論文

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.

【目的】脂肪肝は内臓脂肪蓄積の肝臓における表現型とされており、過量飲酒は脂肪肝のリスク因子であることが知られている。Fatty liver index (FLI) は脂肪肝の予測能に優れ、特定健診の測定項目のみで算出可能であるため健診での活用が期待される。本研究では、地域住民における飲酒習慣およびインスリン抵抗性の指標であるHOMA-IRとFLI高値との関連について検討した。【方法】循環器疾患の既往がなく生活習慣病の治療を受けていない40～74歳の男女を対象とした神戸研究のベースライン調査参加者1,078名のデータを用いた横断研究である。飲酒習慣は現在飲酒の有無と1日飲酒量に基づき、男性を4群 (なし、1合未満／日、1－2合／日、2合以上／日)、女性を3群 (なし、1合未満／日、1合以上／日) に分類し、脂肪肝の存在が疑われるFLI 30以上をFLI高値と定義した。飲酒習慣・HOMA-IRとFLI高値との関連は多変量ロジスティック回帰分析により検討し、オッズ比と95％信頼区間を算出した。【結果】全解析対象者1,078名 (男性323名、女性755名、平均年齢58.9歳) のうち、FLI高値を認める者は172名 (16.0％) であった。飲酒習慣とFLIとの関連において、男性では1－2合／日および≧2合／日の群でFLI高値と有意な正の関連を認め、女性では1合以上／日の群でFLI高値と有意な正の関連を認めた。また、HOMA-IRは男女ともにFLI高値と有意な正の関連を認めた。非肥満者に限定した解析でも同様の結果となった。【結論】非肥満者を中心とした地域住民において、1合以上／日の現在飲酒は男女ともFLI高値と有意な正の関連を認めた。非肥満者であっても日常的な飲酒量が多い者では脂肪肝に伴うインスリン抵抗性の増大が循環器疾患の発症につながる可能性があるため、減酒を推奨することが望ましい。また、FLIは非肥満者でもインスリン抵抗性を反映していることが示唆された。

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.

目的　疫学研究において服薬情報は自記式質問紙を用いて得ることが多いが，高齢者を対象に妥当性を検討した報告は希少である。本研究の目的は自己申告による服薬情報の妥当性をお薬手帳と比較して検討することである。方法　2019–2020年度に山形県鶴岡市の一般地域在住高齢者を対象として実施されたコホート研究の参加者370人において，自記式質問紙による薬剤情報をお薬手帳の薬剤情報と比較した。解析対象薬剤は降圧薬，脂質異常症用薬，抗心筋梗塞・抗狭心症薬，糖尿病用薬，抗リウマチ薬，骨粗鬆症・骨代謝改善薬，便秘薬，胃薬，抗不安・抗うつ薬，抗認知症薬，喘息治療薬，アレルギー治療薬，抗血栓薬，ステロイド，甲状腺疾患治療薬，解熱・鎮痛・抗炎症薬である。お薬手帳の薬剤情報を基準とし，調査日より前90日以内に服薬中で，28日以上処方されている内服薬，骨粗鬆症・骨代謝改善薬は注射薬も対象とした。ATCコード（解剖治療化学分類法）に基づいて薬効分類を行い，各薬剤の感度，特異度，カッパ係数を計算した。お薬手帳の持参がなかった者は「解析対象薬剤の使用なし」と定義し解析に組み込んだ。結果　男性146人，女性224人，平均年齢（標準偏差）は73.3（4.0）歳であった。各薬剤の感度と特異度は，降圧薬（0.97, 0.97），脂質異常症用薬（0.93, 0.98），抗心筋梗塞・抗狭心症薬（0.24, 0.99），糖尿病用薬（0.94, 1.00），抗リウマチ薬（1.00, 1.00），骨粗鬆症・骨代謝改善薬（0.82, 0.99），便秘薬（0.71, 0.98），胃薬（0.63, 0.97），抗不安薬・抗うつ薬（0.36, 1.00），抗認知症薬（0.67, 1.00），喘息治療薬（0.67, 0.98），アレルギー治療薬（0.57, 0.99），抗血栓薬（0.88, 0.98），副腎皮質ホルモン製剤（0.80, 0.99），甲状腺疾患治療薬（1.00, 1.00），解熱・鎮痛・抗炎症薬（0.75, 0.96）であった。結論　薬剤の種類により感度，特異度が異なっていた。とくに感度が8割を超える薬剤（降圧薬，脂質異常症用薬，糖尿病用薬，抗リウマチ薬，骨粗鬆症・骨代謝改善薬，抗血栓薬，副腎皮質ホルモン製剤，甲状腺疾患治療薬）では，高齢者においても自己申告による服薬情報の収集は有用であることが示唆された。

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.