological studies, are limited. We investigated the effect of interaction between PA and macronutrient intake on hemoglobin A1c (HbA1c) levels in the general population. We conducted a cross-sectional study of 55 469 men and women without diabetes who participated in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. A self-administered questionnaire ascertained PA and macronutrient intake (carbohydrate, fat, and protein). Multiple linear regression analyses were performed to adjust for confounding variables and examine the interactions. In addition, we conducted a longitudinal study during a 5-year period within a subcohort (n=6881) with accelerometer-assessed PA data. Overall, PA had a weak inverse association (β=-0.00033, p=0.049) and carbohydrate intake had a strong positive association (β=0.00393, p<0.001) with HbA1c. We observed a tendency of interactions between PA and carbohydrate or fat intake, but not protein intake, on HbA1c levels after adjusting for age, sex, study area, total energy intake, alcohol consumption, smoking, and medication for hypertension or hypercholesterolemia (P=0.054, 0.006, and 0.156, respectively). The inverse associations between PA and HbA1c level were more evident in participants with high-carbohydrate (or low-fat) intake than in participants with low-carbohydrate (or high-fat) intake. Although further adjustment for body mass index slightly attenuated the above interactions (P=0.098 for carbohydrate and 0.068 for fat), the associations between PA and HbA1c level in stratified analyses remained unchanged. Similar associations and interactions were reproduced in the longitudinal study. The present results suggest that the effect of PA on HbA1c levels is modified by intake of macronutrient composition.


The association of reproductive history with hypertension and obesity depending on menopausal status: the J-MICC Study

Previous studies have reported that the number of pregnancies and childbirths affected the risk of cardiovascular diseases (CVDs). However, the influence of reproductive history on hypertension and obesity, which are important risk factors for CVDs, is still unclear. Moreover, this association may vary depending on menopausal status. We evaluated the association of reproductive history with hypertension and obesity using a large cross-sectional dataset from the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study). At the baseline survey, physical data, blood samples, and self-reported health questionnaires were collected. Participants with insufficient data were excluded, and 24,558 women from eight study regions were included in this study. Logistic regression analysis was conducted to evaluate the association of reproductive history with hypertension and obesity using multivariable-adjusted odds ratios. In premenopausal women, childbirth showed a generally protective effect on hypertension but not on obesity. In postmenopausal women, childbirth was positively associated with obesity and hypertension but not with hypertension after adjusting for BMI. In conclusion, reproductive history was associated with hypertension and obesity in a large Japanese population, and this association differed between premenopausal and postmenopausal women.


Association of skipping breakfast and short sleep duration with the prevalence of metabolic syndrome in the general Japanese population: baseline data from the Japan Multi-Institutional Collaborative Cohort Study

Study (J-MICC) Cohort Collaborative Multi-Institutional Japan the

The purpose of the study was to investigate sex-specific associations of skipping breakfast and short sleep duration with metabolic syndrome (MetS) and their interaction. We analyzed baseline data of 14,907 men and 14,873 women aged 35-69 years, who participated in the Japan Multi-Institutional Collaborative Cohort Study from 2005. MetS was diagnosed using a modification of the National Cholesterol Education Program Adult Treatment Panel III revised definition (NCEP-R 2005), using body mass index instead of waist circumference. Breakfast consumption was classified into two categories: ≥6 days/week (consumers) or <6 days/week (skippers). Sleep duration was classified into three categories: <6h, 6 to <8 h, and ≥8 h/day. Multivariate logistic regression analysis was performed to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) and examine the presence of interaction. In men, skipping breakfast and short sleep duration were independently associated with an increased prevalence of MetS (OR 1.26, 95%CI 1.12-1.42 and OR 1.28, 95%CI 1.12-1.45, respectively), obesity, and components of MetS. However, no significant interaction was observed between skipping breakfast and short sleep duration. In women, skipping breakfast and short sleep duration were associated with an increased prevalence of obesity, but not with MetS. These findings indicate that breakfast consumption and moderate sleep duration may be associated with a lower risk of MetS, particularly in men.


Moderate-to-vigorous physical activity and sedentary behavior are independently associated with renal function: a cross-sectional study

Background: Little is known about whether insufficient moderate-to-vigorous physical activity (MVPA) and longer sedentary behavior (SB) are independently associated with estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD), whether they interact with known risk factors for CKD, and the effect of replacing sedentary time with an equivalent duration of physical activity on kidney function.

Methods: We examined the cross-sectional association of MVPA and SB with eGFR and CKD in 66,603 Japanese cohort study in 14 areas from 2004 to 2013. MVPA and SB were estimated using a self-reported questionnaire, and CKD was defined as eGFR <60 mL/min/1.73 m2. Multiple linear regression analyses, logistic regression analyses, and an isotemporal substitution model were applied.

Results: After adjusting for potential confounders, higher MVPA and longer SB were independently associated with higher eGFR (P for trend MVPA <0.0001) and lower eGFR (P for trend SB <0.0001), and a lower odds ratio (OR) of CKD (adjusted OR of MVPA ≥20 MET·h/day, 0.76; 95% confidence interval [CI], 0.68-0.85 compared to MVPA <5 MET·h/day) and a higher OR of CKD (adjusted OR of SB ≥16 h/day, 1.81; 95% CI, 1.52-2.15 compared to SB <7 h/day), respectively. The negative association between MVPA and CKD was stronger in men, and significant interactions between sex and MVPA were detected. Replacing 1 hour of SB with 1 hour of physical activity was associated with about 3 to 4% lower OR of CKD.

Conclusions: These findings indicate that replacing SB with physical activity may benefit kidney function, especially in men, adding to the possible evidence on CKD prevention.


Sex-specific Relationship between Stress Coping Strategies and All-Cause Mortality: Japan Multi-Institutional Collaborative Cohort Study

Stress coping strategies are related to health outcomes. However, there is no clear evidence for sex differences between stress-coping strategies and mortality. We investigated the relationship between all-cause mortality and stress-coping strategies, focusing on sex differences among Japanese adults. A total of 79,580 individuals aged 35-69 years participated in the Japan Multi-Institutional Collaborative Cohort Study between 2004 and 2014 and were followed up for mortality. The frequency of use of the five coping strategies was assessed using a questionnaire. Sex-specific, multivariable-adjusted hazard ratios (HRs) for using each coping strategy "sometimes," and "often/very often" (versus "very few" use) were computed for all-cause mortality. Furthermore, relationships were analyzed in specific follow-up periods when the proportion assumption was violated. During the follow-up (median: 8.5 years), 1,861 mortalities were recorded. In women, three coping strategies were related to lower total mortality. The HRs (95% confidence intervals) for "sometimes" were 0.81 (0.67-0.97) for emotional expression, 0.79 (0.66-0.95) for emotional support-seeking, and 0.80 (0.66-0.98) for disengagement. Men who "sometimes" used emotional expression and sometimes or often used problem-solving and positive reappraisal had a 15-41% lower HRs for all-cause mortality. However, those relationships were dependent on the follow-up period. There was evidence that sex modified the relationships between emotional support-seeking and all-cause mortality (p for interaction = 0.03). In a large Japanese population, selected coping strategies were associated with all-cause mortality. The relationship of emotional support-seeking was different between men and women.


A Proposal For Practical Diagnosis Of Renal Hypouricemia: Evidenced From Genetic Studies Of Nonfunctional Variants Of URAT1/SLC22A12 Among 30,685 Japanese Individuals

Renal hypouricemia (RHUC) is characterized by a low serum uric acid (SUA) level and high fractional excretion of uric acid (FE). Further studies on FE in hypouricemic individuals are needed for a more accurate diagnosis of RHUC. In 30,685 Japanese health-examination participants, we genotyped the two most common nonfunctional variants of (NFV-), W258X (rs121907892) and R90H (rs121907896), in 1040 hypouricemic individuals (SUA ≤ 3.0 mg/dL) and 2240 individuals with FE data. The effects of NFV- on FE and SUA were also investigated using linear and multiple regression analyses. Frequency of hypouricemic individuals (SUA ≤ 3.0 mg/dL) was 0.97% (male) and 6.94% (female) among 30,685 participants. High frequencies of those having at least one allele of NFV- were observed in 1040 hypouricemic individuals. Furthermore, NFV- significantly increased FE and decreased SUA, enabling FE and SUA levels to be estimated. Conversely, FE and SUA data of hypouricemic individuals are revealed to be useful to predict the number of NFV-. Our findings reveal that specific patterns of FE and SUA data assist with predicting the number of nonfunctional variants of causative genes for RHUC, and can also be useful for practical diagnosis of RHUC even before genetic tests.


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

Group Study Cohort Collaborative Multi-Institutional Japan the

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. 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) were selected from the GWAS catalog, and seven representative SNPs were defined, and the population-based impact was estimated using population attributable fraction (PAF). 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. 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.


A Genome-wide Association Study on Meat Consumption in a Japanese Population- The Japan Multi-Institutional Collaborative Cohort study


Effect of Underlying Cardiometabolic Diseases on the Association Between Sedentary Time and All-cause Mortality in a Large Japanese Population: A Cohort Analysis Based on the J-MICC Study

Background This study aimed to determine the association between sedentary time and mortality with regard to leisure-time physical activity with or without cardiometabolic diseases such as hypertension, dyslipidemia, and diabetes mellitus. Methods and Results Using data from the J-MICC (Japan Multi-Institutional Collaborative Cohort) Study, 64 456 participants (29 022 men, 35 434 women) were analyzed. Hazard ratios (HRs) and 95% CIs were used to characterize the relative risk of all-cause mortality to evaluate its association with sedentary time (categorical variables: <5, 5 to <7, 7 to <9, ≥9 h/d and 2-hour increments in exposure) according to the self-reported hypertension, dyslipidemia, and diabetes mellitus using a Cox proportional hazards model. A total of 2257 participants died during 7.7 years of follow-up. The corresponding HRs for each 2-hour increment in sedentary time among participants with all factors, no factors, hypertension, dyslipidemia, and diabetes mellitus were 1.153 (95% CI, 1.114-1.194), 1.125 (95% CI, 1.074-1.179), 1.202 (95% CI, 1.129-1.279), 1.176 (95% CI, 1.087-1.273), and 1.272 (95% CI, 1.159-1.396), respectively. Furthermore, when analyzed according to the combined different factors (hypertension, dyslipidemia, and diabetes mellitus), HRs increased with each additional factor, and participants reporting all 3 conditions had the highest HR of 1.417 (95% CI, 1.162-1.728) independently of leisure-time metabolic equivalents. Conclusions The association between sedentary time and increased mortality is stronger among patients with hypertension, dyslipidemia, and diabetes mellitus regardless of leisure-time physical activity in a large Japanese population.

Journal of the American Heart Association


Reproducibility and validity of food group intake in a short food frequency questionnaire for the middle-aged Japanese population

The purpose of this study was to evaluate the reproducibility and validity of a short food frequency questionnaire (FFQ) for food group intake in Japan, the reproducibility and partial validity of which were previously confirmed for nutrients. A total of 288 middle-aged healthy volunteers from 11 different areas of Japan provided nonconsecutive 3-day weighed dietary records (DRs) at 3-month intervals over four seasons. We evaluated reproducibility based on the first (FFQ1) and second (FFQ2) questionnaires and their validity against the DRs by comparing the intake of 20 food groups. Spearman's rank correlation coefficients (SRs) were calculated between energy-adjusted intake from the FFQs and that from the DRs. The intake of 20 food groups estimated from the two FFQs was mostly equivalent. The median energy-adjusted SRs between the FFQ1 and FFQ2 were 0.61 (range 0.38-0.86) for men and 0.66 (0.45-0.84) for women. For validity, the median de-attenuated SRs between DRs and the FFQ1 were 0.51 (0.17-0.76) for men and 0.47 (0.23-0.77) for women. Compared with the DRs, the proportion of cross-classification into exact plus adjacent quintiles with the FFQ1 ranged from 58 to 86% in men and from 57 to 86% in women. According to the robust Z scores and the Bland-Altman plot graphs, the underestimation errors in the FFQ1 tended to be greater in individuals with high mean levels of consumption for meat for men and for other vegetables for both men and women. The FFQ demonstrated high reproducibility and reasonable validity for food group intake. This questionnaire is short and remains appropriate for identifying associations between diet and health/disease among adults in Japan.

Environmental Health and Preventive Medicine


A Genome-wide Association Study on Confection Consumption in a Japanese Population- The Japan Multi-Institutional Collaborative Cohort study


Assessing the relationship between high-sensitivity C-reactive protein and kidney function employing mendelian randomization in a Japanese community based J-MICC Study

Inflammation is thought to be a risk factor for kidney disease. However, discussion is controversial whether inflammatory status is either a cause or an outcome of chronic kidney disease. We aimed to investigate the causal relationship between high-sensitivity C-reactive protein (hs-CRP) and estimated glomerular filtration rate (eGFR) using mendelian randomization (MR) approaches. A total of 10,521 participants of the Japan Multi-institutional Collaborative Cohort Study was analyzed in this study. We used two-sample MR approaches (the inverse-variance weighted (IVW), the weighted median (WM), and the MR-Egger method) to estimate the effect of genetically determined hs-CRP on kidney function. We selected four and three hs-CRP associated single nucleotide polymorphisms (SNPs) as two instrumental variables (IV): IV and IV, based on SNPs previously identified in European and Asian populations. IV and IV explained 3.4% and 3.9% of the variation in hs-CRP, respectively. Using the IV, genetically determined hs-CRP was not significantly associated with eGFR in the IVW and the WM methods (estimate per 1 unit increase in ln(hs-CRP), 95%CI: 0.000, -0.019 to 0.020 and -0.003, -0.019 to 0.014). For IV, we found similar results using the IVW and the WM methods (estimate, 95% CI: -0.005, -0.020 to 0.010 and -0.004, -0.020 to 0.012). The MR-Egger method also showed no causal relationships between hs-CRP and eGFR (IV: -0.008, -0.058 to 0.042; IV: 0.001, -0.036 to 0.036). Our two-sample MR analyses with different IVs did not support a causal effect of hs-CRP on eGFR.


Association between nutrient patterns and fatty liver index: Baseline survey of the Japan Multi-Institutional Collaborative Cohort Study in Tokushima, Japan

The fatty liver index (FLI) is a good non-invasive approach for fatty liver disease diagnosis. The objective of this study was to examine the associations of nutrient patterns with nonalcoholic fatty liver disease (NAFLD) in a Japanese population. A total of 1,588 subjects (789 men and 799 women) aged 35 to 69 years were recruited in the baseline survey of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study in Tokushima Prefecture. Factor analysis was applied to energy-adjusted intake of 21 nutrients, and nutrient patterns were extracted. Multiple logistic regression analysis was used to analyze the relationships between nutrient patterns and the high FLI category (60). Four nutrient patterns were extracted: Factor 1, vitamins, dietary fiber, iron and potassium pattern; Factor 2, fats and fat-soluble vitamins pattern; Factor 3, saturated fat, calcium, vitamin B and low carbohydrate pattern; and Factor 4, sodium, protein and vitamin D pattern. After adjustment for sex, age, and other potential confounding variables, higher Factor 1 scores were significantly associated with lower odds ratios of NAFLD (P for trend <0.05). Analysis of each component of FLI showed that there were significant inverse associations between Factor 1 scores and high body mass index and large waist circumference. The present findings suggest that a nutrient pattern rich in vitamins, fiber, iron, and potassium was associated with lower prevalence of NAFLD in a Japanese population. Obesity and abdominal obesity may be intermediate variables for the association between this nutrient pattern and NAFLD.


Genome-wide association study of serum PSA levels based on 1000Genomes-imputed data in Japanese: the J-MICC Study


Study profile of the Japan Multi-institutional Collaborative Cohort (J-MICC) Study

The Japan Multi-institutional Collaborative Cohort (J-MICC) study was launched in 2005 to examine gene-environment interactions in lifestyle-related diseases, including cancers, among the Japanese. This report describes the study design and baseline profile of the study participants. The participants of the J-MICC Study were individuals aged 35 to 69 years enrolled from respondents to study announcements in specified regions, inhabitants attending health checkup examinations provided by local governments, visitors at health checkup centers, and first-visit patients at a cancer hospital in Japan. At the time of the baseline survey, from 2005 to 2014, we obtained comprehensive information regarding demographics, education, alcohol consumption, smoking, sleeping, exercise, food intake frequency, medication and supplement use, personal and family disease history, psychological stress, and female reproductive history, and collected peripheral blood samples. The baseline survey included 92,610 adults (mean age: 55.2 [9.4] years, 44.1% men) from 14 study regions in 12 prefectures. The participation rate was 33.5%, with participation ranging from 19.7% to 69.8% in different study regions. The largest number of participants was in the age groups of 65-69 years for men and 60-64 years for women. There were differences in body mass index, educational attainment, alcohol consumption, smoking, and sleep duration between men and women. The J-MICC Study collected lifestyle and clinical data and biospecimens from over 90,000 participants. This cohort is expected to be a valuable resource for the national and international scientific community in providing evidence to support longer healthy lives.


A genome-wide association study on fish consumption in a Japanese population-the Japan Multi-Institutional Collaborative Cohort study


Association of dietary acid load with the prevalence of metabolic syndrome among participants in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study

The association between dietary acid load and metabolic syndrome (MetS) has not been fully investigated. A cross-sectional study was performed on 14,042 men and 14,105 women (aged 35-69 years) who participated in a baseline survey of the Japan Multi-Institutional Collaborative Cohort study. Dietary acid load was assessed using the net-endogenous-acid-production (NEAP) score that is closely correlated with the rate of renal net acid excretion. MetS was diagnosed according to the Joint Interim Statement Criteria of 2009 using body-mass index instead of waist circumference. After adjusting for potential confounders, higher NEAP scores were associated with a significantly increased odds ratio (OR) of MetS, obesity, high blood pressure, and high fasting blood glucose. These associations remained significant after further adjustment for carbohydrate intake or two nutrient-pattern scores significantly associated with MetS. After adjustment for fiber, iron, potassium, and vitamin pattern scores, the OR of MetS for the highest quartile of NEAP scores, relative to the lowest quartile, was 1.25 (95% confidence interval 1.12-1.39). There was no significant interaction between sex, age, or body-mass index and NEAP. Higher dietary acid load was associated with a higher prevalence of MetS and several of its components, independently of carbohydrate intake or nutrient patterns.


Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients

Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000-3000 years. Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype. In addition to the eight loci we reported previously, two novel loci, and , were identified at a genome-wide significance level (p<5.0×10) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, and , from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients' gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on in addition to loci for all subtypes except for normal type gout. Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.


Differential effect of polymorphisms on body mass index across the life course of Japanese: the Japan Multi-Institutional Collaborative Cohort Study

Obesity is a reported risk factor for various health problems. Genome-wide association studies (GWASs) have identified numerous independent loci associated with body mass index (BMI). However, most of these have been focused on Europeans, and little evidence is available on the genetic effects across the life course of other ethnicities. We conducted a cross-sectional study to examine the associations of 282 GWAS-identified single nucleotide polymorphisms with three BMI-related traits, current BMI, BMI at 20 years old (BMI at 20) and change in BMI (BMI change), among 11 586 Japanese individuals enrolled in the Japan Multi-Institutional Collaborative Cohort study. Associations were examined using multivariable linear regression models. We found a significant association (P < 0.05/282 = 1.77×10) between BMI and 11 polymorphisms in or near FTO, BDNF, TMEM18, HS6ST3, and BORCS7. The trend was similar between current BMI and BMI change, but differed from that of the BMI at 20. Among the significant variants, those on FTO were associated with all BMI traits, whereas those on TMEM18 and HS6SR3 were only associated with BMI at 20. The association of FTO loci with BMI remained even after additional adjustment for dietary energy intake. Previously reported BMI-associated loci discovered in Europeans were also identified in the Japanese population. Additionally, our results suggest that the effects of each loci on BMI may vary across the life course and that this variation may be caused by the differential effects of individual genes on BMI via different pathways.


Sedentary time is associated with cardiometabolic diseases in a large Japanese population: a cross-sectional study

Accumulating evidence reveals that sedentary behavior is associated with mortality and cardiometabolic disease; however, there are potential age and sex differences in sedentary behavior and health outcomes that have not been adequately addressed. This study aimed to determine the association of sedentary behavior with cardiometabolic diseases such as hypertension, dyslipidemia, diabetes mellitus, and its risk factors in a large Japanese population according to age and sex. Using data from the Japan Multi-Institutional Collaborative Cohort Study obtained from baseline surveys, data of 62,754 participants (27,930 males, 34,824 females) were analyzed. This study uses a cross-sectional design and self-administered questionnaires to evaluate sedentary time and anamnesis. For the logistic regression analysis, sedentary time <5 h/day was used as the reference and then adjusted for age, research areas, leisure-time metabolic equivalents, and alcohol and smoking status. From the analysis of anthropometric and blood examinations, 35,973 participants (17,109 males, 18,864 females) were analyzed. For hypertension and diabetes, sedentary time was associated with a significantly higher proportion of male participants. Both sexes were associated with a significantly higher proportion of participants with dyslipidemia. Participants who had longer sedentary time tended to have increased levels of blood pressure, triglycerides, and non-high-density lipoprotein cholesterol (HDL-C), and decreased levels of HDL-C, especially in the 60-69 years group. Independent of leisure-time physical activity, sedentary time was associated with cardiometabolic diseases in a large Japanese population classified by age and sex. Our findings indicate that regularly interrupting and replacing sedentary time may contribute to better physical health-related quality of life.

Journal of Atherosclerosis and Thrombosis


Combined effect of weight gain within normal weight range and parental hypertension on the prevalence of hypertension; from the J-MICC Study.

The aim of this study is to show the combined effect of weight gain within normal weight range in adulthood and parental HT on the prevalence of HT. The study subjects were 44,998 individuals (19,039 men and 25,959 women) with normal weight (body mass index [BMI] 18.5-24.9) aged 35-69 years who participated in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. They were categorized into six groups by weight gain from age 20 years (<10 kg, and ≥10 kg) and by the number of parents having HT (no parent, one parent, and both parents). Odds ratios for HT were estimated after adjustment for age, sex, current BMI, estimated daily sodium intake, and other confounding factors. The prevalence of HT (31.5% in total subjects) gradually increased with greater weight gain from age 20 years and with greater number of parents with HT. Subjects who gained weight ≥10 kg and having both parents with HT showed the highest risk of having HT compared with those who gained weight <10 kg without parental HT (59.8% vs. 24.9%, odds ratio 4.25, 95% CI 3.53-5.13 after adjustment). This association was similarly observed in any category of age, sex, and BMI. Subjects who gained weight within normal range of BMI and having one or both parent(s) with HT showed the higher risk of having HT independent of their attained BMI in their middle ages. Thus, subjects having parent(s) with HT should avoid gaining their weight during adulthood, even within normal range of BMI, to reduce the risk of having HT.


The interaction between ABCA1 polymorphism and physical activity on the HDL-cholesterol levels in a Japanese population.

Few studies have investigated the interactions between HDL-cholesterol (HDL-C)-related single nucleotide polymorphisms (SNPs) identified by genome-wide association (GWA) study and physical activity (PA) on HDL-C. First, we conducted a sex-stratified GWA study in a discovery sample (2,231 men and 2,431 women) and replication sample (2,599 men and 3,109 women) to identify SNPs influencing log-transformed HDL-C in Japanese participants in the baseline survey of Japan Multi-Institutional Collaborative Cohort Study. We also replicated previously reported HDL-C-related SNPs in a combined (discovery plus replication) sample (4,830 men and 5,540 women). We then analyzed the interactions of the HDL-C-related SNPs with PA on HDL-C. The sex-stratified GWA analyses identified 11 and 10 HDL-C-related SNPs in men and women as targets for an interaction analysis. Among these, only 1 interaction of ABCA1 rs1883025 with PA was statistically significant in men, after Bonferroni correction (P-interaction = 0.001 [ = 0.05/21 = 0.002]). The per-major-allele (C) increase in log-transformed HDL-C was lost in men with low PA ( = 0.008) compared with those with medium ( = 0.032) or high PA ( = 0.034). These findings suggest that the benefit of carrying a C allele of ABCA1 rs1883025 on enhancing HDL-C may be attenuated in inactive men.


Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout.

The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout. We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia). This new approach enabled us to identify two novel gout loci (rs7927466 of and rs9952962 of ) and one suggestive locus (rs12980365 of ) at the genome-wide significance level (p<5.0 10). The present study also identified the loci of , and . One of them, rs671 of , was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three 'gout vs AHUA GWAS'-specific loci (, and ) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level. This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.


Association of genetic risk score and chronic kidney disease in a Japanese population

Chronic kidney disease (CKD) is a public health problem worldwide including Japan. Recent genome-wide association studies have discovered CKD susceptibility variants. We developed a genetic risk score (GRS) based on CKD-associated variants and assessed a possibility that the GRS can improve the discrimination capability for the prevalence of CKD in a Japanese population. The present study consists of 11 283 participants randomly selected from 12 Japan Multi-Institutional Collaborative Cohort Study sites. Individual GRS was constructed combining 18 single-nucleotide polymorphisms identified in a Japanese population. Participants with eGFR <60 mL/min per 1.73 m was defined as case (stage 3 CKD or higher) in this study. Logistic regression analysis was used to examine the association between the GRS and CKD risk with adjustment for sex, age, hypertension and type 2 diabetes mellitus. The frequency of individuals with CKD was 8.3%, which was relatively low compared with those previously reported in a Japanese population. The odds ratio of having CKD was 1.120 (95% confidence interval: 1.042-1.203) per 10 GRS increment in the fully adjusted model (P = 0.002). The C-statistic was significantly increased in the model with the GRS, comparing with the model without the GRS (0.720 vs 0.719, P = 0.008). Increment of the GRS was associated with increased risk of CKD. Additionally, the GRS significantly improved the discriminatory ability of CKD prevalence in a Japanese population; however, the improvement of discriminatory ability brought about by the GRS seemed to be small compared with that of non-genetic CKD risk factors.


Associations of nutrient patterns with the prevalence of metabolic syndrome: Results from the baseline data of the Japan Multi-Institutional Collaborative Cohort Study

The association between nutrient patterns and metabolic syndrome (MetS) has not been examined in a Japanese population. A cross-sectional study was performed on 30,108 participants (aged 35-69 years) in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. Dietary intake was assessed using a 46-item food frequency questionnaire. MetS was diagnosed according to the Joint Interim Statement Criteria of 2009, using body mass index instead of waist circumference. Factor analysis was applied to energy-adjusted intake of 21 nutrients, and three nutrient patterns were extracted: Factor 1 (fiber, potassium and vitamins pattern); Factor 2 (fats and fat-soluble vitamins pattern); and Factor 3 (saturated fatty acids, calcium and vitamin B pattern). In multiple logistic regression analysis adjusted for sex, age, and other potential confounders, Factor 1 scores were associated with a significantly reduced odds ratio (OR) of MetS and all five components. Factor 2 scores were associated with significantly increased prevalence of MetS, obesity, and high blood pressure. Factor 3 scores were significantly associated with lower OR of MetS, high blood pressure, high serum triglycerides and low HDL cholesterol levels. Analysis of nutrient patterns may be useful to assess the overall quality of diet and its association with MetS.


Independent relationships of daily life activity and leisure-time exercise with metabolic syndrome and its traits in the general Japanese population.

Our results suggest that higher daily life activity and higher moderate-intensity exercise may be independently associated with a lower risk of metabolic syndrome in Japanese adults.


Genome-wide association meta-analysis and Mendelian randomization analysis confirm ALDH2 influencing on sleep duration in the Japanese population.

Usual sleep duration has substantial heritability and is associated with various physical and psychiatric conditions as well as mortality. However, for its genetic locus, only PAX8 and VRK2 has been replicated in previous genome-wide association studies (GWAS). We conducted a GWAS meta-analysis of self-reported usual sleep duration using three population-based cohorts totaling 31,230 Japanese individuals. A genome-wide significant locus was identified at 12q24 (P-value < 5.0×10-8). Subsequently, a functional variant in the ALDH2 locus, rs671, was replicated in an independent sample of 5,140 Japanese individuals (P-value = 0.004). The association signal, however, disappeared after adjusting for alcohol consumption, indicating the possibility that the rs671 genotype modifies sleep duration via alcohol consumption. This hypothesis explained a modest genetic correlation observed between sleep duration and alcohol consumption (rG = 0.23). A Mendelian randomization analysis using rs671 and other variants as instrumental variables confirmed this by showing a causal effect of alcohol consumption, but not of coffee consumption on sleep duration. Another genome-wide significant locus was identified at 5q33 after adjusting for drinking frequency. However, this locus was not replicated, nor was the PAX8 and VRK2 . Our study has confirmed a functional ALDH2 variant, rs671, most strongly influencing on usual sleep duration possibly via alcohol consumption in the Japanese population, and presumably in East Asian populations. This highlights the importance of considering the involvement of alcohol consumption in future GWAS of usual sleep duration, even in non-East Asian populations, where rs671 is monomorphic.


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

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. 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. 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. 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.

Medicine and Science in Sports and Exercise


Association of exposure level to passive smoking with hypertension among lifetime nonsmokers in Japan: a cross-sectional study

.Japan Multi-Institutional Collaborative Cohort (J-MICC) Study

Brief exposure to passive smoking immediately elevates blood pressure. However, little is known about the association between exposure to passive smoking and chronic hypertension. We aimed to examine this association in a cross-sectional study, after controlling multiple potential confounders.Participants included 32,098 lifetime nonsmokers (7,216 men and 24,882 women) enrolled in the Japan Multi-Institutional Collaborative Cohort Study. Passive smoking was assessed using a self-administered questionnaire. The single question about exposure to passive smoking had five response options: "sometimes or almost never," "almost every day, 2 hours/day or less," "almost every day, 2 to 4 hours/day," "almost every day, 4 to 6 hours/day," and "almost every day, 6 hours/day or longer." Hypertension was defined as any of the following: systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or use of antihypertensive medication. Multivariate-adjusted odds ratio (OR) and 95% confidence interval (CI) for hypertension were estimated by exposure level to passive smoking using unconditional logistic regression models.The multivariate-adjusted OR for hypertension in those exposed almost every day was 1.11 (95% CI: 1.03-1.20) compared with those exposed sometimes or almost never. The OR for a 1-hour per day increase in exposure was 1.03 (95% CI: 1.01-1.06, Pfor trend = .006). This association was stronger in men than in women; the ORs were 1.08 (95% CI: 1.01-1.15, Pfor trend = .036) and 1.03 (95% CI: 1.00-1.05, Pfor trend = .055), respectively.Our findings suggest importance of tobacco smoke control for preventing hypertension.


Inverse association between soy food consumption, especially fermented soy products intake and soy isoflavone, and arterial stiffness in Japanese men.

Studies on the associations between soy food consumption and arterial stiffness are rare. The aim of the present study was to evaluate their associations in Japanese men. A total of 652 eligible men, aged 35-69 years, who underwent the measurement of brachial-ankle pulse wave velocity (baPWV) as an index of arterial stiffness were evaluated in this cross-sectional study. Information on their lifestyle characteristics, including dietary behavior, was obtained from a structured self-administered questionnaire. The frequency of total soy products as well as fermented and non-fermented soy products intakes was calculated, and the amounts of soy protein and soy isoflavone intakes were also estimated; these were then divided into tertiles and their associations with baPWV values were evaluated using general linear models. Higher frequency of fermented soy products intake was associated with decreased baPWV after adjusting for the multivariable covariates (P value for trend was 0.002, in Model 3). This association did not alter after further adjustment with a biomarker of systemic inflammation (serum high-sensitivity C-reactive protein (hs-CRP)) (P value for trend was 0.001, in Model 4). Total soy isoflavone consumption was also inversely associated with baPWV even after adjusting for multivariable covariates including serum hs-CRP (P value for trend was 0.043, in Model 4); however total soy protein consumption was not. These results demonstrated that greater consumption of soy food, especially fermented soy products and soy isoflavone was associated with reduced arterial stiffness, independent of systemic inflammation, in Japanese men.


Nutrient-derived dietary patterns and their association with metabolic syndrome in a Japanese population

Nutrients have been proposed to be related to metabolic syndrome (MetS). The aims of this study were to identify dietary patterns that correlated with several nutrients using reduced rank regression (RRR) and to examine the association between extracted dietary patterns and prevalence of MetS in a Japanese population. The study population comprised 1,092 Japanese men and women (35-69 years old) who had participated in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study in Tokushima Prefecture. Dietary patterns were derived with RRR using 46 food items as predictors and six established nutrients (potassium, calcium, vitamin D, vitamin C, insoluble dietary fiber, and carotene) as response variables. Associations between extracted dietary patterns and MetS were then examined with logistic regression models. Among the six dietary patterns, dietary pattern 1 (DP1) explained the largest proportion (60.1%) of variance in the six nutrients. Therefore, only DP1 was selected for further analysis. DP1 was characterized by high intake frequency of vegetables, fruits, fish and small fish, natto (fermented soybeans), and deep-fried tofu. After adjustment for potential confounders, significant inverse associations were found between DP1 score and MetS (odds ratio [OR] for each quartile: 1.00, 0.58, 0.60, 0.52; P = 0.02); DP1 and high blood pressure (P = 0.0002); and DP1 and high blood glucose (P = 0.02). A dietary pattern characterized by high intake of vegetables, fruits, fish and small fish, natto, and deep-fried tofu was associated with reduced prevalence of MetS in a Japanese population.


A genome-wide association study in the Japanese population idetifies 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). 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), 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 for a meta-analysis). These findings indicate that the 12q24.12-13 locus is associated with coffee consumption among a Japanese population.


Dietary calcium intake is associated with serum high-sensitivity C-reactive protein level in the general Japanese population

The beneficial effects of dietary calcium intake on high-sensitivity C-reactive protein levels, a risk factor of cardiovascular disease, have not been fully elucidated. This study investigated the associations between dietary calcium intake and serum high-sensitivity C-reactive protein levels in the general Japanese population. We analyzed the data of 2,019 subjects (1,194 men and 825 women) aged 35 to 69 years in a cross-sectional study of the Japan Multi-Institutional Collaborative Cohort Study. Nutrients intake including calcium were estimated using a validated food-frequency questionnaire. Analysis using a general linear model revealed that dietary calcium intake was inversely associated with serum high-sensitivity C-reactive protein levels ( for trend <0.001) after adjustment for age, sex, research group, leisure-time physical activity, smoking habit, drinking habit, dietary intakes (energy, dietary fiber, saturated fatty acids and vitamin D) and menopausal status. The association was slightly attenuated after additional adjustment for body mass index; however, remained significant ( for trend = 0.008). There were no significant interactions between dietary calcium intakes and sex, body mass index, or vitamin D intake for high-sensitivity C-reactive protein levels. This study have demonstrated that dietary calcium intake was inversely associated with serum high-sensitivity C-reactive protein levels in the general population.

Journal of Clinical Biochemistry and Nutrition


A Genome-wide Association Study in the Diabetic Patients Finds the 13q35.43-35.46 Locus Associated with Estimated Glomerular Filtration Rate: The Japan Multi-Institutional Collaborative Cohort Study


Genetic Variants of RAMP2 and CLR are Associated with Stroke.

Stroke is associated closely with vascular homeostasis, and several complex processes and interacting pathways, which involve various genetic and environmental factors, contribute to the risk of stroke. Although adrenomedullin (ADM) has a number of physiological and vasoprotective functions, there are few studies of the ADM receptor system in humans. The ADM receptor comprises a calcitonin-receptor-like receptor (CLR) and receptor activity-modifying proteins (RAMPs). We analyzed single nucleotide polymorphisms (SNPs) in the RAMP2 and CLR genes to determine their association with stroke in the light of gene-environment interactions. Using cross-sectional data from the Japan Multi-Institutional Collaborative Cohort Study in the baseline surveys, 14,087 participants from 12 research areas were genotyped. We conducted a hypothesis-based association between stroke prevalence and SNPs in the RAMP2 and CLR genes based on data abstracted from two SNPs in RAMP2 and 369 SNPs in CLR. We selected five SNPs from among the CLR variants (rs77035639, rs3815524, rs75380157, rs574603859, and rs147565266) and one RAMP2 SNP (rs753152), which were associated with stroke, for analysis. Five of the SNPs (rs77035639, rs3815524, rs75380157, rs147565266, and rs753152) showed no significant association with obesity, ischemic heart disease, hypertension, dyslipidemia, and diabetes. In the logistic regression analysis, rs574603859 had a lower odds ratio (0.238; 95% confidence interval, 0.076-0.745, adjusted for age, sex, and research area) and the other SNPs had higher odds ratios for association with stroke. This was the first study to investigate the relationships between ADM receptor genes (RAMP2 and CLR) and stroke in the light of gene-environment interactions in human.

Journal of Atherosclerosis and Thrombosis


Comparison of weighed food record procedures for the reference methods in two validation studies of food frequency questionnaires.

Our comparison of WFR procedures in two independent studies revealed several differences. Notwithstanding these procedural differences, however, the subsequent outcomes were similar.


Association between Dietary Patterns and Serum Adiponectin: A Cross-Sectional Study in a Japanese Population

The aim of this study was to evaluate the associations between dietary pattern, adiponectin and insulin resistance. The study population consisted of 612 men and women aged 35-69 years old who had participated in the baseline survey of Japan Multi-Institutional Collaborative Cohort (J-MICC) Study in Tokushima Prefecture. Diets and lifestyle related variables were assessed by questionnaires. Multiple regression analyses were used to analyse the relations between dietary patterns and high molecular weight (HMW) adiponectin. For further analysis, path analysis was used to test the hypothesised model of association between dietary pattern, serum adiponectin and insulin resistance. The result showed that higher score of bread and dairy pattern was directly associated with increased serum level of adiponectin in women, which was inversely related to homeostasis model assessment of insulin resistance (HOMA-IR). In conclusion, higher consumption of bread and dairy products, and low intake of rice may be associated with increased serum adiponectin in women.

International Journal of Food Sciences and Nutrition


Relationships of serum high-sensitivity C-reactive protein and body size with insulin resistance in a Japanese cohort.

Impacts of chronic systemic inflammation and body size and their interaction effect on insulin resistance in Asian populations, in whom obesity is less common, are not fully understood. This study evaluated combined relationships of systemic inflammation and body size with insulin resistance in a Japanese cohort. We analyzed cross-sectional data from 1,074 eligible subjects (536 men and 538 women) aged 35-69 years who participated in the baseline survey of a cohort study in Tokushima Prefecture, Japan. Systemic inflammation level was assessed by serum high-sensitivity C-reactive protein (hs-CRP), and the degree of insulin resistance and beta-cell function were evaluated by the homeostasis model assessment insulin resistance (HOMA-IR) and beta-cell function (HOMA- ), respectively. Overweight and obesity were defined as a body mass index (BMI) of 23.0-24.9 kg/m2 and ·25.0 kg/m2, respectively. Associations between serum hs-CRP (assessed as quartiles and additionally continuous values after log-transformation) and indices of glucose homeostasis were analysed adjusting for probable covariates, including BMI (quartiles). Combined associations of serum hs-CRP ( median, >median) and body size (normal, overweight, obese) with insulin resistance as well as their interaction effect on insulin resistance were also evaluated. Serum hs-CRP was dose-dependently associated with HOMA-IR, but not HOMA- , after adjustment for probable covariates, including BMI. Subjects with obesity and elevated serum hs-CRP (>median) showed a high multivariable-adjusted HOMA-IR value of 1.32 (95% confidence interval (CI) 1.23, 1.41) compared with subjects with normal BMI and low serum hs-CRP ( median) whose multivariable-adjusted HOMA-IR value was 1.14 (95% CI 1.06, 1.21). The interaction effect between body size (normal, overweight, obese) and serum hs-CRP ( median, >median) on HOMA-IR was significant (P for interaction <0.001). Our study suggests that elevated systemic inflammation is dose-dependently associated with increased insulin resistance, independent of the known risk factors, in a Japanese population. Concomitant obesity and elevated systemic inflammation may synergistically contribute to increased insulin resistance.


Matrix metalloproteinase 9 gene polymorphisms are associated with a multiple family history of gastric cancer

The Japan Multi-institutional Collaborative Cohort Study Group

A family history of gastric cancer (GC) is a well-known risk factor of GC. Genetic variations in genes of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have been related to the risk of GC, but their association with familial background is not clear. We investigated whether individuals with a multiple family history of GC have more risk genotypes of MMP/TIMP genes. We genotyped ten common functional polymorphisms of MMP/TIMP genes in 4427 individuals aged 35-69 years without a history of GC who were enrolled in the Japan Multi-institutional Collaborative Cohort Study. Individuals who have two or more first-degree relatives (parents and siblings) with GC were categorized as having a multiple family history. Odds ratios (ORs) for multiple family history compared with no family history were calculated. MMP9 279QQ (rs17576) was more frequently observed in individuals whose both parents had a history of GC (n = 23) and in individuals for whom one parent and their sibling(s) had a history of GC (n = 36) compared with those with no family history (n = 3816) [30.4 % vs 11.6 %, OR 4.34, 95 % confidence interval (CI) 1.45-13.03 and 16.7 % vs 11.6 %, OR 2.26, 95 % CI 0.81-6.27 after adjustment for age, sex, and current smoking]. The population attributable fraction was 38.1 %. The haplotype MMP9-1562C/279Q/668Q was more frequently observed in individuals whose both parents had a history of GC and in individuals for whom one parent and their sibling(s) had a history of GC compared with those with no family history (OR 3.35, 95 % CI 0.75-14.96 and OR 3.51, 95 % CI 1.35-9.15 respectively). MMP9 polymorphisms were associated with a multiple family history of GC. Screening for these genotypes together with familial background may help us to identify individuals at an increased risk of GC.


Systemic inflammation and family history in relation to the prevalence of type 2 diabetes based on an alternating decision tree

To investigate unknown patterns associated with type 2 diabetes in the Japanese population, we first used an alternating decision tree (ADTree) algorithm, a powerful classification algorithm from data mining, for the data from 1,102 subjects aged 35-69 years. On the basis of the investigated patterns, we then evaluated the associations of serum high-sensitivity C-reactive protein (hs-CRP) as a biomarker of systemic inflammation and family history of diabetes (negative, positive or unknown) with the prevalence of type 2 diabetes because their detailed associations have been scarcely reported. Elevated serum hs-CRP levels were proportionally associated with the increased prevalence of type 2 diabetes after adjusting for probable covariates, including body mass index and family history of diabetes (P for trend = 0.016). Stratified analyses revealed that elevated serum hs-CRP levels were proportionally associated with increased prevalence of diabetes in subjects without a family history of diabetes (P for trend = 0.020) but not in those with a family history or with an unknown family history of diabetes. Our study demonstrates that systemic inflammation was proportionally associated with increased prevalence of type 2 diabetes even after adjusting for body mass index, especially in subjects without a family history of diabetes.


Changes in foot function, disease activity, and disability after forefoot resection arthroplasty in patients with rheumatoid arthritis

The purpose of this study was to investigate the changes in foot function, disease activity, and disability in patients with RA after resection arthroplasty of the forefoot (arthroplasty). Arthroplasty was performed on 11 patients with RA. All study patients underwent clinical assessment to measure disease activity (Disease Activity Score in 28 Joints-C-reactive protein, DAS28-CRP), disability (Health Assessment Questionnaire-Disability Index, HAQ-DI) and foot function (Foot Function Index, FFI) at the following stages: preoperatively and 1, 3, and 12 months after surgery. Following arthroplasty, foot function improved significantly, as assessed by FFI total and subscales (pain, disability, and limitation of activity) (P<0.001, P<0.001, P<0.001, and P=0.002, respectively). Disease activity was significantly improved in relation to DAS28-CRP and its subscales of number of swollen joints and patient global assessment (PtGA) (P=0.033, P=0.008, and P=0.038, respectively). There was no significant difference in disability, as assessed by the HAQ-DI and its subscale, HAQ-walking (P=0.150 and P=0.597, respectively). Foot function improved significantly after arthroplasty, and was maintained at 12 months postoperatively. Additionally, our study showed that disease activity and its subscale PtGA improved after arthroplasty.

The Journal of Medical Investigation : JMI


Association between brain-muscle-ARNT-like protein-2 (BMAL2) gene polymorphism and type 2 diabetes mellitus in obese Japanese individuals: A cross-sectional analysis of the Japan Multi-Institutional Collaborative Cohort Study

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. 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 (≥25kg/m(2) and <25kg/m(2)) to investigate an interaction between genotypes and obesity. 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. 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.


A variant of the CLOCK gene and related haplotypes are associated with the prevalence of type 2 diabetes in the Japanese population.

Circadian rhythm disruption is recognized as the cause of various health disorders. This study evaluated associations between single nucleotide polymorphisms in the core circadian gene, CLOCK, and prevalent type 2 diabetes in the Japanese population. We analyzed cross-sectional data from 2,485 subjects (1,243 men and 1,242 women; age, 35-69 years) who were enrolled in the baseline surveys of the Japan Multi-institutional Collaborative Cohort (J-MICC) Study. Associations between 3 CLOCK gene polymorphisms (rs1801260, rs3736544, and rs4864548) and prevalent obesity (BMI ≥25 kg/m(2) ), overweight (BMI ≥23 kg/m(2) ), and diabetes were evaluated by logistic regression analyses; haplotype analysis and stratified analyses for prevalent diabetes were also conducted. Compared to those who were homozygous for the respective major alleles, subjects with the rs1801260 minor allele C showed a significantly higher odds ratio (95% CI) of 1.5 (1.1-2.1) for prevalent diabetes, after adjustment for potential confounding factors, including BMI. When stratified by overweight, the associations between rs1801260 and prevalent diabetes were marked and significant in non-overweight subjects but were not significant in overweight subjects. The TGA (rs1801260 - rs3736544 - rs4864548) haplotype was associated with lower prevalence of diabetes, and the CGG haplotype was associated with higher prevalence of diabetes. CLOCK gene variants and related haplotypes are associated with prevalent type 2 diabetes in the Japanese population in whom obesity is less common, and the association between a CLOCK gene variants at rs1801260 and prevalent diabetes is enhanced in normal-build subjects.


Polymorphisms in CYP19A1, HSD17B1 and HSD17B2 genes and serum sex hormone level among postmenopausal Japanese women

Extraovarian sex hormone production plays an important role in estrogen biosynthesis in postmenopausal women. We examined possible associations between serum sex hormone level and polymorphisms in CYP19A1, HSD17B1, and HSD17B2. We also assessed possible interaction between these polymorphisms and current overweight. We conducted a cross-sectional study. 785 Japanese natural postmenopausal women were randomly selected from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study database. Information on lifestyle factors was obtained from a self-administered questionnaire. Serum estrogens and androgens levels were measured by liquid chromatography-tandem mass spectrometry. Four tag SNPs (single nucleotide polymorphisms) of CYP19A1, one missense SNP of HSD17B1 and three tag SNPs of HSD17B2 were examined by Invader assay. A trend test was conducted using linear regression. After adjustment for multiple comparisons, we found that rs4441215 and rs936306 in CYP19A1 and rs4888202 and rs2955160 in HSD17B2 were associated with differences in serum estrone level. Further, rs4441215 and rs936306 were associated with differences in serum estradiol level. None of these polymorphisms showed a significant interaction with current body mass index (BMI). Our findings suggested that CYP19A1 and HSD17B2 polymorphisms might be associated with circulating sex hormone levels in Japanese postmenopausal women, independent of current BMI.


Inverse association between soy food consumption and insulin resistance in Japanese adults

The purpose of the present study was to examine the association between soya food consumption and insulin resistance using baseline data of the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study in Tokushima, Japan. This cross-sectional study included 1274 subjects, aged 34-70 years at baseline, living in Tokushima Prefecture between 2008 and 2013. Fasting blood samples were collected and information on lifestyle characteristics including soya food intake and medical history were obtained using a structured self-administered questionnaire. The homeostasis model assessment of insulin resistance (HOMA-IR) was measured and those with HOMA-IR ≥ 2.5 were defined as having insulin resistance. Multiple logistic regression models were used to analyse the association between soya product intake and the prevalence of insulin resistance. Rural communities located in Tokushima Prefecture, Japan, between 2008 and 2013. A total of 1148 adults (565 men and 583 women), aged 34-70 years. The frequency of intake of miso soup, total non-fried soya products and total soya products showed significant inverse dose-response relationships with insulin resistance, after adjustments for potential confounders. When soya product intake was calculated as soya protein and isoflavone, the odds ratios of insulin resistance decreased significantly as the estimated intake of soya protein increased. Furthermore, significant inverse dose-response relationships were observed for total non-fried soya products and total soya products, after adjustment for total vegetable or total fibre consumption. The present results indicate that the intake of soya products and non-fried soya products is associated with reduced insulin resistance in the Japanese population.


Relationships of elevated levels of serum hepatic enzymes and alcohol intake with arterial stiffness in men.

The present study aimed to evaluate the relationships between elevated serum levels of hepatic enzymes and arterial stiffness and to investigate whether alcohol intake had a modifying effect on these relationships in Japanese men. A total of 647 eligible men aged 35-69 years who underwent measurement of brachial-ankle pulse wave velocity (baPWV) as an index of arterial stiffness were evaluated. Information on their lifestyle characteristics were obtained from a structured self-administered questionnaire. Serum biochemical factors, including alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), were determined. The serum ALT and GGT levels were divided into tertiles, and their associations with baPWV values were evaluated using general linear models adjusted for potential confounding factors. The interaction effects between serum hepatic enzymes and alcohol intake on baPWV were further evaluated. Elevated serum ALT and GGT levels were proportionally associated with increased baPWV after adjusting for the multivariable covariates (P values for trend, 0.004 and 0.003, respectively). Further analyses revealed that the proportional associations between serum levels of hepatic enzymes and baPWV were striking in the subjects without alcohol intake but not in those with alcohol intake. The interaction effect between serum GGT level and alcohol intake on baPWV was significant (P for interaction, 0.042). These results demonstrate that elevated serum ALT and GGT levels are associated with increased arterial stiffness, independent of the classical atherosclerotic risk factors in Japanese men, and that the association of elevated serum GGT level with arterial stiffness differs according to alcohol intake.


Family history of stroke is potentially associated with arterial stiffness in the Japanese population.

Studies on the association between family history of cardiovascular disease and arterial stiffness are rare. This study evaluated the possible relationship between family history of cardiovascular disease and arterial stiffness in the Japanese population, by measuring brachial-ankle pulse wave velocity (ba-PWV). A total of 1004 eligible subjects (664 men and 340 women) aged 35-69 years, who were enrolled in the baseline survey of a cohort study in Tokushima Prefecture (Japan) and who underwent ba-PWV measurement, were analysed. Information about their lifestyle characteristics and first-degree family histories of ischaemic heart disease (i.e. myocardial infarction or angina pectoris), stroke or hypertension were obtained from a structural self-administered questionnaire. Subjects of both sexes with a family history of stroke showed significantly higher multivariable-adjusted means of ba-PWV than those without that trait (P values were 0.001 in men and 0.002 in women), while those with a family history of ischaemic heart disease did not. Subjects of both sexes with a family history of hypertension showed significantly higher age-adjusted means of ba-PWV than those without that trait, although these differences disappeared after further adjusting for blood pressure or multivariable covariates. When family histories of these diseases were inserted simultaneously into the same model, these results did not alter substantially. A family history of stroke might be associated with increased arterial stiffness, independent of other known atherosclerotic risk factors, including hypertensive elements, in both sexes in the Japanese population.


Association between dietary calcium intake and arterial stiffness according to dietary vitamin D intake in men.

Studies on the associations of dietary Ca and vitamin D intakes with arterial stiffness are scarce. In the present study, these associations were evaluated in Japanese men. Data from a total of 535 eligible men, aged 35-69 years, who participated in the baseline survey of a cohort study in Tokushima Prefecture, Japan, and underwent brachial-ankle pulse wave velocity (ba-PWV) measurements were analysed. ba-PWV is a measure of arterial stiffness and is recognised as a marker of atherosclerotic vascular damage. Information regarding the cohort's lifestyle characteristics including dietary behaviour over the past year was obtained from a structured self-administered questionnaire. Dietary Ca and vitamin D intakes were adjusted for total energy intake using the residual method and divided into quartiles; the highest quartile was used as the reference. General linear models were used to evaluate the associations between dietary Ca and vitamin D intakes and ba-PWV values adjusted for probable covariates. The association between dietary Ca intake and ba-PWV was further evaluated using similar general linear models stratified by dietary vitamin D intake (median or below/above median). Dietary Ca intake was found to be significantly inversely associated with ba-PWV after adjusting for probable covariates (P for trend = 0·020). However, no such association was observed between dietary vitamin D intake and ba-PWV. The inverse association between dietary Ca intake and ba-PWV was striking in subjects with higher dietary vitamin D intake. However, no association was found in subjects with lower dietary vitamin D intake. These results indicate that adequate dietary Ca and vitamin D intakes may be protective against the development of arterial stiffness in Japanese men.


Associations of dietary patterns with metabolic syndrome and insulin resistance: a cross-sectional study in a Japanese population

The associations of dietary patterns with metabolic syndrome (MetS) and insulin resistance have not been fully investigated in the Japanese population. A cross-sectional study was performed on 513 subjects without treatment for diabetes who had participated in the baseline survey of a cohort study in Tokushima Prefecture, Japan. Frequencies of consumption of 46 foods and beverages were assessed using a questionnaire. MetS was diagnosed using the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria. Logistic and linear regression analyses were used to examine the associations of the dietary patterns with the prevalence of MetS, its components, and the Homeostasis Model of Assessment-Insulin Resistance (HOMA-IR). Using principal component analysis, four dietary patterns were extracted: prudent diet (high intake of vegetables and fruits); high fat/Western (high intake of fried foods, fried dishes and meat); bread and dairy products; and seafood patterns. After adjustment for sex, age, and other potential confounders, prudent diet pattern scores were inversely correlated with the prevalence of reduced serum high-density lipoprotein cholesterol (P=0.04) and high blood pressure (P=0.05), and bread and dairy products pattern scores were correlated with a lower prevalence of abdominal obesity (P=0.04) and high plasma glucose (P=0.04). The high fat/Western pattern was positively correlated with HOMA-IR (P=0.04). Prudent dietary pattern and bread and dairy products pattern may be correlated with a lower prevalence of some components of MetS. A high fat/Western dietary pattern may be positively associated with insulin resistance in the Japanese population.

The Journal of Medical Investigation : JMI


A polymorphism near MC4R gene (rs17782313) is associated with serum triglyceride levels in the general Japanese population: the J-MICC Study

Previously reported associations of a common polymorphism near melanocortin-4 receptor (MC4R) gene (rs17782313) with BMI/obesity were inconsistent, especially in East Asia, and the associations of the polymorphism with serum lipid levels have not been fully elucidated. This study evaluated the association between rs17782313 and obesity-related traits and serum lipid levels in the general Japanese population. A total of 2,035 subjects (aged 35-69 years, 1,024 males and 1,011 females) enrolled in the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. We examined the associations between near MC4R polymorphism (rs17782313) and obesity-related traits [height, weight, body mass index (BMI), weight change from 20 years old], serum lipid levels (triglycerides, total and HDL-cholesterol), and intake of nutrients (total energy and macronutrients). Polymorphism of rs17782313 (minor C allele) was positively associated with serum triglyceride levels (P for trend = 0.020) adjusted for age and sex. Analysis using a general linear model revealed that the number of minor C alleles was positively associated with serum triglyceride levels after adjustment for age, sex, and potential confounders (P for trend = 0.004). Statistical significance did not change after further adjustment for total energy intake and BMI. There was no significant association between rs17782313 and obesity-related traits including BMI. Interactions between rs17782313 and sex, BMI, or total energy intake for triglyceride levels were not significant. To our knowledge, this study demonstrated for the first time that rs17782313 was associated with serum triglyceride levels in Asian population. Further studies are needed to confirm this result.


Serum hepatic enzyme activity and alcohol drinking status in relation to the prevalence of metabolic syndrome in the general Japanese population.

Studies on the combined associations of elevated serum hepatic enzyme activity and alcohol drinking with metabolic syndrome are rare. Our objectives were to evaluate the associations of elevated serum hepatic enzyme activity with the prevalence of metabolic syndrome in the general Japanese population and whether alcohol drinking had a modifying effect on these associations. We conducted a cross-sectional study with 1,027 men and 1,152 women throughout Japan during 2002-2010. Biochemical factors including alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) were determined in overnight fasting blood, and a survey on lifestyle was conducted by questionnaire. Serum ALT and GGT levels were divided into tertiles in men and women, and their associations with the prevalence of metabolic syndrome were evaluated by logistic regressions. Elevated serum ALT and GGT, even within the reference range, were independently associated with increased metabolic syndrome prevalence and were associated with most of its components in both sexes, except for the association between GGT and low high-density lipoprotein (HDL) cholesterol in men. Stratified analyses by alcohol drinking status revealed that within the same tertile category of serum ALT and GGT, subjects classified as alcohol abstainers showed higher adjusted odds ratios for metabolic syndrome prevalence than those classified as regular alcohol drinkers in both sexes. The interaction effects of serum GGT with alcohol drinking status on metabolic syndrome prevalence were significant in both sexes. These results suggest that elevated serum ALT and GGT, even within the reference range, are independently associated with increased metabolic syndrome prevalence, especially in alcohol abstainers, in Japanese men and women.