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Objective: The objective of this study was to compare race‐ and ethnicity‐specific BMI cutoffs for the three classes of obesity based on equivalent risk of type 2 diabetes (T2D). Methods: Participants without T2D were included from the UK Biobank, the China Health and Nutrition Survey, and the Singapore Chinese Health Study. Poisson regressions with restricted cubic splines were applied to determine BMI cutoffs for each non‐White race and ethnicity for equivalent incidence rates of T2D at BMI values of 30.0, 35.0, and 40.0 kg/m2 in White adults. Results: During a median follow‐up of 13.8 years among 507,763 individuals, 5.2% developed T2D. In women, BMI cutoffs for an equivalent incidence rate of T2D as observed at 40.0 kg/m2 in White adults were 31.6 kg/m2 in Black, 29.2 kg/m2 in British Chinese, 27.3 kg/m2 in South Asian, 26.9 kg/m2 in Native Chinese, and 25.1 kg/m2 in Singapore Chinese adults. In men, the corresponding BMI cutoffs were 31.9 kg/m2 in Black, 30.6 kg/m2 in British Chinese, 29.0 kg/m2 in South Asian, 29.6 kg/m2 in Native Chinese, and 27.6 kg/m2 in Singapore Chinese adults. The race and ethnicity order was consistent when equivalent BMI cutoffs were estimated for class I and II obesity. Conclusions: Establishing a race‐ and ethnicity‐tailored classification of the three classes of obesity is urgently needed. [ABSTRACT FROM AUTHOR]

Background: Although red meat consumption has been associated with risk of atherosclerotic coronary artery disease and stroke, no prospective study has examined this with the risk of chronic limb-threatening ischemia (CLTI). Methods: In a prospective study of 63,257 Chinese in Singapore, who were aged 45–74 years old at recruitment, diet was assessed via a validated semi-quantitative food frequency questionnaire. Incident CLTI cases were ascertained via linkage with nationwide hospital records for lower extremity amputation or angioplasty for peripheral arterial disease. Multivariable Cox models were used to examine associations between quartiles of meat intake and CLTI risk. Results: After a mean follow-up of 18.8 years, there were 1069 cases of CLTI. Higher intake of red meat intake was associated with increased risk of CLTI in a stepwise manner. Comparing extreme quartiles of red meat intake, the hazard ratio (HR) for the association with CLTI risk was 1.24 [95% confidence interval (CI) = 1.03–1.49; P-trend = 0.02]. In stratified analysis, red meat intake had a stronger association with CLTI risk among those without diabetes [HR (95% CI) comparing extreme quartiles = 1.41 (1.10–1.80); P-trend = 0.03] than among those with diabetes at baseline [HR (95% CI) comparing extreme quartiles = 1.04 (0.79–1.38); P-trend = 0.05] (P-interaction = 0.03). Otherwise, the associations were not different by sex, BMI, smoking status, hypertension, alcohol consumption, or history of cardiovascular diseases. Using a theoretical model in substitution analysis that substituted three servings per week of red meat with poultry or fish/shellfish, the relative risk of CLTI was reduced by 13–14%. Conclusions: Consumption of red meat was associated with higher CLTI risk in this Asian cohort. Substituting red meat with poultry or fish/shellfish may reduce this risk. [ABSTRACT FROM AUTHOR]

There has been growing evidence suggesting that diabetes may be associated with increased liver cancer risk. However, studies conducted in Asian countries are limited. This project considered data of 968,738 adults pooled from 20 cohort studies of Asia Cohort Consortium to examine the association between baseline diabetes and liver cancer incidence and mortality. Cox proportional hazard model and competing risk approach was used for pooled data. Two‐stage meta‐analysis across studies was also done. There were 839,194 subjects with valid data regarding liver cancer incidence (5654 liver cancer cases [48.29/100,000 person‐years]), follow‐up time and baseline diabetes (44,781 with diabetes [5.3%]). There were 747,198 subjects with valid data regarding liver cancer mortality (5020 liver cancer deaths [44.03/100,000 person‐years]), follow‐up time and baseline diabetes (43,243 with diabetes [5.8%]). Hazard ratio (HR) (95% confidence interval [95%CI]) of liver cancer diagnosis in those with vs. without baseline diabetes was 1.97 (1.79, 2.16) (p <.0001) after adjusting for baseline age, gender, body mass index, tobacco smoking, alcohol use, and heterogeneity across studies (n = 586,072; events = 4620). Baseline diabetes was associated with increased cumulative incidence of death due to liver cancer (adjusted HR (95%CI) = 1.97 (1.79, 2.18); p <.0001) (n = 595,193; events = 4110). A two‐stage meta‐analytic approach showed similar results. This paper adds important population‐based evidence to current literature regarding the increased incidence and mortality of liver cancer in adults with diabetes. The analysis of data pooled from 20 studies of different Asian countries and the meta‐analysis across studies with large number of subjects makes the results robust. [ABSTRACT FROM AUTHOR]

Previous studies have investigated the association between reproductive factors and lung cancer risk; however, findings have been inconsistent. In order to assess this association among Asian women, a total of 308,949 female participants from 11 prospective cohorts and four Asian countries (Japan, Korea, China, and Singapore) were included. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CIs). A total of 3,119 primary lung cancer cases and 2247 lung cancer deaths were identified with a mean follow‐up of 16.4 years. Parous women had a lower risk of lung cancer incidence and mortality as compared with nulliparous women, with HRs of 0.82 (95% CI = 0.70–0.96) and 0.78 (95% CI = 0.65–0.94). The protective association of parity and lung cancer incidence was greater among ever‐smokers (HR = 0.66, 95% CI = 0.49–0.87) than in never‐smokers (HR = 0.90, 95% CI = 0.74–1.09) (P‐interaction = 0.029). Compared with age at first delivery ≤20 years, older age at first delivery (21–25, ≥26 years) was associated with a lower risk of lung cancer incidence and mortality. Women who ever used hormone replacements had a higher likelihood of developing non‐small cell lung cancer (HR = 1.31, 95% CI = 1.02–1.68), compared to those who never used hormone replacements. Future studies are needed to assess the underlying mechanisms, the relationships within these female reproductive factors, and the potential changes in smoking habits over time. [ABSTRACT FROM AUTHOR]

Simple Summary: In the last few decades, studies have found many common genetic variants linked to breast cancer. Most of these variants are in non-coding regions or regions that do not directly affect gene function. This study aims to see if a polygenic risk score (PRS) based on functional variants could better predict breast cancer risk compared to an established 313-variant breast cancer PRS. Using publicly available summary data from GWASs, and Quantitative Trait Locus studies of gene expression and DNA methylation, we identified 149 variants potentially causally linked to the risk of developing breast cancer; the weighted sum of these variants was designated as the functional variant. The functional PRS was less effective at predicting breast cancer than the established PRS in 3560 breast cancer patients and 3383 non-breast cancer individuals. Combining both scores did not substantially enhance the prediction accuracy of the established PRS. Purpose: To assess the association of a polygenic risk score (PRS) for functional genetic variants with the risk of developing breast cancer. Methods: Summary data-based Mendelian randomization (SMR) and heterogeneity in dependent instruments (HEIDI) were used to identify breast cancer risk variants associated with gene expression and DNA methylation levels. A new SMR-based PRS was computed from the identified variants (functional PRS) and compared to an established 313-variant breast cancer PRS (GWAS PRS). The two scores were evaluated in 3560 breast cancer cases and 3383 non-cancer controls and also in a prospective study (n = 10,213) comprising 418 cases. Results: We identified 149 variants showing pleiotropic association with breast cancer risk (eQTLHEIDI > 0.05 = 9, mQTLHEIDI > 0.05 = 165). The discriminatory ability of the functional PRS (AUCcontinuous [95% CI]: 0.540 [0.526 to 0.553]) was found to be lower than that of the GWAS PRS (AUCcontinuous [95% CI]: 0.609 [0.596 to 0.622]). Even when utilizing 457 distinct variants from both the functional and GWAS PRS, the combined discriminatory performance remained below that of the GWAS PRS (AUCcontinuous, combined [95% CI]: 0.561 [0.548 to 0.575]). A binary high/low-risk classification based on the 80th centile PRS in controls revealed a 6% increase in cases using the GWAS PRS compared to the functional PRS. The functional PRS identified an additional 12% of high-risk cases but also led to a 13% increase in high-risk classification among controls. Similar findings were observed in the SCHS prospective cohort, where the GWAS PRS outperformed the functional PRS, and the highest-performing PRS, a combined model, did not significantly improve over the GWAS PRS. Conclusions: While this study identified potentially functional variants associated with breast cancer risk, their inclusion did not substantially enhance the predictive accuracy of the GWAS PRS. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Consumption of different types of meat and the risk of chronic limb-threatening ischemia: the Singapore Chinese Health Study." The correction states that the affiliation of Dr. Ying was incorrectly replaced with the affiliation of Dr. Hausenloy in the original article. The correct affiliation for Dr. Ying should be "Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore, Singapore." The correction has been made and the original article has been updated. The publisher remains neutral regarding jurisdictional claims and institutional affiliations. [Extracted from the article]

Background: Adult height has been associated with handgrip strength, which is a surrogate marker of physical frailty. However, it is uncertain if this association is causative or due to confounding bias., Methods: We evaluated pairwise associations among handgrip strength, adult height, and genetically determined height (using a polygenic score [PGS] for height in a mediation framework and a 2-sample Mendelian randomization approach) by means of a multivariable regression model using a prospective cohort of Chinese living in Singapore. We additionally evaluated pathway enrichments of height-related genes in relation to increased handgrip strength to discover common biological mechanisms underlying associations of genetically determined height with handgrip strength., Results: Height PGS exhibited a positive association with handgrip strength at late life after adjusting for midlife body weight and other baseline exposures (cigarette smoking, education, and physical activity status, p = 1.2 × 10-9). Approximately 66.4% of the total effect of height PGS on handgrip strength was mediated through adult height (βindirect-effect = 0.034, pindirect-effect = 1.4 × 10-40). Two-sample Mendelian randomization evaluations showed a consistent causal relationship between increased height and increased handgrip strength in late life (p between 6.6 × 10-4 and 3.9 × 10-18), with insignificant horizontal pleiotropic effects (pMR-Egger intercept = 0.853). Pathway analyses of genes related to both increased adult height and handgrip strength revealed enrichment in ossification and adipogenesis pathways (padj between .034 and 6.8 × 10-4)., Conclusions: The study highlights a potentially causal effect between increased adult height and increased handgrip strength in late life, which may be explained by related biological processes underlying the preservation of muscle mass and strength in aging., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The prospective association between sleep duration and the development of late-life depressive symptomology is unclear., Aims: To investigate sleep duration from midlife to late life in relation to risk of depressive symptoms in late life., Method: A total of 14 361 participants from the Singapore Chinese Health Study were included in the present study. Daily sleep duration was self-reported at baseline (mean age of 52.4 years; 1993-98), follow-up 2 (mean age of 65.2 years; 2006-10) and follow-up 3 (mean age of 72.5 years; 2014-16) interviews. Depressive symptoms were evaluated using the Geriatric Depression Scale at follow-up 3 interviews. Modified Poisson regression models were performed to estimate relative risks and 95% confidence intervals of late-life depressive symptoms in relation to sleep duration at baseline and the two follow-up interviews., Results: Compared with sleeping 7 h per day, a short sleep duration of ≤5 h per day at baseline (i.e. midlife) was related to a higher risk of depressive symptoms (relative risk 1.10, 95% CI 1.06-1.15), and this risk was not affected by subsequent prolongation of sleep. Conversely, a long sleep duration of ≥9 h per day at baseline was not related to risk of depressive symptoms. At follow-up 3 (i.e. late life), both short sleep (relative risk 1.20, 95% CI 1.16-1.25) and long sleep (relative risk 1.12, 95% CI 1.07-1.18) duration were cross-sectionally associated with depressive symptoms., Conclusion: Short sleep duration in midlife, regardless of subsequent prolongation, is associated with an increased risk of depression in late life. Contrariwise, both short and long sleep duration in late life co-occur with depressive symptoms.

Objectives: To evaluate changes in the age at menarche in Asian populations., Study Design: Retrospective cohort study., Methods: We included 548,830 women from six countries in Asia. The data were sourced from 20 cohorts participating in the Asia Cohort Consortium (ACC) and two additional cohort studies: Japan Multi-institutional Collaborative Cohorts (J-MICC), and Japan Nurse Health Study (JNHS) with data on age at menarche. Joinpoint regression was used to evaluate changes in age at menarche by birth year and by country., Results: The study includes data from cohorts in six Asian countries namely, China, Iran, Japan, Korea, Malaysia and Singapore. Birth cohorts ranged from 1873 to 1995. The mean age of menarche was 14.0 years with a standard deviation (SD) of 1.4 years, ranged from 12.6 to 15.5 years. Over 100 years age at menarche showed an overall decrease in all six countries. China showed a mixed pattern of decrease, increase, and subsequent decrease from 1926 to 1960. Iran and Malaysia experienced a sharp decline between about 1985 and 1990, with APC values of -4.48 and -1.24, respectively, while Japan, South Korea, and Singapore exhibited a nearly linear decline since the 1980s, notably with an APC of -3.41 in Singapore from 1993 to 1995., Conclusions: Overall, we observed a declining age at menarche, while the pace of the change differed by country. Additional long-term observation is needed to examine the contributing factors of differences in trend across Asian countries. The study could serve as a tool to strengthen global health campaigns., (Copyright © 2024 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Objectives: Our study evaluated the independent and overall associations of vegetable and fruit consumption at midlife with the likelihood of physical frailty in later life. We also investigated whether specific nutrients in these foods could have accounted for these associations, if present., Design: Prospective cohort study., Setting: A population-based cohort of Chinese adults followed over a period of 20 years in Singapore., Participants: We used data from 11,959 subjects who participated in the baseline (1993-1998) and follow-up 3 (2014-2017) interviews of the Singapore Chinese Health Study., Measurements: At baseline, dietary intake was evaluated using a validated food frequency questionnaire. During the follow-up 3 visits, physical frailty was assessed using a modified Cardiovascular Health Study phenotype that included weakness, slowness, exhaustion and weight loss. Multivariable logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the associations with physical frailty., Results: Participants had mean ages of 52 years at baseline, and 72 years at follow-up 3. Baseline intake of vegetables, but not of fruits, showed a dose-dependent inverse relationship with physical frailty at follow-up 3 (P trend = 0.001). Compared to participants in the lowest quintile of vegetable intake, those in the highest quintile had reduced odds of frailty [OR (95% CI): 0.73 (0.60-0.89)]. Among the components of physical frailty, vegetable intake had the strongest inverse association with weakness defined by handgrip strength [OR (95% CI) between extreme quintiles: 0.62 (0.52-0.73); P trend < 0.001]. In models that were individually adjusted for nutrients, the vegetable-frailty association was attenuated and no longer statistically significant after adjusting for the intake of β-carotene, lutein, folate, α-carotene, and isothiocyanates., Conclusion: Increased midlife intake of vegetables was associated with reduced odds of physical frailty in later life, and the intake of β-carotene, lutein, folate, α-carotene, and isothiocyanates could have accounted for this association., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: Antibodies to select Epstein-Barr virus (EBV) proteins can diagnose early-stage nasopharyngeal carcinoma (NPC). We have previously shown that IgA against EBV nuclear antigen 1 (EBNA1) can predict incident NPC in high- and intermediate-risk cohorts 4 years pre-diagnosis. Here, we tested EBNA1 variants, with mutants, to define the sequence requirements for an NPC risk assay., Design: Mammalian-expressed constructs were developed to represent EBNA1 variants 487V and 487A which can differ by ≥15 amino acids in the N- and C-termini. Denatured lysates were evaluated by a refined IgA and IgG immunoblot assay in a case-control study using pre-diagnostic NPC sera from two independent cohorts in Singapore and Shanghai, P.R. China., Results: At 95% sensitivity, 487V yielded a 94.9% specificity compared to 86.1% for 487A. EBNA1 deleted for the conserved glycine-alanine repeats (GAr) reduced false positives by 22.8%. NPC sera reacted more strongly to the C-terminus than healthy controls, but the C-terminal construct (a.a. 390-641) showed lower specificity (84.8%) than the EBNA1 GAr deleted construct (92.4%) at 95% sensitivity., Conclusion: Although EBNA1 IgA was present in healthy sera, most epitopes localized to the immunodominant GAr. We conclude that a refined EBNA1 antigen deleted for the GAr but with residues consistently detected in Southeast Asian NPC tumors is optimal for risk prediction with an extended sojourn time of 7.5 years. Furthermore, distinct EBNA1 serologic profiles enhanced the utility of the EBNA1 IgA assay for risk stratification. This illustrates the importance of serologically relevant EBNA1 sequences for NPC risk prediction and early detection.

While rapid demographic changes in Asia are driving the incidence of chronic aging-related diseases, the limited availability of high-quality in vivo data hampers our ability to understand complex multi-factorial contributions, including gut microbial, to healthy aging. Leveraging a well-phenotyped cohort of community-living octogenarians in Singapore, we used deep shotgun-metagenomic sequencing for high-resolution taxonomic and functional characterization of their gut microbiomes (n = 234). Joint species-level analysis with other Asian cohorts identified distinct age-associated shifts characterized by reduction in microbial richness, and specific Alistipes and Bacteroides species enrichment (e.g., Alistipes shahii and Bacteroides xylanisolvens). Functional analysis confirmed these changes correspond to metabolic potential expansion in aging towards alternate pathways synthesizing and utilizing amino-acid precursors, vis-à-vis dominant microbial guilds producing butyrate in gut from pyruvate (e.g., Faecalibacterium prausnitzii, Roseburia inulinivorans). Extending these observations to key clinical markers helped identify >10 robust microbial associations to inflammation, cardiometabolic and liver health, including potential probiotic species (e.g., Parabacteroides goldsteinii) and pathobionts (e.g., Klebsiella pneumoniae), highlighting the microbiome's role as biomarkers and potential targets for promoting healthy aging., (© 2024. The Author(s).)

Purpose: There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer., Methods: We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity., Results: Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship ( P nonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2-enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; P het = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity., Conclusion: This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.