研究者詳細 - 宮川　尚子

論文 - 宮川　尚子

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Genome-wide association study of plasma amino acids and Mendelian randomization for cardiometabolic traits

Toki R., Fushiki S., Kojima S., Sutoh Y., Otsuka-Yamasaki Y., Harada S., Iida M., Hirata A., Miyagawa N., Matsumoto M., Edagawa S., Miyake A., Kuwabara K., Hirayama A., Sugimoto M., Sato A., Amano K., Soga T., Tomita M., Arakawa K., Kinoshita K., Sakurai-Yageta M., Tamiya G., Ohmomo H., Shimizu A., Okamura T., Takebayashi T.

Scientific Reports 15 （ 1 ） 14569 2025年12月

ISSN 2045-2322

Plasma amino acids (AAs) have emerged as promising biomarkers for metabolic disorders, yet their causality remains unclear. We aimed to investigate the genetic determinants of AA levels in a cohort of 10,333 individuals and their causal effects on cardiometabolic traits using Mendelian randomization (MR). Plasma levels of 20 AAs were quantified using capillary electrophoresis mass spectrometry. Genome-wide association studies were conducted using BOLT-LMM and heritability estimation via LDSC analysis. Causal effects of AAs on 11 cardiometabolic traits were examined using two-sample MR analyses. We identified 85 locus-metabolite associations across 43 genes for 18 AAs, including 44 novel loci linked to metabolic genes. Heritability for AAs was estimated at 16%. MR analysis demonstrated cystine to positively associate with systolic blood pressure (SBP) (β = 0.056, SE = 0.010), while serine indicated protective effects on SBP (β = − 0.040, SE = 0.011), diastolic BP (β = − 0.044, SE = 0.010), and coronary artery disease (odds ratio 0.888, SE = 0.028). We identified potentially novel genetic loci associated with AA levels and demonstrated robust causal associations between several AAs and cardiometabolic traits. These findings reinforce the importance of AAs as potential biomarkers and therapeutic targets in cardiometabolic health.

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Cross-Sectional Association between Sedentary Behavior and Physical Inactivity with Cardiometabolic Risk Factors among Japanese: The NIPPON DATA2010.

Ohashi M, Miyagawa N, Yanagita M, Okuda N, Fujiyoshi A, Ohkubo T, Kadota A, Okami Y, Kondo K, Harada A, Okamura T, Ueshima H, Okayama A, Miura K, NIPPON DATA2010 Research Group

Journal of atherosclerosis and thrombosis （一般社団法人日本動脈硬化学会） 32 （ 10 ） 1328 - 1346 2025年10月

ISSN 1340-3478

Aim: Sedentary behavior and physical inactivity increase the risk of cardiometabolic diseases. It is important to evaluate physical activity in daily life and understand the influence of these factors on cardiometabolic diseases in the Japanese population, which tends to have a prolonged sitting time. We examined the association between sedentary behavior and physical inactivity, characterized by extended television (TV) viewing and low step counts, which are easily monitored and modifiable, and cardiometabolic risk factors in the Japanese population.Methods: This cross-sectional study included 2,531 Japanese adults (1,087 men and 1,444 women) 20–91 years old, randomly selected throughout Japan. TV viewing was assessed using a self-reported questionnaire, and step counts were measured using pedometers. Cardiometabolic risk factors were determined using physical examinations or blood samples. The association between sedentary behavior and physical inactivity with each risk factor was examined using a cross-sectional analysis with multivariate-adjusted logistic regression models.Results: In both sexes, longer TV viewing positively correlated with low high-density lipoprotein (HDL) cholesterol and high triglycerides (TG). In women, TV viewing time is associated with obesity and increased abdominal circumference (AC). Conversely, in men, lower step counts were positively associated with obesity and increased AC, low HDL cholesterol, and high TG levels.Conclusions: The association between prolonged TV viewing and cardiometabolic risk factors was more pronounced in women than in men, whereas the influence of lower step counts was stronger in men than in women. These findings contribute to the improvement of cardiovascular health by monitoring and managing individual screen times and step counts in daily life.

Causal relationship between body mass index and insulin resistance: Linear and nonlinear Mendelian randomization study in a Japanese population.

Ishida N, Harada S, Toki R, Hirata A, Matsumoto M, Miyagawa N, Iida M, Edagawa S, Miyake A, Kuwabara K, Shibuki T, Kato S, Arakawa K, Kinoshita K, Sakurai-Yageta M, Tamiya G, Nagashima K, Muraoka H, Sato Y, Takebayashi T

Journal of diabetes investigation 16 （ 7 ） 1305 - 1314 2025年04月

ISSN 2040-1116

Aims/Introduction: Obesity is a known risk factor for several chronic diseases, including type 2 diabetes mellitus, which results from increased insulin resistance and impaired insulin secretion. However, the association between obesity and insulin resistance in Asian populations has not yet been fully elucidated. Therefore, we aimed to investigate the causal relationship between body mass index (BMI) and glycemic traits using Mendelian randomization (MR). Materials and Methods: We performed individual-level MR analyses using genetic risk scores based on BMI-related variants in 3,745 individuals without diabetes mellitus from a Japanese cohort. We examined heterogeneity through subgroup analyses based on potential modifiers and determined the shape of the causal relationship using nonlinear MR analyses to further assess the impact of BMI on the homeostasis model assessment of insulin resistance (HOMA-IR). Results: MR analyses revealed a significant positive association between BMI and HOMA-IR (β = 0.077; 95% confidence interval, 0.014–0.141; P = 0.016; outcome variable was log-transformed and standardized). Additional analyses revealed heterogeneity among subgroups differentiated by age, sex, lifestyle habits, and cardiometabolic traits. Nonlinear MR analyses suggested a potential J-shaped causal relationship between BMI and HOMA-IR. Conclusions: Our findings demonstrated that obesity and low BMI may contribute to increased insulin resistance. Furthermore, the impact of BMI on insulin resistance could vary owing to effect modification. Managing BMI is crucial in individuals at high risk of increased insulin resistance and may have important implications for preventing type 2 diabetes, especially given the low insulin secretory capacity observed in East Asian populations.

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Reproducibility and validity of a food frequency questionnaire for nutrient intakes in the study areas of large-scale cohort studies in Japan

Goto C., Imaeda N., Wakai K., Sasakabe T., Michihata N., Oze I., Hosono A., Nagayoshi M., Miyagawa N., Ozaki E., Ikezaki H., Nanri H., Ibusuki R., Katsuura-Kamano S., Kuriki K., Yaguchi Y., Kurihara A., Matsuo K.

Nagoya Journal of Medical Science 87 （ 2 ） 237 - 253 2025年

ISSN 00277622

The Japan Multi-Institutional Collaborative Cohort Study, the Yamagata Molecular Epidemiological Cohort Study, and the Tsuruoka Metabolomics Cohort Study use a 47-item food frequency questionnaire (FFQ) developed in central Japan in 2004. We applied regression analyses to estimate nutrient intakes in the FFQ. The regression equations, however, may not be so robust and may vary among areas, even in Japan. We aimed to evaluate the reproducibility and validity of the FFQ over an expanded area of Japan. Healthy volunteers aged 34–70 years from 13 areas of Japan provided 12-day weighed dietary records (WDRs) and completed two FFQs over 1 year. We evaluated reproducibility and validity by comparing the intakes of 27 nutrients between the two FFQs and the first FFQ (FFQ1) and WDRs, respectively. Spearman's rank correlation coefficients (SRs) between estimates from the FFQs and WDRs were calculated and corrected for intra-individual variation in the WDRs. Intakes of the selected nutrients estimated from the two FFQs were equivalent. The median energy-adjusted SRs between FFQ1 and the second FFQ were 0.66 for both men and women. Regarding validity adjusted for within-individual variation, energy-adjusted SRs for WDRs vs FFQ1 ranged from 0.13 (thiamin) to 0.79 (alcohol) for men, and the median was 0.35. The energy-adjusted SRs ranged from 0.20 (protein) to 0.71 (alcohol) for women, and the median was 0.43. The FFQ demonstrated high reproducibility and moderate validity, which suggests that it is appropriate to clarify associations between diet and health and/or disease among adults in Japan.

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Dietary diversity and the risk of metabolic syndrome in a Japanese population: an analysis of baseline cross-sectional data from the J-MICC study

Htay Z.W., Michihata N., Nakamura Y., Hippo Y., Otonari J., Ikezaki H., Nishida Y., Shimanoe C., Tamura T., Nagayoshi M., Kato Y., Tamada Y., Hishida A., Tanoue S., Nishimoto D., Koyama T., Ozaki E., Kuriki K., Takashima N., Miyagawa N., Katsuura-Kamano S., Watanabe T., Wakai K., Matsuo K.

European Journal of Clinical Nutrition 2025年

ISSN 09543007

Background: With the increasing burden of metabolic syndrome, it is crucial to focus on lifestyle factors to reduce the risk of metabolic syndrome. Objectives: This study aims to quantify the associations between dietary diversity and the risk of metabolic syndrome among the Japanese population. Methods: This study was conducted using baseline data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study. The baseline survey was conducted from 2005 to 2014 by recruiting individuals aged 35–69. Information regarding dietary intake and biometric measurements were obtained. Dietary Diversity Score (DDS) was calculated from the data based on the food frequency questionnaire. A multiple logistic regression analysis was conducted to analyze the association between DDS and metabolic syndrome. Results: In total, 75,332 participants were included for analysis. Inverse associations were observed between a high DDS and metabolic syndrome (adjusted odds ratio, 0.83 [95% confidential interval 0.76–0.92]). Likewise, a high DDS was associated with reduced odds of a high body mass index and hypertension. No significant associations were observed between the DDS and serum triglyceride, fasting blood glucose, or high-density lipoprotein cholesterol values. Conclusion: The findings of this study emphasize that dietary diversity has inversed associations with metabolic syndrome. Promoting a diverse and balanced diet can be a potential strategy for mitigating the burden of metabolic syndrome.

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Asymptomatic Intracranial Vascular Lesions and Cognitive Function in a General Population of Japanese Men: Shiga Epidemiological Study of Subclinical Atherosclerosis (SESSA)

Ito T., Fujiyoshi A., Ohkubo T., Shiino A., Shitara S., Miyagawa N., Torii S., Hisamatsu T., Segawa H., Kondo K., Kadota A., Tooyama I., Watanabe Y., Yoshida K., Nozaki K., Miura K.

Cerebrovascular Diseases 1 - 11 2025年

ISSN 10159770

Introduction: Intracranial subclinical vessel diseases are considered important indicators of cognitive impairment. However, a comprehensive assessment of various types of vessel disease, particularly in Asian populations, is lacking. We aimed to compare multiple types of intracranial vessel disease in association with cognitive function among a communitybased Japanese male population. Methods: The Shiga Epidemiological Study of Subclinical Atherosclerosis (SESSA) randomly recruited and examined a community-based cohort of Japanese men from Shiga, Japan. We analyzed those who underwent the Cognitive Abilities Screening Instrument (CASI) assessment and cranial magnetic resonance imaging/ angiogram (MRI/MRA) in 2010 2015. Using MRI/MRA, we assessed lacunar infarction, microbleeds, periventricular hyperintensity (PVH), deep subcortical white matter hyperintensity (DSWMH), and intracranial artery stenosis (ICAS). We divided these subclinical cerebrovascular diseases (SCDs) into three categories according to severity. Using linear regression, we calculated the CASI score according to the grade of each vessel disease, adjusted for age and years of education. Results: In the adjusted models, CASI scores were significantly associated with both PVH and DSWMH. Specifically, multivariable-adjusted CASI scores declined across increasing severity categories of DSWMH (91.7, 91.2, and 90.4; p for trend = 0.011) and PVH (91.5, 90.4, and 89.7; p for trend = 0.006). Other SCDs did not show significant associations. In stratified analyses based on the presence or absence of each SCD, both DSWMH and PVH demonstrated significant inverse trends with CASI scores in the absence of lacunar infarcts and microbleeds and in the presence of ICAS. Additionally, among participants with PVH (+), ≥moderate ICAS was significantly associated with lower CASI scores. Conclusion: PVH and DSWMH showed significant dose-response relationships with cognitive function among community-based Japanese men. These findings suggest that white matter lesions may be an important indicator of early cognitive impairment, and severe ICAS may also play a role in those with PVH.

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Dairy Intake and All-Cause, Cancer, and Cardiovascular Disease Mortality Risk in A Large Japanese Population: A 12-Year Follow-Up of the J-MICC Study.

Miyagawa N, Takashima N, Harada A, Kadota A, Kondo K, Miura K, Imaeda N, Goto C, Otonari J, Ikezaki H, Tanaka K, Shimanoe C, Nagayoshi M, Tamura T, Kubo Y, Kato Y, Koyanagi YN, Ito H, Michihata N, Nakamura Y, Tanoue S, Ibusuki R, Suzuki S, Nishiyama T, Ozaki E, Watanabe I, Kuriki K, Watanabe T, Ishizu M, Hishida A, Kita Y, Wakai K, Matsuo K, J-MICC Study Group

Journal of atherosclerosis and thrombosis （一般社団法人日本動脈硬化学会） advpub （ 0 ） 596 - 607 2024年11月

ISSN 1340-3478

Aim: We examined the association between dairy intake and all-cause, cancer, and cardiovascular disease mortality in a cohort of the general population followed up for 12 years across Japan. Methods: We conducted a longitudinal cohort study of 79,715 participants from the Japan Multi-Institutional Collaborative Cohort study (57.2% women, mean age 54.7 years old). The amount of dairy (milk and yogurt) intake was determined using a validated short-food frequency questionnaire. The hazard ratio for mortality according to sex-specific tertile of dairy intake was calculated using Cox proportional hazards regression models with adjustment for potential confounding factors and dietary factors by sex. Results: During the follow-up period (932,738 person-years), 3,723 participants died, including 2,088 cancer and 530 cardiovascular disease deaths. The highest tertile of total dairy intake (versus the lowest tertile) was associated with a 19% lower all-cause mortality risk (hazard ratio =0.81, 95% confidence interval: 0.70-0.92; P for trend=0.001) in women. Similarly, we observed inverse associations between milk intake and all-cause and cancer mortality risk in women, yogurt intake and cardiovascular disease risk in women, and yogurt intake and all-cause mortality risk in both sexes. Conclusion: A higher total dairy and milk intakes in women and yogurt intake in both sexes were associated with a reduced risk of all-cause mortality in the general population across Japan during the 12-year follow-up period.

Food group intakes and high-sensitivity C-reactive protein among community-dwelling Japanese adults: a cross-sectional study

Matsunaga T., Wakai K., Imaeda N., Goto C., Tamada Y., Kato Y., Kubo Y., Okada R., Nagayoshi M., Tamura T., Hishida A., Ikezaki H., Otonari J., Takashima N., Miyagawa N., Matsuo K.

Public Health Nutrition 27 （ 1 ） e212 2024年10月

ISSN 13689800

Objective: Healthy dietary patterns have been linked to lower levels of chronic inflammation. The present study aimed to investigate the associations between food group intakes and high-sensitivity C-reactive protein (hsCRP) among community-dwelling adults. Design: Cross-sectional. Setting: Three areas in Japan (Shiga, Fukuoka, or Kyushu and Okinawa). Participants: The present analysis included 13 648 participants (5126 males and 8522 females; age range, 35-69 years) who had been enrolled in the baseline survey of the Japan Multi-Institutional Collaborative Cohort Study. Food group intakes were estimated using a FFQ. Multiple linear regression was used to examine associations between the quartiles of each energy-adjusted food group intake and log-transformed hsCRP. Results: The following concentration ratios of hsCRP after comparing the highest and lowest quartiles of food group intake were significant: in males, 1.12 (95 % CI 1.02, 1.22) for processed meat, 1.13 (95 % CI 1.03, 1.24) for fish and 0.83 (95 % CI 0.76, 0.90) for nuts; in females, 0.89 (95 % CI 0.81, 0.97) for bread, 1.11 (95 % CI 1.03, 1.19) for processed meat, 0.86 (95 % CI 0.80, 0.92) for vegetables, 1.19 (95 % CI 1.11, 1.29) for fruit, 0.90 (95 % CI 0.84, 0.97) for nuts and 0.88 (95 % CI 0.82, 0.95) for green tea. Conclusions: Processed meat and nut intakes were associated with higher and lower hsCRP levels, respectively, in both sexes. However, for several food groups, including fish and fruit, previous findings from dietary pattern analyses were not supported by the present analyses at the food group level.

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[Validity assessment of self-reported medication use in a pharmacoepidemiologic study by comparison with prescription record review].

Yajima R, Matsumoto M, Iida M, Harada S, Shibuki T, Hirata A, Kuwabara K, Miyagawa N, Nakamura T, Okamura T, Takebayashi T

[Nihon koshu eisei zasshi] Japanese journal of public health （日本公衆衛生学会） 71 （ 8 ） 430 - 437 2024年08月

ISSN 0546-1766

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。

Evaluation of Medication Adherence Among Prevalent Users in Hypertension, Dyslipidemia, and Diabetes Using Health Insurance Claims: A Population-Based Cohort Study in Japan

Matsumoto M., Harada S., Ikuta H., Iida M., Kato S., Sata M., Shibuki T., Ishibashi Y., Miyagawa N., Hisamatsu M., Hirata A., Kuwabara K., Takeuchi A., Sugiyama D., Suzuki S., Nakamura T., Okamura T., Takebayashi T.

Pharmacoepidemiology and Drug Safety 33 （ 8 ） e5855 2024年08月

ISSN 10538569

Purpose: Hypertension (HT), dyslipidemia (DL), and diabetes mellitus (DM) are major risk factors for cardiovascular diseases. Despite the wide availability of medications to reduce this risk, poor adherence to medications remains an issue. The aim of this study is to evaluate medication adherence of prevalent users in these disease medications (HT, DL, DM) using claims data. Factors associated with non-adherence were also examined. Methods: Of 7538 participants of the Tsuruoka Metabolomics Cohort Study, 3693 (HT: 2702, DL: 2112, DM: 661) were identified as prevalent users of these disease medications. Information on lifestyle was collected through a questionnaire. Adherence was assessed by a proportion of days covered (PDC) and participants with PDC ≥0.8 were defined as adherent. Predictors of non-adherence were determined by performing multivariable logistic regression. Results: Medication adherence differed by treatment status. Among those without comorbidities, those with HT-only showed the highest adherence (90.2%), followed by those with DM-only (81.2%) and those with DL-only (80.8%). Factors associated with non-adherence in each medication group were skipping breakfast and poor understanding of medications among those with HT medications, females, having comorbidities, having a history of heart disease, and drinking habit among those with DL medications, and good sleep quality and skipping breakfast among those with DM medications. Conclusion: While participants showed high medication adherence, differences were observed across medication groups. The identified predictors of non-adherence could help target those in need of adherence support.

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Association between consumption of small fish and all-cause mortality among Japanese: the Japan Multi-Institutional Collaborative Cohort Study

Kasahara C., Tamura T., Wakai K., Tamada Y., Kato Y., Kubo Y., Okada R., Nagayoshi M., Hishida A., Imaeda N., Goto C., Otonari J., Ikezaki H., Nishida Y., Shimanoe C., Oze I., Koyanagi Y.N., Nakamura Y., Kusakabe M., Nishimoto D., Shimoshikiryo I., Suzuki S., Watanabe M., Ozaki E., Omichi C., Kuriki K., Takashima N., Miyagawa N., Arisawa K., Katsuura-Kamano S., Takeuchi K., Matsuo K.

Public Health Nutrition 27 （ 1 ） e135 - 40 2024年05月

ISSN 13689800

Objective: Although small fish are an important source of micronutrients, the relationship between their intake and mortality remains unclear. This study aimed to clarify the association between intake of small fish and all-cause and cause-specific mortality. Design: We used the data from a cohort study in Japan. The frequency of the intake of small fish was assessed using a validated FFQ. The hazard ratio (HR) and 95 % confidence interval (CI) for all-cause and cause-specific mortality according to the frequency of the intake of small fish by sex were estimated using a Cox proportional hazard model with adjustments for covariates. Setting: The Japan Multi-Institutional Collaborative Cohort Study. Participants: A total of 80 802 participants (34 555 males and 46 247 females), aged 35-69 years. Results: During a mean follow-up of 9·0 years, we identified 2482 deaths including 1495 cancer-related deaths. The intake of small fish was statistically significantly and inversely associated with the risk of all-cause and cancer mortality in females. The multivariable-adjusted HR (95 % CI) in females for all-cause mortality according to the intake were 0·68 (0·55, 0·85) for intakes 1-3 times/month, 0·72 (0·57, 0·90) for 1-2 times/week and 0·69 (0·54, 0·88) for ≥ 3 times/week, compared with the rare intake. The corresponding HR (95 % CI) in females for cancer mortality were 0·72 (0·54, 0·96), 0·71 (0·53, 0·96) and 0·64 (0·46, 0·89), respectively. No statistically significant association was observed in males. Conclusions: Intake of small fish may reduce the risk of all-cause and cancer mortality in Japanese females.

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Association of Nonalcoholic Fatty Liver Disease with Arterial Stiffness and its Metabolomic Profiling in Japanese Community-Dwellers.

Hirata A, Harada S, Iida M, Kurihara A, Fukai K, Kuwabara K, Kato S, Matsumoto M, Sata M, Miyagawa N, Toki R, Edagawa S, Sugiyama D, Sato A, Hirayama A, Sugimoto M, Soga T, Tomita M, Okamura T, Takebayashi T

Journal of atherosclerosis and thrombosis （一般社団法人日本動脈硬化学会） advpub （ 0 ） 1031 - 1047 2024年02月

ISSN 1340-3478

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.

スポット尿中のナトリウム・カリウム排泄状況と栄養素等摂取量・食品群摂取量の関連

中川夕美, 由田克士, 宮川尚子, 岡見雪子, 大久保孝義, 岡村智教, 三浦克之, NIPPON DATA2010研究グループ

栄養学雑誌（特定非営利活動法人日本栄養改善学会） 82 （ 1 ） 13 - 23 2024年02月

ISSN 00215147

【目的】スポット尿から推定した24時間尿中のナトリウム (Na)・カリウム (K) 排泄量と食事記録法により求められた栄養素等摂取量および食品群摂取量の関連を検討する。【方法】平成22年国民健康・栄養調査およびNIPPON DATA2010の参加者から，重篤な循環器疾患，腎臓病または腎機能低下と指摘された者および高血圧，糖尿病，脂質異常症の治療中の者を除いた男性581人，女性923人を対象とした。性別に推定24時間尿中のNaとKの排泄量の中央値で多／少を組み合わせた4群間 (尿中K多Na少群，尿中K多Na多群，尿中K少Na少群，尿中K少Na多群) で栄養素等摂取量と食品群別摂取量を比較した。【結果】尿中へのK排泄量が多くNa排泄量も多い群（尿中K多Na多群）は男女ともK摂取量が尿中K少群より多く，女性においてNaおよび漬け物の摂取量が尿中Na少群より多く，野菜類摂取量が尿中K少群より多かった。尿中K少Na少群は男女ともK摂取量が尿中K多群より少なかった。尿中K少Na多群は食事中Na/K比が女性で最も高かった。尿中K多Na少群は，食事中Na/K比が女性で最も低く，男女ともK摂取量，乳類の摂取量が尿中K少群より多かった。【結論】集団レベルにおいて，スポット尿から推定した24時間尿中のNaとKの排泄量は，NaやKの摂取状況，およびKの寄与率が高い食品群の摂取量と関連している可能性が示唆された。

スポット尿中のナトリウム・カリウム排泄状況と栄養素等摂取量・食品群摂取量の関連　NIPPON DATA2010

中川夕美, 由田克士, 宮川尚子, 岡見雪子, 大久保孝義, 岡村智教, 三浦克之

栄養学雑誌（(NPO)日本栄養改善学会） 82 （ 1 ） 13 - 23 2024年02月

ISSN 0021-5147

【目的】スポット尿から推定した24時間尿中のナトリウム(Na)・カリウム(K)排泄量と食事記録法により求められた栄養素等摂取量および食品群摂取量の関連を検討する。【方法】平成22年国民健康・栄養調査およびNIPPON DATA2010の参加者から,重篤な循環器疾患,腎臓病または腎機能低下と指摘された者および高血圧,糖尿病,脂質異常症の治療中の者を除いた男性581人,女性923人を対象とした。性別に推定24時間尿中のNaとKの排泄量の中央値で多/少を組み合わせた4群間(尿中K多Na少群,尿中K多Na多群,尿中K少Na少群,尿中K少Na多群)で栄養素等摂取量と食品群別摂取量を比較した。【結果】尿中へのK排泄量が多くNa排泄量も多い群(尿中K多Na多群)は男女ともK摂取量が尿中K少群より多く,女性においてNaおよび漬け物の摂取量が尿中Na少群より多く,野菜類摂取量が尿中K少群より多かった。尿中K少Na少群は男女ともK摂取量が尿中K多群より少なかった。尿中K少Na多群は食事中Na/K比が女性で最も高かった。尿中K多Na少群は,食事中Na/K比が女性で最も低く,男女ともK摂取量,乳類の摂取量が尿中K少群より多かった。【結論】集団レベルにおいて,スポット尿から推定した24時間尿中のNaとKの排泄量は,NaやKの摂取状況,およびKの寄与率が高い食品群の摂取量と関連している可能性が示唆された。(著者抄録)

Seven-plus hours of daily sedentary time and the subsequent risk of breast cancer: Japan Multi-Institutional Collaborative Cohort Study

Tomida S., Koyama T., Ozaki E., Takashima N., Morita M., Sakaguchi K., Naoi Y., Nishida Y., Hara M., Hishida A., Tamura T., Okada R., Kubo Y., Otonari J., Ikezaki H., Nakamura Y., Kusakabe M., Tanoue S., Koriyama C., Koyanagi Y.N., Ito H., Suzuki S., Otani T., Miyagawa N., Okami Y., Arisawa K., Watanabe T., Kuriki K., Wakai K., Matsuo K.

Cancer Science （Cancer Science） 115 （ 2 ） 611 - 622 2024年02月

ISSN 13479032

This study aimed to investigate the association between daily sedentary time and the risk of breast cancer (BC) in a large Japanese population. The participants were 36,023 women aged 35–69 years from the Japan Multi-Institutional Collaborative Cohort Study. Cox proportional hazards analysis was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for BC incidence in relation to time spent sedentarily (categorical variables: <7 and ≥7 hours/day [h/d]). Additionally, the associations of BC incidence to the joint effect of sedentary time with each component of physical activity, such as leisure-time metabolic equivalents (METs), frequency of leisure-time physical activity, and daily walking time, were examined. During 315,189 person-years of follow-up, 554 incident cases of BC were identified. When compared to participants who spent <7 h/d sedentary, those who spent ≥7 h/d sedentary have a significantly higher risk of BC (HR, 1.36; 95% CI, 1.07–1.71). The corresponding HRs among participants who spent ≥7 h/d sedentary with more physical activity, such as ≥1 h/d for leisure-time METs, ≥3 days/week of leisure-time physical activity, and ≥1 h/d of daily walking were 1.58 (95% CI, 1.11–2.25), 1.77 (95% CI, 1.20–2.61), and 1.42 (95% CI, 1.10–1.83), respectively, compared with those who spent <7 h/d sedentary. This study found that spending ≥7 h/d of sedentary time is associated with the risk of BC. Neither leisure-time physical activity nor walking had a BC-preventive effect in those with ≥7 h/d of sedentary time.

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Association of step counts with cognitive function in apparently healthy middle-aged and older Japanese men

Shibukawa T., Fujiyoshi A., Moniruzzaman M., Miyagawa N., Kadota A., Kondo K., Saito Y., Kadowaki S., Hisamatsu T., Yano Y., Arima H., Tooyama I., Ueshima H., Miura K.

Preventive Medicine Reports （Preventive Medicine Reports） 38 102615 - 102615 2024年02月

ISSN 2211-3355

Background: Increasing physical activity may prevent cognitive decline. Previous studies primarily focused on older adults and used self-reported questionnaires to assess physical activity. We examined the relationship between step count, an objective measure of physical activity, and cognitive function in community-based middle-aged and older Japanese men. Methods: The Shiga Epidemiological Study of Subclinical Atherosclerosis randomly recruited community-dwelling healthy men aged 40–79 years from Shiga, Japan, and measured their step counts over 7 consecutive days using a pedometer at baseline (2006–2008). Among men who returned for follow-up (2009–2014), we assessed their cognitive function using the Cognitive Abilities Screening Instrument (CASI) score. We restricted our analyses to those with valid 7-day average step counts at baseline and those who remained free of stroke at follow-up (n = 676). Using analysis of covariance, we calculated the adjusted means of the CASI score according to the quartiles of the average step counts. Results: The mean (standard deviation) of age and unadjusted CASI score were 63.8 (9.1) years and 90.8 (5.8), respectively. The CASI score was elevated in higher quartiles of step counts (90.2, 90.4, 90.6, and 91.8 from the lowest to the highest quartile, respectively, [p for trend = 0.004]) in a model adjusted for age and education. Further adjustment for smoking, drinking, and other cardiovascular risk factors resulted in a similar pattern of association (p for trend = 0.005). Conclusion: In apparently healthy middle-aged and older Japanese men, a greater 7-day average step count at baseline was associated with significantly higher cognitive function score.

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Study Profile of the Tsuruoka Metabolomics Cohort Study (TMCS).

Harada S, Iida M, Miyagawa N, Hirata A, Kuwabara K, Matsumoto M, Okamura T, Edagawa S, Kawada Y, Miyake A, Toki R, Akiyama M, Kawai A, Sugiyama D, Sato Y, Takemura R, Fukai K, Ishibashi Y, Kato S, Kurihara A, Sata M, Shibuki T, Takeuchi A, Kohsaka S, Sawano M, Shoji S, Izawa Y, Katsumata M, Oki K, Takahashi S, Takizawa T, Maruya H, Nishiwaki Y, Kawasaki R, Hirayama A, Ishikawa T, Saito R, Sato A, Soga T, Sugimoto M, Tomita M, Komaki S, Ohmomo H, Ono K, Otsuka-Yamasaki Y, Shimizu A, Sutoh Y, Hozawa A, Kinoshita K, Koshiba S, Kumada K, Ogishima S, Sakurai-Yageta M, Tamiya G, Takebayashi T

Journal of epidemiology （日本疫学会） advpub （ 0 ） 393 - 401 2024年01月

ISSN 0917-5040

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.

Reliability of Time-Series Plasma Metabolome Data over 6 Years in a Large-Scale Cohort Study

Miyake A., Harada S., Sugiyama D., Matsumoto M., Hirata A., Miyagawa N., Toki R., Edagawa S., Kuwabara K., Okamura T., Sato A., Amano K., Hirayama A., Sugimoto M., Soga T., Tomita M., Arakawa K., Takebayashi T., Iida M.

Metabolites （Metabolites） 14 （ 1 ） 2024年01月

ISSN 2218-1989

Studies examining long-term longitudinal metabolomic data and their reliability in large-scale populations are limited. Therefore, we aimed to evaluate the reliability of repeated measurements of plasma metabolites in a prospective cohort setting and to explore intra-individual concentration changes at three time points over a 6-year period. The study participants included 2999 individuals (1317 men and 1682 women) from the Tsuruoka Metabolomics Cohort Study, who participated in all three surveys—at baseline, 3 years, and 6 years. In each survey, 94 plasma metabolites were quantified for each individual and quality control (QC) sample. The coefficients of variation of QC, intraclass correlation coefficients, and change rates of QC were calculated for each metabolite, and their reliability was classified into three categories: excellent, fair to good, and poor. Seventy-six percent (71/94) of metabolites were classified as fair to good or better. Of the 39 metabolites grouped as excellent, 29 (74%) in men and 26 (67%) in women showed significant intra-individual changes over 6 years. Overall, our study demonstrated a high degree of reliability for repeated metabolome measurements. Many highly reliable metabolites showed significant changes over the 6-year period, suggesting that repeated longitudinal metabolome measurements are useful for epidemiological studies.

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Association between awareness of limiting food intake and all-cause mortality: A cohort study in Japan.

Nishimoto D, Ibusuki R, Shimoshikiryo I, Shibuya K, Tanoue S, Koriyama C, Takezaki T, Oze I, Ito H, Hishida A, Tamura T, Kato Y, Tamada Y, Nishida Y, Shimanoe C, Suzuki S, Nishiyama T, Ozaki E, Tomida S, Kuriki K, Miyagawa N, Kondo K, Arisawa K, Watanabe T, Ikezaki H, Otonari J, Wakai K, Matsuo K

Journal of epidemiology （日本疫学会） advpub （ 0 ） 286 - 294 2023年11月

ISSN 0917-5040

Background: Improving diets requires an awareness of the need to limit foods for which excessive consumption is a health problem. Since there are limited reports on the link between this awareness and mortality risk, we examined the association between awareness of limiting food intake (energy, fat, and sweets) and all-cause mortality in a Japanese cohort study. Methods: Participants comprised 58,772 residents (27,294 men; 31,478 women) aged 35–69 years who completed baseline surveys of the Japan Multi-Institutional Collaborative Cohort Study from 2004 to 2014. Hazard ratios (HRs) for all-cause mortality and 95% confidence intervals (CIs) were estimated by sex using a Cox proportional hazard model, with adjustment for related factors. Mediation analysis with fat intake as a mediator was also conducted. Results: The mean follow-up period was 11 years, and 2,516 people died. Estimated energy and fat intakes according to the Food Frequency Questionnaire were lower in those with awareness of limiting food intake than in those without this awareness. Women with awareness of limiting fat intake showed a significant decrease in mortality risk (HR 0.73; 95% CI, 0.55–0.94). Mediation analysis revealed that this association was due to the direct effect of the awareness of limiting fat intake and that the total effect was not mediated by actual fat intake. Awareness of limiting energy or sweets intake was not related to mortality risk reduction. Conclusion: Awareness of limiting food intake had a limited effect on reducing all-cause mortality risk.

Metabolomics profiles alterations in cigarette smokers and heated tobacco product users.

Harada S, Ohmomo H, Matsumoto M, Sata M, Iida M, Hirata A, Miyagawa N, Kuwabara K, Kato S, Toki R, Edagawa S, Sugiyama D, Sato A, Hirayama A, Sugimoto M, Soga T, Tomita M, Shimizu A, Okamura T, Takebayashi T

Journal of epidemiology （日本疫学会） advpub （ 0 ） 403 - 410 2023年11月

ISSN 0917-5040

BACKGROUND: Heated tobacco products (HTPs) have gained global popularity, but their health risks remain unclear. Therefore, the current study aimed to identify plasma metabolites associated with smoking and HTP use in a large Japanese population to improve health risk assessment. METHODS: Metabolomics data from 9,922 baseline participants of the Tsuruoka Metabolomics Cohort Study (TMCS) were analyzed to determine the association between smoking habits and plasma metabolites. Moreover, alterations in smoking-related metabolites among HTP users were examined based on data obtained from 3,334 participants involved from April 2018 to June 2019 in a follow-up survey. RESULTS: Our study revealed that cigarette smokers had metabolomics profiles distinct from never smokers, with 22 polar metabolites identified as candidate biomarkers for smoking. These biomarker profiles of HTP users were closer to those of cigarette smokers than those of never smokers. The concentration of glutamate was higher in cigarette smokers, and biomarkers involved in glutamate metabolism were also associated with cigarette smoking and HTP use. Network pathway analysis showed that smoking was associated with the glutamate pathway, which could lead to endothelial dysfunction and atherosclerosis of the vessels. CONCLUSION: Our study showed that the glutamate pathway is affected by habitual smoking. These changes in the glutamate pathway may partly explain the mechanism by which cigarette smoking causes cardiovascular disease. HTP use was also associated with glutamate metabolism, indicating that HTP use may contribute to the development of cardiovascular disease through mechanisms similar to those in cigarette use.

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