Published papers

Aims: The association between alcohol consumption and the risk of cardiovascular disease (CVD) varies according to the presence of underlying cardiovascular risk factors. Incorporating such risk factors may be important to effectively reduce harmful alcohol use through health guidance. However, whether the risk of alcohol consumption is affected due to renal impairment remains unclear.Methods: A total of 10,583 community-dwelling Japanese adults (mean age 59.4 (SD 10.1) years; 46% men) were followed for 10 years. Alcohol consumption was categorized into five groups for men: never drinkers, former drinkers, light drinkers (＜20 g/day), moderate drinkers (20-39 g/day), and heavy drinkers (≥ 40 g/day), and four groups for women with moderate and heavy combined. Cox proportional hazards models estimated hazard ratios for incident CVD stratified by the presence or absence of reduced estimated glomerular filtration rate (eGFR) (＜60 mL/min/1.73m²) and proteinuria, with adjustment for confounders.Results: Among men with proteinuria, alcohol consumption was associated with a higher risk of atherosclerotic CVD, whereas an inverse association was observed in men without proteinuria [hazard ratio (95% confidence interval): moderate drinkers without proteinuria, 0.58 (0.34-0.97); moderate drinkers with proteinuria, 3.49 (1.15-10.56)]. Moderate to heavy drinking increased the risk of intracerebral hemorrhage irrespective of the renal status. In women, moderate to heavy drinking was associated with an increased CVD risk only when proteinuria was present. In contrast, a reduced eGFR did not clearly affect the association in either sex.Conclusions: The CVD risk associated with alcohol consumption may differ according to the renal status, particularly depending on the presence or absence of proteinuria.

Objective: Fatty liver is a phenotype of visceral fat accumulation in the liver, and excessive alcohol consumption is known to be a risk factor for fatty liver. In this study, we investigated the association between drinking habits and homeostatic model assessment for insulin resistance (HOMA-IR), a marker of insulin resistance, and higher levels of fatty liver index (FLI) in community residents.Methods: We conducted a cross-sectional study using data from 1,078 participants in the baseline survey of the KOBE study, which included men and women aged 40-74 years who had no history of cardiovascular disease and were not receiving treatment for lifestyle-related diseases. Drinking habits were classified into 4 groups for men (none, <1 gou/day, 1-2 gou/day, and ≥2 gou/day) and 3 groups for women (none, <1 gou/day, and ≥1 gou/day) based on the amount of alcohol consumed per day, and higher FLI was defined as FLI 30 or higher, which is suspicious for the presence of fatty liver. The association between drinking habits, HOMA-IR, and higher FLI was examined by multivariate logistic regression analysis, and odds ratios and 95% confidence intervals were calculated.Results: Among 1,078 subjects (323 men and 755 women, mean age 58.9 years), 172 (16.0%) had higher FLI. Regarding the association between drinking habits and FLI, there was a significant positive association with higher FLI prevalence in the 1-2 gou/day and ≥2 gou/day groups for men, and a significant positive association with higher FLI prevalence in the ≥1 gou/day group for women. HOMA-IR was also significantly positively associated with higher FLI in both men and women. Similar results were obtained in analyses restricted to non-obese individuals.Conclusions: Current drinkers of ≥1 gou/day was significantly positively associated with higher FLI prevalence in both men and women in community residents, mainly among non-obese individuals. Even among non-obese individuals who drink heavily on a daily basis, moderation in alcohol consumption should be recommended because the increased insulin resistance associated with fatty liver may lead to the development of cardiovascular disease. In addition, FLI reflects insulin resistance even in non-obese individuals.

Background: Dehydration, a risk factor for ischemic cerebrovascular diseases, is common in summer; however, the incidence of ischemic diseases is not necessarily higher in summer. Therefore, this study aimed to clarify the relationships between serum osmolarity, hematocrit, daily non-alcohol drink (NAD) intake and factors such as season and age as risk factors for dehydration.Method: Participants (703 women and 306 men) in the follow-up survey, in 2012 and 2013, of the Kobe Orthopedic and Biomedical Epidemiologic (KOBE) Study, consisting of healthy individuals living in Kobe, Japan, were categorized into two groups based on the examination month: the warmer and colder seasons. Multivariate analyses were conducted to examine disparities in serum osmolarity, hematocrit, and NAD intake between these two groups.Results: The colder season was found to be negatively correlated with serum osmolarity and NAD intake, but positively correlated with hematocrit, even after adjusting for relevant factors. Age was independently associated with serum osmolarity, but not with hematocrit and NAD intake.Conclusions: This study suggests that intra-vascular volume depletion is more likely in the colder season despite lower serum osmolarity compared to the warmer season. Age-related increases in serum osmolarity without a corresponding rise in water intake may contribute to this. These findings support the importance of addressing dehydration in the colder season, particularly in older adults.

Background: The association between alcohol consumption and atherosclerotic cardiovascular disease (ASCVD) was controversial, and no previous studies have shown the impact of dyslipidemia on the association. We aimed to clarify the association between alcohol consumption and death from cardiovascular disease (CVD) and its subtypes and the impact of dyslipidemia on the association.Methods: We conducted a 20-year cohort study to clarify the association between alcohol intake and death from CVD and its subtypes in 2,909 Japanese men. We estimated the hazard ratio (HR) and 95% confidence intervals (CIs) for current drinkers with non-drinkers as the reference, after adjusting for potential confounders using Cox proportional hazards models. We also investigated the association between alcohol consumption and ASCVD or CVD death stratified by the presence or absence of dyslipidemia.Results: During 50,782 person-years of follow-up period, 223 participants died from total CVD, 110 participants died from ASCVD, and 25 participants died from cerebral hemorrhage. Current drinkers with 1 gou/day were significantly associated with lower risk of ASCVD (HR: 0.60, 95%CI: 0.37–0.98), which is more apparent in those without dyslipidemia, and current drinkers with ≥3 gou/day were significantly associated with higher risk of cerebral hemorrhage (HR: 4.13, 95%CI: 1.12–15.19).Conclusions: Small amounts of alcohol drinking were associated with lower risk of ASCVD in Japanese men, especially those without dyslipidemia. Meanwhile, excessive alcohol drinking was associated with higher risk of cerebral hemorrhage. Our findings suggest that it is important for current Japanese drinkers to reduce alcohol consumption for preventing ASCVD or cerebral hemorrhage.

Background: Whether smoking is associated with worse quality of life (QoL) or not is relatively controversial. The current study is to investigate the relationship between smoking and subjective QoL in a long cohort study.Methods: The NIPPON DATA 90 project collected 8,383 community residents in 300 randomly selected areas as baseline data in 1990, administered four follow-up QoL surveys, and evaluated mortality statistics. We conducted multinomial logistic regression analysis to compare past smokers and current smokers to never smokers, with impaired QoL and mortality as outcomes.Results: In four follow-ups, QoL data was collected from 2,035, 2,252, 2,522, and 3,280 participants in 1995, 2000, 2005, and 2012, respectively. In the 1995 follow-up, current smoking at baseline was not associated with worse QoL. In 2000 and 2005 follow-ups, smoking was significantly associated with worse QoL (odds ratio [OR] 2.1; 95% confidence interval [CI], 1.33–3.36 and OR 2.29; 95% CI, 1.38–3.80, respectively). In the 2012 follow-up, smoking was not associated with QoL. Sensitivity analysis did not change the result significantly.Conclusion: In this study we found that baseline smoking was associated with worse QoL in long-follow-up.

The Tsuruoka Metabolomics Cohort Study (TMCS) is an ongoing population-based cohort study being conducted in the rural area of Yamagata Prefecture, Japan. This study aimed to enhance the precision prevention of multi-factorial, complex diseases, including non-communicable and aging-associated diseases, by improving risk stratification and prediction measures. At baseline, 11,002 participants aged 35–74 years were recruited in Tsuruoka City, Yamagata Prefecture, Japan, between 2012 and 2015, with an ongoing follow-up survey. Participants underwent various measurements, examinations, tests, and questionnaires on their health, lifestyle, and social factors. This study uses an integrative approach with deep molecular profiling to identify potential biomarkers linked to phenotypes that underpin disease pathophysiology and provide better mechanistic insights into social health determinants. The TMCS incorporates multi-omics data, including genetic and metabolomic analyses of 10,933 participants, and comprehensive data collection ranging from physical, psychological, behavioral, and social to biological data. The metabolome is used as a phenotypic probe because it is sensitive to changes in physiological and external conditions. The TMCS focuses on collecting outcomes for cardiovascular disease, cancer incidence and mortality, disability and functional decline due to aging and disease sequelae, and the variation in health status within the body represented by omics analysis that lies between exposure and disease. It contains several sub-studies on aging, heated tobacco products, and women’s health. This study is notable for its robust design, high participation rate (89%), and long-term repeated surveys. Moreover, it contributes to precision prevention in Japan and East Asia as a well-established multi-omics platform.

Objectives　Although self-reported questionnaires are widely used to collect information on medication use in epidemiological studies, their validity for studies involving older adults has not been sufficiently assessed. This study evaluated the validity of self-reported medication use using questionnaires in comparison with drug notebooks.Methods　The study enrolled 370 older community dwellers who participated in an aging sub-study survey of the Tsuruoka Metabolomics Cohort Study between April 2019 and March 2021. Medication use was assessed by comparing self-reported questionnaire data with drug notebook records. We analyzed medications used for hypertension, dyslipidemia, myocardial infarction, angina, diabetes, rheumatism, osteoporosis/metabolic bone disease, constipation, anxiety/depression, dementia, asthma, allergy, thrombosis, and thyroid disease. Moreover, gastrointestinal (GI) medications, steroids, and antipyretic analgesics were assessed, and data on injectable medications for osteoporosis/metabolic bone disease was collected. Using drug notebook records, we identified regular medication users by assessing whether they had received oral medication prescriptions covering over 28 days and took the medication within the 90 days preceding the day of their survey. To define medication categories, we used Anatomical Therapeutic Chemical (ATC) classification codes. Sensitivity, specificity, and kappa statistics were calculated for each medication using drug notebooks as standards. Those who did not bring their drug notebooks on the day of the survey were defined as non-medication users.Results　The mean age (standard deviation) of the 370 participants (146 men and 224 women) was 73.3 (4.0) years. The sensitivity and specificity for each medication were as follows: hypertension (0.97, 0.97), dyslipidemia (0.93, 0.98), myocardial infarction (0.24, 0.99), diabetes (0.94, 1.00), rheumatism (1.00, 1.00), osteoporosis/metabolic bone disease (0.82, 0.99), constipation (0.71, 0.98), GI conditions (0.63, 0.97), anxiety/depression (0.36, 1.00), dementia (0.67, 1.00), asthma (0.67, 0.98), allergy (0.57, 0.99), thrombosis (0.88, 0.98), steroids (0.80, 0.99), thyroid disease (1.00, 1.00) and antipyretic analgesics (0.75, 0.96).Conclusions　Although sensitivity and specificity differed by medication categories, the results of our population-based cohort study suggested that self-reported questionnaires on medication use among older adults are valid, especially for medications with high sensitivity (≥ 0.8).

Background: The application of metabolomics-based profiles in environmental epidemiological studies is a promising approach to refine the process of health risk assessment. We aimed to identify potential metabolomics-based profiles in urine and plasma for the detection of relatively low-level cadmium (Cd) exposure in large population-based studies.Method: We analyzed 123 urinary metabolites and 94 plasma metabolites detected in fasting urine and plasma samples collected from 1,412 men and 2,022 women involved in the Tsuruoka Metabolomics Cohort Study. Regression analysis was performed for urinary N-acetyl-beta-D-glucosaminidase (NAG), plasma, and urinary metabolites as dependent variables, and urinary Cd (U-Cd, quartile) as an independent variable. The multivariable regression model included age, gender, systolic blood pressure, smoking, rice intake, BMI, glycated hemoglobin, low-density lipoprotein cholesterol, alcohol consumption, physical activity, educational history, dietary energy intake, urinary Na/K ratio, and uric acid. Pathway-network analysis was carried out to visualize the metabolite networks linked to Cd exposure.Result: Urinary NAG was positively associated with U-Cd, but not at lower concentrations (Q2). Among urinary metabolites in the total population, 45 metabolites showed associations with U-Cd in the unadjusted and adjusted models after adjusting for the multiplicity of comparison with FDR. There were 12 urinary metabolites which showed consistent associations between Cd exposure from Q2 to Q4. Among plasma metabolites, six cations and one anion were positively associated with U-Cd, whereas alanine, creatinine, and isoleucine were negatively associated with U-Cd. Our results were robust by statistical adjustment of various confounders. Pathway-network analysis revealed metabolites and upstream regulator changes associated with mitochondria (ACACB, UCP2, and metabolites related to the TCA cycle).Conclusion: These results suggested that U-Cd was associated with metabolites related to upstream mitochondrial dysfunction in a dose-dependent manner. Our data will help develop environmental Cd exposure profiles for human populations.

Aims: Nonalcoholic fatty liver disease (NAFLD) is known to be associated with atherosclerosis. This study focused on upstream changes in the process by which NAFLD leads to atherosclerosis. The study aimed to confirm the association between NAFLD and the cardio-ankle vascular index (CAVI), an indicator of subclinical atherosclerosis, and explore metabolites involved in both by assessing 94 plasma polar metabolites.Methods: A total of 928 Japanese community-dwellers (306 men and 622 women) were included in this study. The association between NAFLD and CAVI was examined using a multivariable regression model adjusted for confounders. Metabolites commonly associated with NAFLD and CAVI were investigated using linear mixed-effects models in which batch numbers of metabolite measurements were used as a random-effects variable, and false discovery rate-adjusted p-values were calculated. To determine the extent to which these metabolites mediated the association between NAFLD and CAVI, mediation analysis was conducted.Results: NAFLD was positively associated with CAVI (coefficients [95% Confidence intervals (CI)]=0.23 [0.09–0.37]; p=0.001). A total of 10 metabolites were involved in NAFLD and CAVI, namely, branched-chain amino acids (BCAAs; valine, leucine, and isoleucine), aromatic amino acids (AAAs; tyrosine and tryptophan), alanine, proline, glutamic acid, glycerophosphorylcholine, and 4-methyl-2-oxopentanoate. Mediation analysis showed that BCAAs mediated more than 20% of the total effect in the association between NAFLD and CAVI.Conclusions: NAFLD was associated with a marker of atherosclerosis, and several metabolites related to insulin resistance, including BCAAs and AAAs, could be involved in the process by which NAFLD leads to atherosclerosis.

Background: The current study aimed to investigate the determinants of high double product (DP) by evaluating the association between resting DP, which is calculated as systolic blood pressure (SBP) multiplied by heart rate (HR), and blood test results and lifestyle factors.Methods: This research included 973 participants in the baseline survey of the KOBE study, which included a cohort of urban residents. The possible DP determinants were identified by examining the association between lifestyle factors and laboratory findings and DP by analyzing covariance adjusted for sex and age. Logistic regression analysis was performed with high DP (SBP × HR ≥ 9145 mmHg beats/min or quintile according to sex) as outcome and DP determinants as independent variables.Results: Age, hematocrit, and gamma-glutamyl transferase (log) level were positively associated with a high DP in both men and women. In addition, a high DP was positively associated with Homeostatic Model Assessment for Insulin Resistance score in women alone. Meanwhile, the amount of exercise was negatively associated with a high DP in men alone.Conclusions: High DP values at rest were associated with insulin resistance, gamma-glutamyl transferase, and the amount of exercise in participants without underlying disease.