Epigenome-wide association study of total nicotine equivalents in multiethnic current smokers from three prospective cohorts.

The impact of tobacco exposure on health varies by race and ethnicity and is closely tied to internal nicotine dose, a marker of carcinogen uptake. DNA methylation is strongly responsive to smoking status and may mediate health effects, but study of associations with internal dose is limited. We performed a blood leukocyte epigenome-wide association study (EWAS) of urinary total nicotine equivalents (TNEs; a measure of nicotine uptake) and DNA methylation measured using the MethylationEPIC v1.0 BeadChip (EPIC) in six racial and ethnic groups across three cohort studies. In the Multiethnic Cohort Study (discovery, n = 1994), TNEs were associated with differential methylation at 408 CpG sites across >250 genomic regions (p < 9 × 10-8). The top significant sites were annotated to AHRR, F2RL3, RARA, GPR15, PRSS23, and 2q37.1, all of which had decreasing methylation with increasing TNEs. We identified 45 novel CpG sites, of which 42 were unique to the EPIC array and eight annotated to genes not previously linked with smoking-related DNA methylation. The most significant signal in a novel gene was cg03748458 in MIR383;SGCZ. Fifty-one of the 408 discovery sites were validated in the Singapore Chinese Health Study (n = 340) and the Southern Community Cohort Study (n = 394) (Bonferroni corrected p < 1.23 × 10-4). Significant heterogeneity by race and ethnicity was detected for CpG sites in MYO1G and CYTH1. Furthermore, TNEs significantly mediated the association between cigarettes per day and DNA methylation at 15 sites (average 22.5%-44.3% proportion mediated). Our multiethnic study highlights the transethnic and ethnic-specific methylation associations with internal nicotine dose, a strong predictor of smoking-related morbidities.

Association of female reproductive and hormonal factors with gallbladder cancer risk in Asia: A pooled analysis of the Asia Cohort Consortium.

The female predominance of gallbladder cancer (GBC) has led to a hypothesis regarding the hormone-related aetiology of GBC. We aimed to investigate the association between female reproductive factors and GBC risk, considering birth cohorts of Asian women. We conducted a pooled analysis of 331,323 women from 12 cohorts across 4 countries (China, Japan, Korea, and Singapore) in the Asia Cohort Consortium. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) to assess the association between reproductive factors (age at menarche, parity, age at first delivery, breastfeeding, and age at menopause) and GBC risk. We observed that a later age at menarche was associated with an increased risk of GBC (HR 1.4, 95% CI 1.16-1.70 for 17 years and older vs. 13-14 years), especially among the cohort born in 1940 and later (HR 2.5, 95% CI 1.50-4.35). Among the cohort born before 1940, women with a later age at first delivery showed an increased risk of GBC (HR 1.56, 95% CI 1.08-2.24 for 31 years of age and older vs. 20 years of age and younger). Other reproductive factors did not show a clear association with GBC risk. Later ages at menarche and at first delivery were associated with a higher risk of GBC, and these associations varied by birth cohort.

Association between reproductive factors with lung cancer incidence and mortality: A pooled analysis of over 308,000 females in the Asia cohort consortium.

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.

Diabetes is associated with increased liver cancer incidence and mortality in adults: A report from Asia Cohort Consortium.

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.

A meta-analysis of previous falls and subsequent fracture risk in cohort studies.

The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. INTRODUCTION: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). METHODS: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. RESULTS: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1.32 (95% CI 1.20-1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men. CONCLUSIONS: A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.

APOE Genotype Modifies the Association between Midlife Adherence to the Planetary Healthy Diet and Cognitive Function in Later Life among Chinese Adults in Singapore.

BACKGROUND: It remains unclear if adherence to the planetary healthy diet (PHD), designed to improve human and environmental health, is associated with better cognitive function in aging, and if this association differs by apolipoprotein E (APOE) genotype. OBJECTIVES: We aimed to examine the association between the PHD pattern and risk of poor cognitive function, and to further assess whether the APOE ε4 allele could modify this association. METHODS: The study included 16,736 participants from the Singapore Chinese Health Study. The PHD score was calculated using data from a validated 165-item food frequency questionnaire at baseline (1993-1998), with higher scores indicating greater adherence to the PHD. Cognitive function was assessed by the Singapore-modified Mini-Mental State Examination at follow-up 3 visits (2014-2016). A subset of 9313 participants had APOE genotype data. Logistic regression models were used to estimate the odds ratios (ORs) and 95% confidence intervals (CIs), with adjustment for potential confounders. RESULTS: We identified 2397 (14.3%) cases of poor cognitive function. In the total population, OR (95% CI) of poor cognitive function for each one-SD increment in the PHD score was 0.89 (0.85, 0.93). Carriers of APOE ε4 allele had increased risk of poor cognitive function (OR: 1.36, 95% CI: 1.15, 1.61). There was a significant interaction between the PHD score and the APOE ε4 allele (P-interaction = 0.042). Each one-SD increment in the PHD score was significantly associated with lower risk of poor cognitive function (OR: 0.89; 95% CI: 0.83, 0.96) in non-carriers of APOE ε4 allele, but not in APOE ε4 allele carriers (OR: 1.04, 95% CI: 0.89, 1.23). CONCLUSIONS: Midlife adherence to the PHD was associated with reduced risk of poor cognitive function in later life. However, this was not observed in carriers of APOE ε4 allele who had higher risk of poor cognitive function.

Diet quality from mid to late life and its association with physical frailty in late life in a cohort of Chinese adults.

BACKGROUND: It is unclear if improving diet quality after midlife could reduce the risk of physical frailty at late life. We aimed to associate changes in diet quality after midlife with physical frailty at late life. METHODS: Diet quality in 12,580 participants from the Singapore Chinese Health Study was assessed with the Dietary Approaches to Stop Hypertension (DASH) scores at baseline (1993-1998; mean age 53 years) and follow-up 3 (2014-2016; mean age 73 years). Physical frailty was assessed using the modified Cardiovascular Health Study phenotype at follow-up 3. Multivariable logistic regressions examined associations between DASH scores and physical frailty. RESULTS: Comparing participants in extreme quartiles of DASH scores, the odds ratios (OR) [95% confidence interval (CI)] for physical frailty were 0.85 (0.73,0.99) at baseline and 0.49 (0.41, 0.58) at follow-up 3. Compared to participants with consistently low DASH scores, participants with consistently high scores (OR 0.74, 95% CI: 0.59, 0.94) and those with > 10% increase in scores (OR 0.78, 95% CI: 0.64, 0.95) had lower odds of frailty. Compared to those in the lowest DASH tertiles at both time-points, significantly lower odds of physical frailty were observed in those who were in the highest DASH tertiles at both time points [0.59 (0.48, 0.73)], and in those who improved their scores from the lowest [0.68 (0.51, 0.91)] or second tertile at baseline [0.61 (0.48, 0.76)] to the highest tertile at follow-up 3. CONCLUSIONS: Maintaining a high diet quality or a substantial improvement in diet quality after midlife could lower the risk of physical frailty at late life.

Myocardial Aging among a Population-Based Cohort Is Associated with Adverse Cardiovascular Outcomes and Sex-Specific Differences among Older Adults.

INTRODUCTION: Despite growing calls to tackle aging-related cardiovascular disease (CVD), the role of detecting early diastolic dysfunction such as those observed in aging, prior to clinical disease, is of unclear clinical benefit. METHODS: Myocardial function determined by echocardiography was examined in association with incident cardiovascular outcomes or all-cause death by Cox proportional hazards model. Sex-based differences in outcomes were included. RESULTS: A total of 956 participants (mean age 63 ± 12.9 years, n = 424 males [44%]) were categorized based on mitral peak early-to-late diastolic filling velocity (E/A) ratios: E/A <0.8 (28%), E/A 0.8-1.2 (39%), E/A (29%), E/A >2.0 (4%). Incidence rate (IR) for non-fatal cardiovascular outcomes was 2.83 per 100 person-years (95% CI: 2.24-3.56) and 0.45 per 100 person-years (95% CI: 0.26-0.80) for all-cause death. Event-free survival from non-fatal cardiovascular outcomes was significantly different among E/A categories (log-rank p = 0.0269). E/A <0.8 (HR 1.80, 95% CI: 1.031, 3.14, p = 0.039) was associated with non-fatal cardiovascular outcomes. Among men, IR for cardiovascular outcomes was 3.56 per 100 person-years (95% CI: 2.62-4.84) and 0.75 per 100 person-years (95% CI: 0.39-1.44) for all-cause death. Among women, IR for cardiovascular outcomes was 2.22 per 100 person-years (95% CI: 1.56-3.16) and 0.21 per 100 person-years (95% CI: 0.067-0.64) for all-cause death. For E/A <0.8 category, women had significantly higher risks of non-fatal cardiovascular outcomes, compared to E/A 0.8-1.2 category (HR 2.49, 95% CI: 1.18, 5.23, p = 0.017). CONCLUSION: Myocardial aging was an independent predictor of cardiovascular outcomes in community-dwelling older adults prior to clinical CVD. Impaired myocardial relaxation was prevalent in both sexes but associated with worse outcomes in women, suggestive of sex differences in age-related biology.

Circulating immune markers and risks of non-Hodgkin lymphoma subtypes: A pooled analysis.

Although prediagnostic circulating concentrations of the immune activation markers soluble CD27 (sCD27), sCD30 and chemokine ligand-13 (CXCL13) have been associated with non-Hodgkin lymphoma (NHL) risk, studies have been limited by sample size in associations with NHL subtypes. We pooled data from eight nested case-control studies to investigate subtype-specific relationships for these analytes. Using polytomous regression, we calculated odds ratios (ORs) with 95% confidence intervals (CIs) relating study-specific analyte tertiles to selected subtypes vs controls (n = 3310): chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; n = 623), diffuse large B cell lymphoma (DLBCL; n = 621), follicular lymphoma (FL; n = 398), marginal zone lymphoma (MZL; n = 138), mantle cell lymphoma (MCL; n = 82) and T cell lymphoma (TCL; n = 92). We observed associations with DLBCL for elevated sCD27 [OR for third vs first tertile (ORT3 ) = 2.2, 95% CI = 1.6-3.1], sCD30 (ORT3  = 2.0, 95% CI = 1.6-2.5) and CXCL13 (ORT3  = 2.3, 95% CI = 1.8-3.0). We also observed associations with sCD27 for CLL/SLL (ORT3  = 3.3, 95% CI = 2.4-4.6), MZL (ORT3  = 7.7, 95% CI = 3.0-20.1) and TCL (ORT3  = 3.4, 95% CI = 1.5-7.7), and between sCD30 and FL (ORT3  = 2.7, 95% CI = 2.0-3.5). In analyses stratified by time from phlebotomy to case diagnosis, the sCD27-TCL and all three DLBCL associations were equivalent across both follow-up periods (<7.5, ≥7.5 years). For other analyte-subtype comparisons, associations were stronger for the follow-up period closer to phlebotomy, particularly for indolent subtypes. In conclusion, we found robust evidence of an association between these immune markers and DLBCL, consistent with hypotheses that mechanisms related to immune activation are important in its pathogenesis. Our other findings, particularly for the rarer subtypes MZL and TCL, require further investigation.

Soluble CD137 and risk of hepatocellular carcinoma: nested case-control studies in cohorts in Shanghai and Singapore.

BACKGROUND: The majority of hepatocellular carcinoma (HCC) cases occur in the presence of cirrhosis. Biomarkers of cirrhosis-associated immune dysfunction such as CD8+ T cell cytokines could aid HCC risk assessment. METHODS: CD8+ T cell cytokines were determined in pre-diagnostic serum in two studies including 315 HCC case-control pairs in the Shanghai Cohort Study (SCS) and 197 pairs in the Singapore Chinese Health Study (SCHS). Conditional logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) for HCC with levels of five cytokines-soluble CD137 (sCD137), soluble Fas (sFas), perforin, macrophage inflammatory protein 1-beta (MIP-1ß), and tumour necrosis factor alpha (TNF-α). RESULTS: sCD137 levels were significantly higher in HCC cases than controls in both cohorts (Ps < 0.001). Compared with the lowest quartile, multivariable-adjusted ORs (95% CI) of HCC for the highest sCD137 quartile were 3.79 (1.73, 8.30) in the SCS and 3.49 (1.44, 8.48) in the SCHS. The sCD137-HCC association was independent of hepatitis B seropositivity and follow-up time. No other cytokine was consistently associated with HCC risk. CONCLUSION: sCD137 was associated with higher risk of HCC in two studies nested in general population cohorts. sCD137 may be a long-term risk marker of HCC development.

Increased BMI and late-life mobility dysfunction; overlap of genetic effects in brain regions.

BACKGROUND: How obesity earlier in life impacts upon mobility dysfunctions in late life is not well understood. Pernicious effects of excess weight on the musculoskeletal system and mobility dysfunctions are well-recognized. However, increasingly more data support the link of obesity to overall motor defects that are regulated in the brain. OBJECTIVES: To assess the causal relationship between body mass index (BMI) at midlife and performance of the Timed Up-and-Go test (TUG) in late life among a population-based longitudinal cohort of Chinese adults living in Singapore. METHODS: We evaluated genetic predispositions for BMI in 8342 participants who were followed up from measurement of BMI at average 53 years, to TUG test (as a functional mobility measure) 20 years later. RESULTS: A robust 75.83% of genetically determined BMI effects on late-life TUG scores were mediated through midlife BMI (Pindirect-effect = 9.24 × 10-21). Utilizing Mendelian randomization, we demonstrated a causal effect between BMI and functional mobility in late life (ßIVW = 0.180, PIVW = 0.001). Secondary gene enrichment evaluations highlighted down-regulation of genes at BMI risk loci that were correlated with poorer functional mobility in the substantia nigra and amygdala regions as compared to all other tissues. These genes also exhibit differential expression patterns during human brain development. CONCLUSIONS: We report a causal effect of obesity on mobility dysfunction. Our findings highlight potential neuronal dysfunctions in regulating predispositions on the causal pathway from obesity to mobility dysfunction.

Profiles of Successful Aging and Their Association with All-Cause Mortality Risk among the Oldest-Old Chinese in Singapore.

INTRODUCTION: Although successful aging (SA) studies have examined objective indicators such as disease and disability, physical and cognitive function, and social and productive engagement, as well as subjective indicators such as self-rated health, function, and well-being, the interplay among these indicators is rarely studied. We studied SA profiles that captured this interplay and evaluated the association of these profiles with mortality in the oldest-old. METHODS: Respondents were 1,000 Chinese Singaporeans aged ≥85 years during interview visits from 2017 to 2018. Latent class analysis examined 12 objective and subjective indicators to identify SA profiles. Multivariable Cox regression assessed the relationship between these profiles and all-cause mortality risk through 2020. RESULTS: Four distinct SA profiles were identified: "frail and dejected" (poor performance in nearly all objective and subjective indicators), "frail but resilient" (poor in objective but good in subjective indicators), "fairly fit and neutral" (good in about half of the indicators), and "fit and positive" (good in nearly all indicators). Compared with "frail and dejected," the adjusted hazard ratio (95% confidence interval) for mortality risk was 0.63 (0.40-0.97) in "frail but resilient," 0.56 (0.34-0.93) in "fairly fit and neutral," and 0.31 (0.19-0.49) in "fit and positive." DISCUSSION: SA in the oldest-old could take different profiles based on objective and subjective indicators, and these profiles have implications for mortality risk. Individuals with good subjective indicators have advantage in survival despite poor objective indicators.

Left Atrial Phasic Function in Older Adults Is Associated with Fibrotic and Low-Grade Inflammatory Pathways.

INTRODUCTION: Concomitant risk factors challenge the mechanistic understanding of cardiac aging. We determined the degree to which the left atrial function could be distinguished by advanced cardiac magnetic resonance (CMR) imaging in older adults and assessed associations between the left atrial function and the plasma biomarkers related to biological aging and cardiovascular disease [serum monocyte chemoattractant protein-1 (MCP1), matrix metallopeptidase 9 (MMP-9), B-type natriuretic peptides (BNPs), galectin-3 (Gal-3), high-sensitivity cardiac troponin I (hsTn1), high-sensitivity C-reactive protein (hs-CRP), and soluble urokinase plasminogen activator receptor (sUPAR)]. METHODS: Among a cross-sectional population-based cohort of older adults, longitudinal LA strain including reservoir strain (εs), conduit strain (εe), and booster strain (εa) as well as peak strain rates (SRs, SRe, SRa) were determined using CMR and studied in association with blood biomarkers. RESULTS: We studied 243 community adults (42.8% female, mean age 70.3 ± 9.5 years). In bivariate analysis, εe and SRe were reduced in gradation with increasing risk factors (all p values <0.0001). Corresponding levels of sUPAR (ng/mL) were quantitatively higher in older adults with <2 risk factors (2.5 ± 1.6 vs. 1.7 ± 1.3, p = 0.0005), in those with ≥2 risk factors (3.3 ± 2.4 vs. 1.7 ± 1.3, p < 0.0001), compared to young adults; including between older adults with ≥2 risk factors and older adults with <2 risk factors (3.3 ± 2.4 vs. 2.5 ± 1.6, p = 0.017). Based on multivariate analysis, sUPAR was significantly associated with both εe (OR 1.52, p = 0.006) and SRe decline (OR 1.5, p = 0.019). The associations between Gal-3 and εe reduction (OR 1.2, p = 0.022) and between BNP and SRe decline were generally weaker (OR 1.03, p = 0.027). The addition of sUPAR to a model consisting of age, risk factors, Gal-3, and BNPs increased the area under the curve of εe from 0.72 to 0.77 (p = 0.015). CONCLUSION: By advanced CMR imaging, a panel of circulating biomarkers comprising galectin, MMP-9 and sUPAR were associated with left atrial dysfunction in older adults. Higher levels of Gal-3 and MMP-9 may be suggestive of fibrotic mechanisms in left atrial aging while impairments in left atrial strain seen in association with circulating sUPAR may be related to immune activation in the left atrium in response to left atrial remodeling and fibrotic processes.

A polygenic risk score improves risk stratification of coronary artery disease: a large-scale prospective Chinese cohort study.

AIMS: To construct a polygenic risk score (PRS) for coronary artery disease (CAD) and comprehensively evaluate its potential in clinical utility for primary prevention in Chinese populations. METHODS AND RESULTS: Using meta-analytic approach and large genome-wide association results for CAD and CAD-related traits in East Asians, a PRS comprising 540 genetic variants was developed in a training set of 2800 patients with CAD and 2055 controls, and was further assessed for risk stratification for CAD integrating with the guideline-recommended clinical risk score in large prospective cohorts comprising 41 271 individuals. During a mean follow-up of 13.0 years, 1303 incident CAD cases were identified. Individuals with high PRS (the highest 20%) had about three-fold higher risk of CAD than the lowest 20% (hazard ratio 2.91, 95% confidence interval 2.43-3.49), with the lifetime risk of 15.9 and 5.8%, respectively. The addition of PRS to the clinical risk score yielded a modest yet significant improvement in C-statistic (1%) and net reclassification improvement (3.5%). We observed significant gradients in both 10-year and lifetime risk of CAD according to the PRS within each clinical risk strata. Particularly, when integrating high PRS, intermediate clinical risk individuals with uncertain clinical decision for intervention would reach the risk levels (10-year of 4.6 vs. 4.8%, lifetime of 17.9 vs. 16.6%) of high clinical risk individuals with intermediate (20-80%) PRS. CONCLUSION: The PRS could stratify individuals into different trajectories of CAD risk, and further refine risk stratification for CAD within each clinical risk strata, demonstrating a great potential to identify high-risk individuals for targeted intervention in clinical utility.

Joint Associations of Multiple Lifestyle Factors With Risk of Active Tuberculosis in the Population: The Singapore Chinese Health Study.

BACKGROUND: Little is known about the joint associations of multiple lifestyle risk factors including smoking, low body mass index, physical inactivity, alcohol consumption, and low diet quality with risk of active tuberculosis. METHODS: We analyzed data from the Singapore Chinese Health Study, a prospective cohort study of 63 257 Chinese adults aged 45-74 years enrolled between 1993 and 1998. Incident cases of active tuberculosis were identified via linkage with the National TB Registry through 31 December 2016. Cox proportional hazards regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) of tuberculosis risk in relation to the combined scores of lifestyle risk factors. RESULTS: Compared with participants with none of the risk factors, the adjusted HRs (95% CI) of active tuberculosis for participants with 1, 2, 3, 4, and 5 risk factors were 1.24 (1.02-1.51), 1.84 (1.51-2.23), 2.52 (2.03-3.14), 4.07 (3.07-5.41), and 9.04 (5.44-15.02), respectively (Ptrend < .0001). The HR for those with 5 factors was ~1.5 times the product of individual risk estimates from the 5 factors on a multiplicative scale. The stepwise increase in risk of active tuberculosis with increasing number of lifestyle risk factors was significantly stronger in participants with diabetes than their counterparts without diabetes at recruitment (Pinteraction = .01). CONCLUSIONS: Multiple lifestyle risk factors were associated with risk of active tuberculosis in a synergistic manner. Our findings highlight the importance of public health programs and interventions targeting these factors simultaneously to reduce the tuberculosis burden among the general population.

Composite dietary antioxidant index and the risk of colorectal cancer: Findings from the Singapore Chinese Health Study.

Colorectal cancer (CRC) is a major contributor to cancer death globally. Several studies showed some protections by certain individual dietary antioxidants against CRC development. Epidemiologic data on the composite dietary antioxidant index (CDAI) in relation to CRC risk are sparse. Using the Singapore Chinese Health Study, an ongoing prospective cohort consisting of 61 321 cancer-free participants aged 45 to 74 years at baseline, a food-based CDAI was calculated according to a previously established and validated method that included six food-sourced antioxidants including vitamins A, C and E, manganese, selenium and zinc. Cox proportional hazard regression method was used to estimate the hazard ratios (HRs) and their 95% confidence intervals (CIs) for CRC associated with various levels of CDAI with adjustment for multiple potential confounders. After an average of 17.5 years of follow-up, 2140 participants developed CRC. HRs (95% CIs) of CRC for quartiles 2, 3 and 4 of CDAI were 0.94 (0.83-1.07), 0.86 (0.75-1.00) and 0.80 (0.66-0.98), respectively, compared to the lowest quartile (Ptrend  = .02). This inverse association between CDAI and CRC risk was more apparent in women or those without a history of diabetes, without family history of CRC, never smokers or overweight/obese individuals. However, none of the heterogeneity tests for the CDAI-CRC risk association reached statistical significance. Our findings suggest that food-based antioxidants may be beneficial for reducing the risk of CRC in the general population.

Overlap of high-risk individuals predicted by family history, and genetic and non-genetic breast cancer risk prediction models: implications for risk stratification.

BACKGROUND: Family history, and genetic and non-genetic risk factors can stratify women according to their individual risk of developing breast cancer. The extent of overlap between these risk predictors is not clear. METHODS: In this case-only analysis involving 7600 Asian breast cancer patients diagnosed between age 30 and 75 years, we examined identification of high-risk patients based on positive family history, the Gail model 5-year absolute risk [5yAR] above 1.3%, breast cancer predisposition genes (protein-truncating variants [PTV] in ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, or TP53), and polygenic risk score (PRS) 5yAR above 1.3%. RESULTS: Correlation between 5yAR (at age of diagnosis) predicted by PRS and the Gail model was low (r=0.27). Fifty-three percent of breast cancer patients (n=4041) were considered high risk by one or more classification criteria. Positive family history, PTV carriership, PRS, or the Gail model identified 1247 (16%), 385 (5%), 2774 (36%), and 1592 (21%) patients who were considered at high risk, respectively. In a subset of 3227 women aged below 50 years, the four models studied identified 470 (15%), 213 (7%), 769 (24%), and 325 (10%) unique patients who were considered at high risk, respectively. For younger women, PRS and PTVs together identified 745 (59% of 1276) high-risk individuals who were not identified by the Gail model or family history. CONCLUSIONS: Family history and genetic and non-genetic risk stratification tools have the potential to complement one another to identify women at high risk.

Diabetes and other vascular risk factors in association with the risk of lower extremity amputation in chronic limb-threatening ischemia: a prospective cohort study.

BACKGROUND: Patients with diabetes are at increased risk of developing chronic limb-threatening ischemia (CLTI) due to peripheral arterial disease, and this often results in lower extremity amputation (LEA). Little is known of the interaction between diabetes and other vascular risk factors in affecting the risk of CLTI. METHODS: We investigated the association of diabetes, and its interaction with hypertension, body mass index (BMI) and smoking, with the risk of LEA due to CLTI in the population-based Singapore Chinese Health Study. Participants were interviewed at recruitment (1993-1998) and 656 incident LEA cases were identified via linkage with nationwide hospital database through 2017. Multivariate-adjusted Cox proportional hazards models were used to compute hazard ratios (HRs) and 95% CIs for the associations. RESULTS: The HR (95% CI) for LEA risk was 13.41 (11.38-15.79) in participants with diabetes compared to their counterparts without diabetes, and the risk increased in a stepwise manner with duration of diabetes (P for trend < 0.0001). Hypertension and increased BMI independently increased LEA risk in those without diabetes but did not increase the risk in those with diabetes (P for interaction with diabetes ≤ 0.0006). Conversely, current smoking conferred a risk increment of about 40% regardless of diabetes status. CONCLUSIONS: Although diabetes conferred more than tenfold increase in risk of LEA, hypertension and increased BMI did not further increase LEA risk among those with diabetes, suggesting a common mechanistic pathway for these risk factors. In contrast, smoking may act via an alternative pathway and thus confer additional risk regardless of diabetes status.

Interaction between cigarette smoking and genetic polymorphisms on the associations with age of natural menopause and reproductive lifespan: the Singapore Chinese Health Study.

STUDY QUESTION: Are there genetic variants that interact with smoking to reduce reproductive lifespan in East-Asian women? SUMMARY ANSWER: Our study corroborates several recently identified genetic loci associated with reproductive lifespan and highlights specific genetic predispositions that may interact with smoking status to adversely affect reproductive lifespan in East-Asian women. WHAT IS KNOWN ALREADY: Epidemiological data as well as evaluations on genetic predisposition to smoke indicate on the importance of smoking in adverse effects on reproductive lifespan in women. However, there are no previous smoking and gene interaction studies for reproductive traits in East-Asian women. STUDY DESIGN, SIZE, DURATION: This population-based prospective cohort study comprised 11 643 East-Asian Chinese women with overlapping genome-wide genotyping and reproductive data. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a genome-wide association study for reproductive lifespan in women (n = 11 643) from the Singapore Chinese Health Study (SCHS) and carried out a genome-wide interaction study to identify loci that interacted with smoking status to affect age of natural menopause and reproductive-time. MAIN RESULTS AND THE ROLE OF CHANCE: Two known loci associated with menopause, rs113430717 (near HMCES, chromosome 3, Pmeta = 5.72 × 10-15) and rs3020136 (near RAD21, chromosome 8, Pmeta = 1.38 × 10-8) were observed beyond genome-wide levels of association with age at menopause in this study. For reproductive lifespan, the genome-wide association observed at rs79784106 (chromosome 3, Pmeta = 5.05 × 10-12) was in linkage disequilibrium with the menopause lead single-nucleotide polymorphism (SNP) (rs113430717). Four additional loci, first reported to be associated with menopause, were also associated with reproductive lifespan in our study (PAdj between 7.42 × 10-5 to 4.51 × 10-3). A significant interaction was observed between smoking and an East-Asian specific SNP, rs140146885, for reduced reproductive lifespan, per copy of the minor C allele (beta = -1.417 years, Pinteraction = 2.31 × 10-10). This interaction was successfully replicated in additional independent samples (beta = -1.389 years, Pinteraction = 6.78 × 10-3). Another known variant associated with menopause, rs11031006 (near FSHB), was also observed to interact with smoking status to reduce age at menopause in our dataset (beta = -0.450 years, Padj = 0.042). LIMITATIONS, REASONS FOR CAUTION: The modest sample size of the replication datasets used likely affected the statistical power to firmly replicate all identified novel loci observed in our smoking interaction analyses. WIDER IMPLICATIONS OF THE FINDINGS: Age of natural menopause and reproductive lifespan have clear genetic predispositions with distinct ethnic differences, and they may be adversely truncated by lifestyle factors such as smoking, which can pose a significant impact on the reproductive lifespan and future health outcomes in women. STUDY FUNDING/COMPETING INTEREST(S): The Singapore Chinese Health Study is funded by the National Medical Research Council, Singapore (NMRC/CIRG/1456/2016), National Institutes of Health (R01 CA144034 and UM1 CA182876) and National Research Foundation, Singapore (Project Number 370062002). W.-P.K. is supported by the National Medical Research Council, Singapore (MOH-CSASI19nov-0001). The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. The authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Quantity and variety of fruit and vegetable intake in midlife and cognitive impairment in late life: a prospective cohort study.

There is limited evidence on fruit and vegetable intake in relation to cognitive function. This study aimed to evaluate the associations of quantity and variety in fruit and vegetable intake in midlife with cognitive impairment in late life. We used data from 16 737 participants of the Singapore Chinese Health Study, a population-based cohort study. The participants provided dietary data at recruitment at median age of 52·5 (range: 45-74) years and also participated in the third follow-up interview 20 years later at median age of 72·2 (range: 61-96) years. Quantity and variety of fruits and vegetables consumed at baseline were measured using a validated FFQ. Cognitive impairment at the third follow-up was defined using a Singapore-modified version of Mini-Mental State Examination. About 14·3 % participants had cognitive impairment. In multivariable logistic regression models, comparing extreme quartiles for intake of fruits and vegetables combined, the OR (95 % CI) associated with cognitive impairment was 0·83 (95 % CI: 0·73, 0·95; P-trend = 0·006) for quantity and 0·76 (95 % CI: 0·67, 0·87; P-trend< 0·001) for variety scores. Independently, those with increased variety of fruit intake or higher quantity of vegetable intake also had significantly 22 % and 15 % reduced odds of cognitive impairment, respectively. Finally, compared with those with low intake for both quantity and variety, those with both high quantity and variety for fruits and vegetables had 23 % reduction in odds of cognitive impairment. In conclusion, increase in quantity and variety of fruits and vegetables in midlife may reduce the risk of cognitive impairment in late life.