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Recent experimental work has identified CXCL9 as a promoter for the differentiation of osteoclast progenitors into osteoclasts, with resultant bone resorption. However, no human study has validated an association between this chemokine and osteoporosis or fracture risk. We conducted a matched case-control study nested in the prospective, population-based Singapore Chinese Health Study. Fifty-five men and 119 women with incident hip fractures, occurring median 6.2 years after blood collection, were matched individually to controls by age at recruitment, sex, and duration of blood storage. Serum chemokines, CXCL9 and CXCL10, were measured using immunoassays. Multivariable conditional logistic regression models that included age at blood collection, body mass index, smoking, and diabetes as covariates were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for association with hip fracture risk. Predictive utility of chemokine for hip fracture risk was examined by comparing area under receiver operating characteristic curves (AUC) between prognostic models with and without the chemokine. Increasing CXCL9 levels were associated with increasing hip fracture risk in men but not in women (p

BACKGROUND: Understanding the genetic predisposition to cardiovascular disease (CVD) may help to improve clinical intervention strategies. Lifestyle factors, such as diet, may differ among ethnic groups and may, in turn, modify individuals’ risks to diseases. OBJECTIVES: We examined the genetic predisposition to ever smoking in relation to CVD mortality and assessed whether such an association could be modified by dietary intake. METHODS: A total of 23,760 Chinese adults from the Singapore Chinese Heath Study who were free of cancer and CVD at recruitment (1993–1998) were included in the study. A weighted genetic risk score (wGRS) was calculated to define the genetically determined regular smoking behavior (never or ever). Multivariable-adjusted Cox regression models were used to assess the association between the wGRS and CVD mortality. We also conducted a 1-sample Mendelian randomization analysis for ever smoking and CVD mortality. RESULTS: Over a mean of 22.6 years of follow-up, 2301 CVD deaths were identified. A genetic predisposition to ever smoking was significantly associated with CVD mortality; the multivariable-adjusted HR of CVD mortality was 1.07 (95% CI: 1.03–1.12), with a per-SD increment in the wGRS. However, the Mendelian randomization analysis did not support a causal relationship between ever smoking and CVD mortality (OR, 1.13; 95% CI: 0.87–1.45). Additionally, the Dietary Approaches to Stop Hypertension (DASH) score significantly modified the association between the smoking wGRS and CVD mortality; the association between a genetic predisposition to smoking and CVD mortality was only observed among individuals with a low DASH score (P-interaction = 0.004). CONCLUSIONS: A genetic predisposition to smoking was associated with CVD mortality in the Chinese population. In addition, we detected a significant interaction showing higher CVD mortality related to genetically determined smoking among those with lower DASH scores.

It is difficult to identify people with nonalcoholic fatty liver disease (NAFLD) who are at high risk for developing hepatocellular carcinoma (HCC). A polygenic risk score (PRS) for hepatic fat (HFC-PRS) derived from non-Asians has been reported to be associated with HCC risk in European populations. However, population-level data of this risk in Asian populations are lacking. Utilizing resources from 24,333 participants of the Singapore Chinese Health Study (SCHS), we examined the relationship between the HFC-PRS and HCC risk. In addition, we constructed and evaluated a NAFLD-related PRS (NAFLD-PRS) with HCC risk in the SCHS. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of HCC incidence with both HFC-PRS and NAFLD-PRS. The HFC-PRS and NAFLD-PRS were highly correlated (Spearman r = 0.79, p 0.001). The highest quartiles of both the HFC-PRS and the NAFLD-PRS were associated with significantly increased risk of HCC with HR of 2.39 (95% CI 1.51, 3.78) and 1.77 (95% CI 1.15, 2.73), respectively, compared with their respective lowest quartile. Conclusion: The PRS for hepatic fat content or NAFLD may be useful for assessing HCC risk in both Asian and European populations. The findings of this and prior studies support a potential causal role of genetically determined NAFLD in HCC development.

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.

Purpose Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. Methods The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). Results The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. Conclusion PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.

Background The association between body mass index (BMI) and oesophageal cancer (OC) has been consistently negative among Asians, whereas different associations based on histological OC subtypes have been observed in Europeans and North Americans. We examined the association between BMI and OC mortality in the Asia Cohort Consortium. Methods We performed a pooled analysis to evaluate the association between BMI and OC mortality among 842 630 Asians from 18 cohort studies. Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs. Results A wide J-shaped association between BMI and overall OC mortality was observed. The OC mortality risk was increased for underweight (BMI Conclusion Extreme obesity and being underweight were associated with an OC mortality risk among Asians. OC mortality and BMI formed a wide J-shaped association mirrored by OSCC mortality. Although the effect of BMI on OSCC and oesophageal adenocarcinoma mortality can be different in Asians, further research based on a large case–control study is recommended.

Introduction: Body mass index (BMI), despite being widely used as a marker of obesity, fails to fully capture cardiovascular risks as it is an insufficient biomarker of abdominal adiposity, unlike waist circumference (WC). We aimed to characterize associations between BMI and WC with cardiovascular structure and function in older adults. Methods: Among an observational cohort study of a community of older adults, transthoracic echocardiography determined cardiovascular structure and function, while aerobic capacity was determined by peak oxygen uptake (VO2) metrics. The cut-offs for obesity were 27.5 kg/m2 for BMI, and >90 cm for males and >80 cm for females for WC. Results: Of 970 older adults without cardiovascular disease (mean age 73 ± 4 years, 432 [44%] males), 124 (12.8%) were obese by BMI definition while 347 (35.7%) were obese by WC definition. Inter-definitional agreement was fair (Cohen’s κ = 0.345). Unlike the BMI definition, participants defined as obese by WC were more likely to be women (65% vs. 50%, p < 0.001), older (65 ± 11 vs. 63 ± 14 years, p = 0.007), and had lower handgrip strength (24 ± 0.6 vs. 26 ± 0.4 kg, p = 0.022). Across BMI categories, high WC was associated with more impaired myocardial relaxation (E/A), and VO2 measurements (all p < 0.05). Among those with low BMI, high WC was associated with larger left atrial (LA) volumes (p = 0.003). WC, but not BMI, was independently associated with E/A (β = −0.114, SE −0.114 ± 0.024, p < 0.001) in regression analysis. Conclusion: WC identified a higher prevalence of obesity, possibly related to central adiposity. Across BMI categories, WC identified more adverse measurements in E/A, aerobic capacity, and LA structure. Trial Registration: ClinicalTrials.gov Identifier: NCT02791139.

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 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.

Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry metaanalysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk., United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) R01HL127564 R01HL142711, Wellcome Trust 201543/B/16/Z 202802/Z/16/Z, European Commission HEALTH-F2-2013-601456 608765 786833, TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation NNF15CC0018486, American Diabetes Association 1-19-ICTS-068, Academy of Finland 312062 Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation, Finnish innovation fund Sitra (EW) Finska Lakaresallskapet, American Heart Association 15POST24470131 17POST33650016, University of Bristol NIHR Biomedical Research Centre BRC-1215-2001, MRC & WT 217065/Z/19/Z, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MC_UU_00011, CRUK Integrative Cancer Epidemiology Programme C18281/A19169, Medical Research Council UK (MRC) MC_UU_00011/1, UK National Institute for Health Research Academic Clinical Fellowship, American Heart Association 18CDA34110116, Miguel Servet contract from the ISCIII Spanish Health Institute CP17/00142, European Social Fund (ESF), Westlake Education Foundation, British Heart Foundation FS/14/66/3129 Z01HG200362 R01HL142302 R01HL105756

Purpose: The favorable prognosis of stage I and II nasopharyngeal carcinoma (NPC) has motivated a search for biomarkers for the early detection and risk assessment of Epstein-Barr virus (EBV)–associated NPC. Although EBV seropositivity is ubiquitous among adults, a spike in antibodies against select EBV proteins is a harbinger of NPC. A serologic survey would likely reveal which EBV antibodies could discriminate those at risk of developing NPC. Experimental Design: Lysates from a new EBV mammalian expression library were used in a denaturing multiplex immunoblot assay to survey antibodies against EBV in sera collected from healthy individuals who later developed NPC (incident cases) in a prospective cohort from Singapore and validated in an independent cohort from Shanghai, P.R. China. Results: We show that IgA against EBV nuclear antigen 1 (EBNA1) discriminated incident NPC cases from matched controls with 100% sensitivity and 100% specificity up to 4 years before diagnosis in both Singapore and Shanghai cohorts. Incident NPC cases had a greater IgG repertoire against lytic-classified EBV proteins, and the assortment of IgA against EBV proteins detected by the immunoblot assay increased closer to diagnosis. Conclusions: Although NPC tumors consistently harbor latent EBV, the observed heightened systemic and mucosal immunity against lytic-classified antigens years prior to clinical diagnosis is consistent with enhanced lytic transcription. We conclude that an expanding EBV mucosal reservoir (which can be latent and/or lytic) is a risk factor for NPC. This presents an opportunity to identify those at risk of developing NPC using IgA against EBNA1 as a biomarker.

Background Accumulating evidence suggests that consuming coffee may lower the risk of death, but evidence regarding tea consumption in Asians is limited. We examined the association between coffee and tea consumption and mortality in Asian populations. Methods We used data from 12 prospective cohort studies including 248 050 men and 280 454 women from the Asia Cohort Consortium conducted in China, Japan, Korea and Singapore. We estimated the study-specific association of coffee, green tea and black tea consumption with mortality using Cox proportional-hazards regression models and the pooled study-specific hazard ratios (HRs) using a random-effects model. Results In total, 94 744 deaths were identified during the follow-up, which ranged from an average of 6.5 to 22.7 years. Compared with coffee non-drinkers, men and women who drank at least five cups of coffee per day had a 24% [95% confidence interval (CI) 17%, 29%] and a 28% (95% CI 19%, 37%) lower risk of all-cause mortality, respectively. Similarly, we found inverse associations for coffee consumption with cardiovascular disease (CVD)-specific and cancer-specific mortality among both men and women. Green tea consumption was associated with lower risk of mortality from all causes, CVD and other causes but not from cancer. The association of drinking green tea with CVD-specific mortality was particularly strong, with HRs (95% CIs) of 0.79 (0.68, 0.91) for men and 0.78 (0.68, 0.90) for women who drank at least five cups per day of green tea compared with non-drinkers. The association between black tea consumption and mortality was weak, with no clear trends noted across the categories of consumption. Conclusions In Asian populations, coffee consumption is associated with a lower risk of death overall and with lower risks of death from CVD and cancer. Green tea consumption is associated with lower risks of death from all causes and CVD.

BACKGROUND Although higher diet quality at mid-life has been associated with better cognitive function in late adulthood, it is unclear whether dietary improvement after mid-life may reduce the risk of cognitive impairment. OBJECTIVES We examined associations between changes in diet quality and risk of cognitive impairment in the Singapore Chinese Health Study cohort. METHODS We used data from 14,683 Chinese men and women who were recruited at ages 45 to 74 y from 1993 to 1998 and re-interviewed after 20 y at ages 61 to 96 y during follow-up 3 (2014-2016). Diet quality was measured using the Dietary Approaches to Stop Hypertension (DASH) scores at baseline and follow-up 3 interviews. Cognitive impairment was defined using scores from the Singapore-modified Mini-Mental State Examination at the follow-up 3 interview. Multivariable logistic regression models were used to estimate ORs and 95% CIs for the associations between change in DASH scores and cognitive impairment. RESULTS Higher quintiles in DASH scores at baseline and follow-up 3 interviews were associated with lower odds of cognitive impairment in a dose-dependent manner (both: P-trend

Background: Limited research has been conducted on the effect of quality diet index (QDI), which represents a comprehensive assessment of healthy diet quality and quantity, on pancreatic cancer risk in Asian populations. Methods: Using data from the Singapore Chinese Health Study, a prospective cohort of 63,257 middle-aged or older Chinese men and women, four QDI scores: the Alternative Health Eating Index-2010 (AHEI-2010), the alternate Mediterranean Diet (aMED), the Dietary Approaches to Stop Hypertension (DASH), and the Heathy Diet Indicator (HDI), at baseline were calculated. After 25 years of follow-up, 311 cohort participants developed pancreatic cancer. Cox proportional hazard regression method was used to estimate HR and 95% confidence interval (CI) for pancreatic cancer associated with higher QDI scores. Results: Higher scores of AHEI-2010, aMED, and DASH were significantly associated with lower pancreatic cancer risk (all Ptrend < 0.05). Compared with the lowest quartile, HRs (95% CIs) of pancreatic cancer for the highest quartiles of AHEI-2010, aMED, and DASH scores were 0.65 (0.46–0.90), 0.57 (0.38–0.85), and 0.66 (0.46–0.95), respectively. These associations were more apparent among men. Overall, there was no statistically significant difference in the QDI–pancreatic cancer risk association between subgroups stratified by levels of body mass index, history of diabetes, and smoking status. Conclusions: Higher QDI scores were significantly associated with reduced risk of pancreatic cancer. Impact: The consistent results across multiple QDIs shows that adherence to a healthy diet may lower pancreatic cancer risk, suggesting that dietary modification may be a promising approach for primary prevention of pancreatic cancer.

Introduction: Although living alone is associated with social disconnection, older adults could be socially disconnected despite living with others. Understanding the factors associated with social disconnection by living arrangement could help identify vulnerable older adults in the community. We examined the sociodemographic and health factors associated with social disconnection among two groups of older adults: those living alone and those living with others. Methods: We used data from 16,943 community-dwelling older adults from the third follow-up of the Singapore Chinese Health Study (mean age: 73 years, range: 61–96 years). We defined social disconnection as having no social participation and scoring in the lowest decile on the Duke Social Support Scale of perceived social support. We ran logistic regression models to study the sociodemographic (age, gender, and education) and health (self-rated health, instrumental limitations, cognitive function, and depression) factors associated with social disconnection, stratified by living arrangement. Results: About 6% of our participants were socially disconnected. Although living alone was significantly associated with social disconnection (OR 1.93, 95% CI: 1.58–2.35), 85.6% of socially disconnected older adults lived with others, most of them (92%) with family. Lower education level, cognitive impairment, fair/poor self-rated health, instrumental limitations, and depression were independently associated with social disconnection. Among those living alone, men were more likely to experience social disconnection than women (OR 2.18, 95% CI: 1.43–3.32). Discussion/Conclusion: Though living alone is associated with social disconnection, most socially disconnected individuals lived with family. Community interventions could focus on those in poor health despite living with family and older men living alone.

Objective: To demonstrate differences in cardiovascular structure and function between diabetic and non-diabetic older adults. To investigate associations between acyl-carnitines and cardiovascular function as indexed by imaging measurements. Methods: A community-based cohort of older adults without cardiovascular disease underwent current cardiovascular imaging and metabolomics acyl-carnitines profiling based on current and archived sera obtained fifteen years prior to examination. Results: A total of 933 participants (women 56%, n=521) with a mean age 63±13 years were studied. Old diabetics compared to old non-diabetics had lower myocardial relaxation (0.8±0.2 vs 0.9±0.3, p=0.0039); lower left atrial conduit strain (12±4.3 vs 14±4.1, p=0.045), lower left atrial conduit strain rate (-1.2±0.4 vs -1.3±0.5, p=0.042) and lower ratio of left atrial conduit strain to left atrial booster strain (0.5±0.2 vs 0.7±0.3, p=0.0029). Higher levels of archived short chain acyl-carnitine were associated with present-day impairments in myocardial relaxation (C5:1; OR 1.03, p=0.011), worse left atrial conduit strain function (C5:1; OR 1.03, p=0.037). Increases in hydroxylated acyl-carnitines were associated with worse left atrial conduit strain [(C4-OH; OR 1.05, p=0.0017), (C16:2-OH; OR 1.18, p=0.037)]. Current, archived and changes in long chain acyl-carnitines were associated with cardiovascular functions [(C16; OR 1.02, p=0.002), (C20:3; OR 1.01, p=0.014), (C14:3; OR 1.12, p=0.033), (C18:1; OR 1.01, p=0.018), (C18:2; OR 1.01, p=0.028), (C20:4; OR 1.10, p=0.038)] (all p

Background Little is known about the time course of mortality reduction following smoking cessation in Asians who have smoking behaviours distinct from their Western counterparts. We evaluated the level of reduction in all-cause, cardiovascular disease (CVD) and lung cancer mortality by years since quitting smoking, in Asia. Methods Using Cox regression, we analysed individual participant data (n = 709 151) from 16 prospective cohorts conducted in China, Japan, Korea/Singapore, and India/Bangladesh, separately by cohorts. Cohort-specific hazard ratios (HRs) were combined using a random-effects meta-analysis. Results During a mean follow-up of 12.0 years, 108 287 deaths were ascertained—35 658 from CVD and 7546 from lung cancer. Among Asian men, a dose-response relationship of risk reduction in deaths from all causes, CVD and lung cancer was observed with an increase in years after smoking cessation. Compared with never smokers, however, all-cause and CVD mortality among former smokers remained elevated 10–14 years after quitting [multivariable-adjusted HR (95% confidence interval (CI) = 1.25 (1.13–1.37) and 1.20 (1.02–1.41), respectively]. Lung cancer mortality stayed almost 2-fold higher than among never smokers 15–19 years after smoking cessation [1.97 (1.41–2.73)], particularly among former heavy smokers [2.62 (1.71–4.00)]. Women who quitted for ≥5 years retained a significantly elevated mortality from all causes, CVD and lung cancer. Overall patterns of the cessation-mortality associations were similar across countries. Conclusions Our findings suggest that adverse effects of tobacco smoking persist for an extended time period, even for more than two decades, which is beyond the time windows defined in current clinical guidelines for risk assessment of lung cancer and CVD.

Background Blood type has been associated with the risk of gastric cancer, but few studies have examined the association with esophageal squamous cell carcinoma (ESCC). Methods We conducted a case-control study using genotyping data of Chinese individuals, including cases of 2022 ESCC, 1189 gastric cardia adenocarcinoma, 1161 gastric noncardia adenocarcinoma, and 2696 controls. Genetic blood type was imputed using three single nucleotide polymorphisms. We used logistic regression to examine the association between blood type and the risk of each cancer. Results Compared to blood type O, the risk of ESCC was significantly elevated for blood type B and AB, with the highest risk for type AB (OR, 95%CI: 1.34, 1.07–1.67). Analysis of genotype suggested that the association of ESCC was from carrying the B allele. Similarly, blood type was significantly associated with gastric noncardia adenocarcinoma (P P = 0.13). Conclusions This study provides novel insights into the association between blood type and the risk of ESCC and restricted previously observed association to only gastric noncardia cancer, providing important evidence to clarify the pattern of association and suggesting mechanisms of action.

Background The role of smoking in nasopharyngeal carcinoma (NPC) remains uncertain, especially in endemic regions. We conducted an individual participant data (IPD) meta-analysis of prospective cohort studies to investigate the associations between smoking exposure and risk of NPC. Methods We obtained individual participant data of 334 935 male participants from six eligible population-based cohorts in NPC-endemic regions, including two each in Guangzhou and Taiwan, and one each in Hong Kong and Singapore. We used one- and two-stage approaches IPD meta-analysis and Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of NPC for smoking exposure adjusting for age and drinking status. Results During 2 961 315 person-years of follow-up, 399 NPC evens were ascertained. Risks of NPC were higher in ever versus never smokers (HRone-stage = 1.32, 95% CI = 1.07-1.63, P = 0.0088; HRtwo-stage = 1.27, 1.01-1.60, 0.04). These positive associations appeared to be stronger in ever smokers who consumed 16+ cigarettes/day (HRone-stage = 1.67, 95% CI = 1.29-2.16, P = 0.0001), and in those who started smoking at age younger than 16 (2.16, 1.33-3.50, 0.0103), with dose-response relationships (P-values for trend = 0.0028 and 0.0103, respectively). Quitting (versus daily smoking) showed a small reduced risk (stopped for 5+ years: HRone-stage = 0.91, 95% CI = 0.60-1.39, P = 0.66; for former smokers: HRtwo-stage = 0.84, 0.61-1.14, 0.26). Conclusions This first IPD meta-analysis from six prospective cohorts in endemic regions has provided robust observational evidence that smoking increased NPC risk in men. NPC should be added to the 12–16 cancer sites known to be tobacco-related cancers. Strong tobacco control policies, preventing young individuals from smoking, would reduce NPC risk in endemic regions.

BACKGROUND. Since previous epidemiological studies reported inconsistent associations between dietary vitamin B(12) intake and lung cancer risk, more studies are warranted to clarify this association in different populations. METHODS. The association between dietary B(12) intake and lung cancer risk was examined in the Singapore Chinese Health Study, an ongoing prospective cohort study of 63,257 Singaporean Chinese men and women, 45–74 years of age at enrollment during 1993–1998 and were followed up for incidence of lung cancer for up to 25 years. Dietary vitamin B(12) intake was derived from a validated food frequency questionnaire. Cox proportional hazard regression method was used to estimate hazard ratio (HR) and 95% confidence interval (CI) of lung cancer associated with dietary vitamin B(12) intake with adjustment for multiple potential confounders. RESULTS. After a mean follow-up of 17.64 years, 2,001 study participants developed lung cancer. High levels of vitamin B(12) intake were associated with significantly increased risk of lung cancer (P(trend)= 0.03). Compared with the lowest quintile, HRs (95% CIs) of lung cancer for quintile 2, 3, 4, and 5 of vitamin B(12) intake were 1.09 (0.95–1.25), 1.11 (0.96–1.28), 1.11 (0.97–1.29) and 1.18 (1.03–1.35), respectively. This positive association was more apparent in men than in women, in adenocarcinoma patients, or in participants with equal or less than 2 years follow-up than those with longer duration of follow-up. CONCLUSION. Higher intake of dietary vitamin B(12) was associated with increased risk of lung cancer. This highlights the potential harmful effect of vitamin B(12) supplementation for lung cancer.

Background: While the associations between individual lifestyle factors and risk of hepatocellular carcinoma (HCC) have been described previously, their combined impact on HCC risk is unknown. Methods: The association of a composite score of healthy lifestyle factors, including body mass index, alcohol consumption, cigarette smoking, alternative Mediterranean diet, and sleep duration, and HCC risk was examined in the Singapore Chinese Health Study, an ongoing prospective cohort study of 63,257 Chinese men and women. Cox proportional hazard regression method was used to estimate HR and its 95% confidence interval (CI). Conditional logistic regression method was used to evaluate this composite lifestyle score–HCC risk association among a subset of individuals who tested negative for hepatitis B surface antigen (HBsAg) and anti–hepatitis C antibody. Results: After a mean follow-up of 17.7 years, 561 participants developed HCC. Individuals with higher composite scores representing healthier lifestyles (range 0–8) were at significantly lower risk of HCC. Compared with the lowest composite score category (0–4), the HRs (95% CIs) for the composite scores of 5, 6, 7, and 8 were 0.67 (0.62–0.85), 0.61 (0.48–0.77), 0.49 (0.37–0.65), and 0.13 (0.06–0.30), respectively (Ptrend < 0.0001). A similar inverse association was observed in participants with negative HBsAg and anti–hepatitis C virus (HCV)-negative serology (HR, 0.38; 95% CI, 0.19–0.79; for the highest vs. the lowest category of the composite scores; Ptrend = 0.001). Conclusions: Healthy lifestyles protect against HCC development, especially for individuals without hepatitis B virus and HCV infections. Impact: This study highlights the importance of a comprehensive lifestyle modification strategy for HCC primary prevention.

Background The aim of the study was to examine the relations of individual lifestyle factors and its composite score with healthy ageing among Chinese adults. Method We included 14 159 participants aged 45–74 years at baseline from the Singapore Chinese Health Study, a population-based prospective cohort. A protective lifestyle score (0–5 scale) was calculated at baseline (1993–1998) and updated at the second follow-up visit (2006–2010) on the basis of optimal body mass index (18.5–22.9 kg/m2), healthy diet (upper 40% of the Alternative Healthy Eating Index score), being physically active (≥2 h/wk of moderate activity or ≥0.5 h/wk of strenuous activity), nonsmoking (never smoking), and low-to-moderate alcohol drinking (>0 to ≤14 drinks/wk for men and >0 to ≤7 drinks/wk for women). Healthy ageing was assessed at the third follow-up visit (2014–2016) and was defined as absence of specific chronic diseases, absence of cognitive impairment and limitations in instrumental activities of daily living, good mental and overall self-perceived health, good physical functioning, and no function-limiting pain. Results About 20.0% (2834) of the participants met the criteria of healthy ageing after a median follow-up of 20 years. Each 1-point increase in the protective lifestyle score computed at baseline and second follow-up visits was associated with higher likelihood of healthy ageing by 25% (95% CI: 20%–30%) and 24% (18%–29%), respectively. The population-attributable risk percent of adherence to 4–5 protective lifestyle factors was 34.3% (95% CI: 25.3%–42.3%) at baseline and 31.3% (23.0%–38.7%) at second follow-up visits for healthy ageing. In addition, positive increase in lifestyle scores from baseline to second follow-up visits was also significantly associated with a higher likelihood of healthy ageing with an odds ratio of 1.18 (95% CI: 1.12%–1.24%) for each increment in protective lifestyle score. Conclusions Our findings confirmed that adopting healthy lifestyle factors, even after midlife, was associated with healthy ageing at old age.

Abdominal obesity is associated with functional disability in older adults.We evaluated whether this association was modified by gender and/or physical frailty.We used cross-sectional data from 12,583 participants in the third follow-up of the population-based Singapore Chinese Health Study, when participants had mean age of 74 years (range 63-97). Abdominal obesity was defined using waist circumference, physical frailty was established using the modified Cardiovascular Health Study phenotype, and functional disability was determined by the Lawton Instrumental Activities of Daily Living Scale. We used logistic regression models to compute odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between abdominal obesity and disability.Abdominal obesity was associated with increased likelihood of functional disability, and this association was stronger in women than in men [OR (95% CI): 1.27 (1.11-1.46) vs. 1.08 (0.93-1.25); P for interaction 0.001]. Furthermore, there was a significantly stronger association between abdominal obesity and functional disability in participants who were physically frail compared to those who were not [OR (95% CI): 1.57 (1.19-2.08) vs. 1.11 (0.99-1.23); P for interaction = 0.003], and this phenomenon was observed in both genders. When compared to participants who were neither abdominally obese nor physically frail, participants who were both abdominally obese and physically frail had a synergistically increased risk of functional disability [OR (95% CI): 3.61 (3.03-4.30)].Women with abdominal obesity had higher risk of functional disability compared to men, and older adults who were both abdominally obese and physically frail had a synergistically increased risk of disability.

Background Few studies have evaluated the association between changes in diet quality from mid-life to late-life and healthy ageing. Methods We included 12,316 Chinese adults aged 45–74 years at baseline (1993–1998) from the Singapore Chinese Health Study. Diet quality was measured using the Dietary Approaches to Stop Hypertension (DASH) scores at baseline and follow-up 3 interviews (2014–2016). Healthy ageing was assessed at follow-up 3 interviews, and was defined as absence of specific chronic diseases, good mental and overall self-perceived health, good physical functioning and absence of cognitive impairment, limitations in instrumental activities of daily living or function-limiting pain. Multivariable-adjusted logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between changes in DASH scores and healthy ageing. Results Compared with participants who maintained relatively stable DASH scores, a >10% decrease in DASH score was associated with a 16% (95% CI, 4–26%) lower likelihood of healthy ageing, whereas a >10% increase in DASH score was associated with a 19% (95% CI, 3–37%) higher likelihood of healthy ageing. Compared with participants who were in the low-score group consistently, participants who increased their DASH scores from moderate-score at baseline to high-score at follow-up 3 had a 53% (95% CI, 21–92%) higher likelihood of healthy ageing, whereas those who were in the high-score group consistently had 108% (95% CI, 71–152%) higher likelihood of healthy ageing. Conclusions Improving diet quality from mid- to late-life was associated with a higher likelihood of healthy ageing.

BACKGROUND: n-3 and n-6 PUFAs have physiologic roles in sleep processes, but little is known regarding circulating n-3 and n-6 PUFA and sleep parameters. OBJECTIVES: We sought to assess associations between biomarkers of n-3 and n-6 PUFA intake with self-reported sleep duration and difficulty falling sleeping in the Fatty Acids and Outcome Research Consortium. METHODS: Harmonized, de novo, individual-level analyses were performed and pooled across 12 cohorts. Participants were 35-96 y old and from 5 nations. Circulating measures included α-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA), DHA, EPA + DPA + DHA, linoleic acid, and arachidonic acid. Sleep duration (10 cohorts, n = 18,791) was categorized as short (≤6 h), 7-8 h (reference), or long (≥9 h). Difficulty falling asleep (8 cohorts, n = 12,500) was categorized as yes or no. Associations between PUFAs, sleep duration, and difficulty falling sleeping were assessed by cross-sectional multinomial logistic regression using standardized protocols and covariates. Cohort-specific multivariable-adjusted ORs per quintile of PUFAs were pooled with inverse-variance weighted meta-analysis. RESULTS: In pooled analysis adjusted for sociodemographic characteristics and health status, participants with higher very long-chain n-3 PUFAs were less likely to have long sleep duration. In the top compared with the bottom quintiles, the multivariable-adjusted ORs (95% CIs) for long sleep were 0.78 (95% CI: 0.65, 0.95) for DHA and 0.76 (95% CI: 0.63, 0.93) for EPA + DPA + DHA. Significant associations for ALA and n-6 PUFA with short sleep duration or difficulty falling sleeping were not identified. CONCLUSIONS: Participants with higher concentrations of very long-chain n-3 PUFAs were less likely to have long sleep duration. While objective biomarkers reduce recall bias and misclassification, the cross-sectional design limits assessment of the temporal nature of this relation. These novel findings across 12 cohorts highlight the need for experimental and biological assessments of very long-chain n-3 PUFAs and sleep duration.

There is limited research on the effect of dietary quality on hepatocellular carcinoma (HCC) risk in populations with relatively high risk of HCC. Using data from Singapore Chinese Health Study, a prospective cohort study, of 63 257 Chinese aged 45 to 74, we assessed four diet-quality index (DQI) scores: the Alternative Health Eating Index-2010 (AHEI-2010), Alternate Mediterranean Diet (aMED), Dietary Approaches to Stop Hypertension (DASH) and Heathy Diet Indicator (HDI). We identified 561 incident HCC cases among the cohort participants after a mean of 17.6 years of follow-up. Cox proportional hazard regression model was used to estimate hazard ratio (HR) and 95% confidence interval (CI) for HCC in relation to these DQI scores. Unconditional logistic regression method was used to evaluate the associations between DQIs and HCC risk among a subset of individuals who tested negative for hepatitis B surface antigen (HBsAg). High scores of AHEI-2010, aMED and DASH, representing higher dietary quality, were associated with lower risk of HCC (all Ptrend

Background Telomere attrition has been proposed as a hallmark of aging. We previously reported on the association between blood leukocyte telomere length (LTL) at midlife and risk of chronic diseases and mortality. Methods In this study, we investigated the effect of midlife LTL and genetic proxies on 5 markers of aging outcomes, namely handgrip strength, timed up-and-go (TUG), Singapore-modified Mini-Mental State Examination (SM-MMSE) scores, anxiety, and depression indices, measured after a median 20-year follow-up in the Singapore Chinese Health Study (N = 9581). Results We observed a significant association between midlife LTL and handgrip strength later in life (p = .004, padjust = .020), as well as a nominal significant association between midlife LTL and TUG later in life (p = .036, padjust = .180). The weighted Genetic Risk Score (wGRS) comprising 15 previously reported LTL reducing loci in East Asians was not significantly associated with handgrip strength. However, results from Structural Equation Modeling showed that the effect of this wGRS on handgrip strength was mediated through LTL (proportion of wGRS effect on handgrip strength mediated through LTL = 33.3%, p = .010). Conclusions Longer midlife LTL was associated with increased handgrip strength later in life.

Background Shorter telomere length (TL) has been associated with poor health behaviors, increased risks of chronic diseases and early mortality. Excessive shortening of telomere is a marker of accelerated aging and can be influenced by oxidative stress and nutritional deficiency. Plasma n6:n3 polyunsaturated fatty acid (PUFA) ratio may impact cell aging. Increased dietary intake of marine n-3 PUFA is associated with reduced telomere attrition. However, the effect of plasma PUFA on leukocyte telomere length (LTL) and its interaction with genetic variants are not well established. Methods A nested coronary artery disease (CAD) case-control study comprising 711 cases and 638 controls was conducted within the Singapore Chinese Health Study (SCHS). Samples genotyped with the Illumina ZhongHua-8 array. Plasma n-3 and n-6 PUFA were quantified using mass spectrometry (MS). LTL was measured with quantitative PCR method. Linear regression was used to test the association between PUFA and LTL. The interaction between plasma PUFAs and genetic variants was assessed by introducing an additional term (PUFA×genetic variant) in the regression model. Analysis was carried out in cases and controls separately and subsequently meta-analyzed using the inverse-variance weighted method. We further assessed the association of PUFA and LTL with CAD risk by Cox Proportional-Hazards model and whether the effect of PUFA on CAD was mediated through LTL by using structural equation modeling. Results Higher n6:n3 ratio was significantly associated with shorter LTL (p = 0.018) and increased CAD risk (p = 0.005). These associations were mainly driven by elevated plasma total n-3 PUFAs, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (p p − 8). Mediation analysis showed that PUFA and LTL affected CAD risk independently. Conclusions Higher plasma n6:n3 PUFA ratio, and lower EPA and DHA n-3 PUFAs were associated with shorter LTL and increased CAD risk in this Chinese population. Furthermore, genetic variants may modify the effect of PUFAs on LTL. PUFA and LTL had independent effect on CAD risk in our study population.

Telomeres play a key role in chromosomal maintenance and stability. To date, few studies have investigated the association of leukocyte telomere length with risk of cancer incidence and all-cause mortality in a large prospective cohort, particularly of the Asian population. Relative telomere lengths in genomic DNA from peripheral blood samples were quantified using a validated quantitative real-time PCR among 26 540 middle-aged or older Chinese adults. Hazard ratios (HRs) and 95% confidence intervals (CIs) of cancer and deaths by quintiles of telomere length were calculated using the Cox proportional hazards regression method with adjustment for age, sex and other potential confounders. After baseline blood collection, 4353 persons developed cancer and 7609 died. Participants with the longest decile of telomeres had a 26% (95% CI: 11%-44%) higher risk of total cancer incidence compared to the shortest decile after controlling for age, sex and other potential founders (Ptrend < .0001). In contrast, longer telomeres were associated with lower risk of all-cause mortality (HR = 0.93; 95% CI: 0.84-1.03), noncancer death (HR = 0.81; 95% CI: 0.71-0.92), specifically, death from chronic obstructive pulmonary disease and pneumonia (HR = 0.79, 95% CI: 0.70-0.89) and digestive diseases (HR = 0.60, 95% CI: 0.42-0.88). Our findings demonstrated that longer telomeres are associated with increased risk of cancer development overall and several common cancer types including breast, rectal, prostate, pancreatic cancer and lung adenocarcinoma. Our study also confirmed that longer telomeres are associated with a reduced risk of noncancer related death.

Background Despite experimental evidence implicating oxidative stress in the pathogenesis of PD, epidemiological studies have provided inconsistent associations between dietary antioxidants and risk of developing PD. Furthermore, no study has been done in any Asian population. Objectives We examined the associations for intake levels of dietary carotenoids (α‐carotene, β‐carotene, lycopene, β‐cryptoxanthin, and lutein) and vitamins (vitamin A, C and E) and the risk of developing PD. Methods We used data from the Singapore Chinese Health Study, a population‐based prospective cohort of 63,257 men and women aged 45 to 74 years during enrollment in 1993–1998. Antioxidant intake was derived from a validated semiquantitative food frequency questionnaire. Incident cases were identified through follow‐up interviews, hospital records, or PD registries through 31 July 2018. Hazard ratios and corresponding 95% confidence intervals were derived from multivariable Cox proportional hazard regression models with adjustment for other lifestyle and dietary factors. Results During an average 19.4 years of follow‐up, 544 incident PD cases were identified. No association was found for dietary carotenoids, individually or summed. Hazard ratio comparing highest to lowest quartile for total carotenoids was 0.98 (95% confidence interval: 0.76–1.28; P trend = 0.83). There were also no clear dose‐dependent associations of dietary vitamins A, C, and E with risk of developing PD (all P trend ≥ 0.10). Sensitive analyses with lag time and excluding supplement use did not materially alter results. Conclusions Intake of dietary antioxidants, such as carotenoids and vitamins, was not associated with the risk of developing PD in Singaporean Chinese. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BackgroundLittle is known about the health harms associated with low-intensity smoking in Asians who, on average, smoke fewer cigarettes and start smoking at a later age than their Western counterparts.MethodsIn this pooled analysis of 738 013 Asians from 16 prospective cohorts, we quantified the associations of low-intensity (FindingsDuring a mean follow-up of 11.3 years, 92 068 deaths were ascertained. Compared with never smokers, current smokers who consumed twofold risk of lung cancer mortality. Furthermore, current smokers who started smoking after age 35 and smoked ConclusionsOur study showed that smokers who smoked a small number of cigarettes or started smoking later in life also experienced significantly elevated all-cause and major cause-specific mortality but benefited from cessation. There is no safe way to smoke—not smoking is always the best choice.

Deficiencies in methyl donor status may render DNA methylation changes and DNA damage, leading to carcinogenesis. Epidemiological studies reported that higher dietary intake of choline is associated with lower risk of pancreatic cancer, but no study has examined the association of serum choline and its metabolites with risk of pancreatic cancer. Two parallel case-control studies, one nested within the Shanghai Cohort Study (129 cases and 258 controls) and the other within the Singapore Chinese Health Study (58 cases and 104 controls), were conducted to evaluate the associations of baseline serum concentrations of choline, betaine, methionine, total methyl donors (i.e., sum of choline, betaine and methionine), dimethylglycine and trimethylamine N-oxide (TMAO) with pancreatic cancer risk. In the Shanghai cohort, odds ratios and 95% confidence intervals of pancreatic cancer for the highest quartile of choline, betaine, methionine, total methyl donors and TMAO were 0.27 (0.11-0.69), 0.57 (0.31-1.05), 0.50 (0.26-0.96), 0.37 (0.19-0.73) and 2.81 (1.37-5.76), respectively, compared to the lowest quartile. The corresponding figures in the Singapore cohort were 0.85 (0.23-3.17), 0.50 (0.17-1.45), 0.17 (0.04-0.68), 0.33 (0.10-1.16) and 1.42 (0.50-4.04). The inverse associations of methionine and total methyl donors including choline, betaine and methionine with pancreatic cancer risk in both cohorts support that DNA repair and methylation play an important role against the development of pancreatic cancer. In the Shanghai cohort, TMAO, a gut microbiota-derived metabolite of dietary phosphatidylcholine, may contribute to higher risk of pancreatic cancer, suggesting a modifying role of gut microbiota in the dietary choline-pancreatic cancer risk association.

BACKGROUND: Epidemiological studies have demonstrated separately that patients with kidney stone may have higher dietary intake of zinc and higher risk of developing kidney cancer. We prospectively assessed the associations of dietary zinc and other trace elements with kidney cancer risk for the first time. METHODS: We used data from the prospective Singapore Chinese Health Study that recruited 63,257 adult Chinese residing in Singapore between 1993 and 1998. A validated food frequency questionnaire and the Singapore Food Composition Database was used to compute the values of intake for zinc, copper and manganese. We identified incident cancer cases via linkage with nationwide cancer registry, and used Cox proportional hazard models to compute hazard ratio (HR) and 95% confidence interval (CI) for the association with kidney cancer risk. RESULTS: There were 229 incident kidney cancer cases after median follow-up of 20.1 years. Dietary zinc intake was positively associated with higher kidney cancer risk; the HR comparing the extreme quartiles of zinc intake was 1.74 (95% CI: 1.02–2.97; P-trend=0.033). Conversely, intakes of copper and manganese were not associated with kidney cancer risk. CONCLUSIONS: The positive association between dietary zinc and risk of kidney cancer suggests that zinc may be implicated in renal carcinogenesis.

Background Previous studies have shown inconsistent results for the relation between dietary fat intake and cognitive function in the elderly. Furthermore, prospective studies on this topic among the Chinese population are scarce. Objectives We aimed to examine the association between midlife dietary fat intake and risk of cognitive impairment in the elderly. Methods Prospective cohort analysis was conducted among 16,736 participants from the Singapore Chinese Health Study. Dietary information was assessed by a validated FFQ at baseline (1993-1998) when participants aged 45-74 y (mean: 53.5; SD: 6.22). Cognitive impairment was identified using the Singapore modified Mini-Mental State Examination at the third follow-up visit (2014-2016) when participants aged 61-96 y (mean: 73.2; SD: 6.41). Multivariable logistic regression models were used to calculate ORs and 95% CIs. Results Cognitive impairment was presented in 2397 participants. When substituted for total carbohydrate, dietary fat intake was inversely related to cognitive impairment (OR comparing extreme quartiles: 0.80; 95% CI: 0.67, 0.94; P-trend = 0.003). The OR (95% CI) comparing extreme quartiles of specific dietary fats was 1.08 (0.89, 1.31; P-trend = 0.51) for SFAs, 0.80 (0.64, 0.99; P-trend = 0.02) for MUFAs, 0.84 (0.72, 0.99; P-trend = 0.02) for PUFAs, 0.92 (0.77, 1.09; P-trend = 0.49) for n-3 PUFAs, and 0.83 (0.70, 0.98; P-trend = 0.01) for n-6 PUFAs. An inverse association was found for plant-based fat (OR: 0.84; 95% CI: 0.72, 0.98; P-trend = 0.02), but not for animal-based fat (OR: 0.96; 95% CI: 0.81, 1.15; P-trend = 0.76). When substituted for SFAs, the OR (95% CI) was 0.77 (0.61, 0.97; P-trend = 0.02) for MUFAs and 0.82 (0.70, 0.95; P-trend = 0.003) for PUFAs. Conclusions We found that substitution of total carbohydrate or SFAs with MUFAs and PUFAs, particularly n-6 PUFAs, was related to a lower risk of cognitive impairment in elderly Chinese participants. In addition, an inverse association with cognitive impairment was found for plant-based fat.

The relationship between alcohol intake and end-stage kidney disease (ESKD) risk is controversial. Moreover, while evidence has shown that the relationship between alcohol and atherosclerosis may be modified by diabetes, whether this applies to ESKD is unknown.We examined these associations in the Singapore Chinese Health Study, a prospective cohort of 63 257 adults aged 45 to 74 years. Information on alcohol intake, diet, lifestyle factors, and medical history was collected at recruitment. We identified 1217 ESKD cases via linkage with the Singapore Renal Registry after a mean follow-up of 17.5 years. Cox regression models were used to estimate hazard ratios (HRs) and 95% CI of ESKD.Among the participants without diabetes at baseline, monthly to weekly drinking was associated with a decreased risk of ESKD (HR 0.69; 95% CI, 0.54-0.87) compared to nondrinkers. In contrast, this association was attenuated and not significant among those with diabetes (HR 0.82; 95% CI, 0.58-1.16; PLow-dose drinking is associated with a reduced risk of ESKD among individuals without diabetes. However, joint exposure to heavy drinking and diabetes is associated with a substantially higher risk of ESKD.背景: 酒精的摄入与终末期肾病(ESKD)风险之间的关系仍存在着争议。此外, 有证据表明糖尿病可能会影响酒精与动脉粥样硬化之间的关联, 但这是否适用于ESKD尚不清楚。 方法: 利用前瞻性队列“新加坡华人健康研究”探讨酒精的摄入与ESKD风险的关联, 该研究由63257名45-74岁的成年人组成。基线收集了关于酒精摄入量、饮食习惯、生活方式及疾病史的资料。经过平均17.5年的随访, 通过新加坡肾脏病登记处的链接, 确定了1,217例ESKD病例。使用比例风险(Cox)回归模型估算ESKD的风险比(HRs)和95%置信区间(CI)。 结果: 在无基线糖尿病的参与者中, 与非饮酒者相比, 每月至每周饮酒与ESKD风险降低相关(HR 0.69, 95%置信区间0.54-0.87)。相反, 该关联在基线糖尿病患者中减弱并且不再显著(HR 0.82, 95%置信区间0.58-1.16; P交互作用= 0.19)。相比之下, 在基线糖尿病患者中, 与非饮酒者相比, 每天摄入≥2个标准饮酒单位与ESKD风险增加显著相关(HR 2.00, 95%置信区间1.14-3.53), 而在无基线糖尿病参与者中无统计学意义(HR 0.91, 95%置信区间0.53-1.56; P相互作用= 0.01)。与无基线糖尿病的非饮酒者相比, 患有糖尿病且每天饮酒≥2个标准饮酒单位的人患ESKD的风险增加了近12倍(HR 11.6, 95%置信区间6.73-19.9)。 结论: 在非糖尿病患者中, 低剂量饮酒与ESKD风险降低显著相关。然而, 大量饮酒和糖尿病的联合效应与ESKD的风险大幅增高显著相关。.

BACKGROUND Few prospective studies with long duration of follow-up have assessed the relations of body mass index (BMI) and weight change with cognitive function, especially in Asian populations. OBJECTIVE To investigate whether BMI and weight change in midlife are associated with cognitive impairment in old age. METHODS We used data from 14,691 participants in the Singapore Chinese Health Study and computed weight change as the difference between weight reported at baseline (1993-1998) at mean age of 53.0 years and follow-up 1 (1999-2004) at mean age of 58.6 years. Cognitive impairment was determined using education-specific cut-offs of the Singapore Modified Mini-Mental State Examination at follow-up 3 (2014-2016) at mean age of 72.9 years. We used multivariable logistic regression models to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the associations. RESULTS Obesity (as defined BMI ≥27.5 kg/m2) was associated with a higher risk of cognitive impairment at baseline (OR 1.33, 95% CI 1.12-1.58) and follow-up 1 (OR 1.30, 95% CI 1.10-1.54) compared to BMI of 18.5-22.9 kg/m2. Underweight (BMI

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 45–74 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, 2,140 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 with the lowest quartile (P(trend)=0.02). 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.

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 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.

Tea and coffee are widely consumed beverages. Tea flavonoids have been shown to inhibit lung tumorigenesis using in vitro and in vivo models. Conversely, coffee contains complex mixtures of biochemically active compounds, some of which may have genotoxic and mutagenic properties. However, previous epidemiologic studies have shown inconsistent results on tea and coffee in relation to lung cancer risk. The Singapore Chinese Health Study is a population-based prospective cohort of 63,257 Singaporean Chinese men and women, with an average of 17.7 years of follow-up. Information on tea and coffee consumption and other lifestyle factors was collected through in-person interviews at baseline. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations with adjustment for potential confounders. There were 1486 incident lung cancer cases. Compared to non-daily coffee drinkers, HRs (95% CIs) of lung cancer risk for those consuming one, two, and three or more cups of coffee per day were 1.18 (1.02–1.36), 1.21 (1.05–1.40), and 1.32 (1.08–1.62) respectively (P for trend = 0.0034). The highest category of black tea consumption (at least 2 cups per day) was inversely associated with risk of lung cancer [HR (95% CI) = 0.73 (0.53–0.99)], particularly among men [HR (95% CI) = 0.67 (0.47–0.95)], compared to less-than-weekly black tea drinkers, although the interaction by sex was not statistically significant. Coffee beverage consumption was associated with higher risk of developing lung cancer. On the other hand, black tea intake was associated with lower risk of lung cancer among men in our cohort, and further studies are needed to confirm this association.

The substantial social and economic burden attributable to smoking is well-known, with heavy smokers at higher risk of chronic disease and premature mortality than light smokers and nonsmokers. In aging societies with high rates of male smoking such as in East Asia, smoking is a leading preventable risk factor for extending lives (including work-lives) and healthy aging. However, little is known about whether smoking interventions targeted at heavy smokers relative to light smokers lead to disproportionately larger improvements in life expectancy and prevalence of chronic diseases and how the effects vary across populations. Using a microsimulation model, we examined the health effects of smoking reduction by simulating an elimination of smoking among subgroups of smokers in South Korea, Singapore, and the United States. We found that life expectancy would increase by 0.2 to 1.5 years among light smokers and 2.5 to 3.7 years among heavy smokers. Whereas both interventions led to an increased life expectancy and decreased the prevalence of chronic diseases in all three countries, the life-extension benefits were greatest for those who would otherwise have been heavy smokers. Our findings illustrate how smoking interventions may have significant economic and social benefits, especially for life extension, that vary across countries.

Background: Although previous meta-analyses have suggested a dose-response relationship between body mass index (BMI) and thyroid cancer risk, limited evidence has been presented about Asian populations. To assess this association among Asian populations, where underweight is more prevalent than in other regions, a pooled analysis from the Asia Cohort Consortium was conducted.Methods: Baseline height and weight were measured in five cohorts and self-reported in eight cohorts. Thyroid cancer incidence was ascertained by linkage to local cancer registries. Cohorts were treated as a stratum in the Cox proportional hazard model to estimate the pooled hazard ratios (HRs) and corresponding confidence intervals (CIs) from the estimates for each cohort. All analyses were stratified by sex.Results: A total of 538,857 men and women from 13 cohorts from mainland China, Korea, Japan, and Singapore were included in the analysis. During a mean of 15.1 years of follow-up, 1132 thyroid cancer cases were ascertained. Using a BMI of 18.5-22.9 kg/m(2) as a reference, an elevated risk of thyroid cancer was observed for groups with a BMI between 25 and 29.9 kg/m(2) (HR: 1.31, [CI: 0.95-1.80]) and a BMI of 30 kg/m(2) and greater (HR: 1.84, [CI: 0.89-3.81]) in men. Thyroid cancer risk was elevated in women with a BMI of 23-24.9 kg/m(2) (HR: 1.26, [CI: 1.07-1.48]). The HRs for 5-U increment of BMI showed a linear association among men (HR: 1.25, [CI 1.10-1.55]) but not among women (HR: 1.07, [CI: 0.97-1.18]). Although the overall thyroid cancer risk was lower among underweight men and women, the papillary cancer risk may be elevated among underweight men (HR: 2.24, [CI: 0.75-6.66]).Conclusion: While higher BMI is associated with an elevated risk of thyroid cancer in both men and women, the association of underweight BMI may differ by sex and histological subtype.

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.

We studied sociodemographic and health factors associated with depression across three age groups of community-dwelling older adults.We used data from 16,785 participants from the third follow-up of the Singapore Chinese Health Study (mean age: 73, range: 61-96 years). We defined depression as having a score of ≥5 using the 15-item Geriatric Depression Scale. We used regression splines to examine the pattern of depression risk with age and applied multivariable logistic regression to study factors associated with depression.Increasing age was associated with depression in an inverted J-shape relationship with the highest odds ratio (OR) at age 75. Compared to the youngest-old (70 years), the middle-old (70-80 years) had higher odds of depression [OR = 1.20, 95% confidence interval (CI) = 1.09-1.31], while the oldest-old (80 years) had no increased risk (OR = 1.01, 95% CI = 0.89-1.15). We also found demographic (men, lower education, unemployment), social (living alone, poor social support, no social activity) and health factors (instrumental limitations, poor physical function, function-limiting pain, chronic diseases, cognitive impairment, poor sleep quality, poor self-rated health) associated with depression. In stratified analysis by age groups, the OR estimates for lower education level, instrumental limitations and cognitive impairment decreased with age, whereas the risk of depression for men increased with age (all p-values for interaction0.03).Compared to the youngest-old, the likelihood of depression was highest among middle-old adults and decreased to null in the oldest-old. The associations between some factors and depression were attenuated with age, suggesting a coping mechanism among oldest-old survivors.

Background Among older adults, living alone is often associated with higher risk of Emergency Department (ED) admissions. However, older adults living alone are very heterogeneous in terms of health. As more older adults choose to live independently, it remains unclear if the association between living alone and ED admissions is moderated by health status. We studied the association between living alone and ED admission outcomes (number of admissions, inpatient days and inpatient costs) among older adults with and without multimorbidity. Methods We used data from 16,785 individuals of the third follow-up of the Singapore Chinese Health Study, a population-based cohort of older Singapore Chinese (mean age: 73(61-96) years). Participants were interviewed face-to-face from 2014 to 2016 for sociodemographic/health factors and followed-up for one year on ED admission outcomes using Singapore Ministry of Health’s Mediclaim Database. We first applied multivariable logistic regression and two-part models to test if living alone is a risk factor for ED admission outcomes. We then ran stratified and joint effect analysis to examine if the associations between living alone and ED admission outcomes were moderated by multimorbidity. Results Compared to living with others, living alone was associated with higher odds of ED admission [Odds Ratio (OR) 1.28, 95 % Confidence Interval(CI) 1.08-1.51)], longer inpatient days (+0.61, 95 %CI 0.25-0.97) and higher inpatient costs (+322 USD, 95 %CI 54-591). The interaction effects of living arrangement and multimorbidity on ED admissions and inpatient costs were not statistically different, whereas the interaction between living arrangements and multimorbidity on inpatient days was borderline significant (p-value for interaction=0.050). Compared to those living with others and without multimorbidity, the relative mean increase was 1.13 inpatient days (95 %CI 0.39-1.86) for those living alone without multimorbidity, and 0.73 inpatient days ( 95 %CI 0.29-1.17) for those living alone with multimorbidity. Conclusions Older adults living alone were at higher risk of ED admission and higher inpatient costs regardless of multimorbidity, while those living alone without multimorbidity had the longest average inpatient days. To enable aging in place while avoiding ED admissions, interventions could provide instrumental support and regular health monitoring to older adults living alone, regardless of their health status.

Objectives Motivators and barriers are pivotal factors in the adoption of health behaviors. This study aims to identify patterns of the motivators and barriers influencing heart health behaviors among multi-ethnic Asian adults with behavior-modifiable risk factors for heart disease, namely obesity, physical inactivity and smoking. Methods A population-based survey of 1,000 participants was conducted in Singapore. Participants were assessed for behavior-modifiable risk factors and asked about motivators and barriers to heart health behaviors. Exploratory and confirmatory factor analyses were conducted to identify factors underlying motivator and barrier question items. Logistic regression was conducted to examine the associations of motivator and barrier factors with sociodemographic characteristics. Results The twenty-five motivator and barrier items were classified into three (outcome expectations, external cues and significant others including family and friends) and four (external circumstances, limited self-efficacy and competence, lack of perceived susceptibility, benefits and intentions and perceived lack of physical capability) factors respectively. Among participants with behavior-modifiable risk factors, those with lower education were more likely to be low in motivation factor of “outcome expectations” and “external cues”. The well-educated were more likely to be high in the barrier factor of “lack of perceived susceptibility, benefits and intention” and were less likely to have the motivation factor of “significant others (family or friends)”. Those aged 60–75 years had low motivations and high barriers compared to their younger counterparts. Older age was more likely to be low in motivation factor of “outcome expectations” and “external cues” and high in barrier factor of “limited self-efficacy and competence” and “perceived lack of physical capability”. Conclusions Findings underscore the importance of a targeted intervention and communication strategy addressing specific motivation and barrier factors in different population segments with modifiable risk factors.

Background Ethnic-specific genetic risk assessment framework for Parkinson's disease (PD) is lacking for the Asian population. Objective We investigated the association of a polygenic risk score (PRS) with PD incidence in a population-based Asian prospective cohort. Methods Genetic, dietary, and lifestyle information were prospectively collected from 25,646 participants within the Singapore Chinese Health Study cohort. PRS was constructed with Asian-specific and top genome-wide association study variants. The association between PRS and PD incidence was evaluated with multivariable Cox proportional hazard models, Kaplan-Meier survival analysis, and concordance statistics. Results A total of 333 incident cases were identified after a follow-up period of more than 20 years. Participants with PRS in the top tertile (hazard ratio [HR], 1.81; 95% confidence interval [CI], 1.37-2.39) and middle tertile (HR, 1.35; 95% CI, 1.00-1.83) are at higher risk of developing PD after adjusting for dietary and lifestyle risk factors, with a shorter time to PD event in a Kaplan-Meier survival analysis (P Conclusion We identified a PRS that was significantly associated with PD incidence in a prospective Chinese cohort after adjusting for dietary and lifestyle factors. © 2021 International Parkinson and Movement Disorder Society.

Introduction Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. Hyperlipidemia is one of the important modifiable risk factors for CVDs. Raising public awareness of CVD risks is an important step in reducing CVD burdens. In this study, we aimed to assess public awareness and knowledge of cholesterol and its management in a multiethnic Asian population. Methods We recruited 1000 participants from three major ethnic groups for this nationwide population-based survey. A structured questionnaire was used to collect socio-demographics, knowledge of cholesterol and cholesterol-lowering medications. Univariate and multivariate analyses were conducted to identify factors associated with good knowledge on cholesterol and its management. Results Of the participants, 65% thought that high cholesterol produces symptoms and that lifestyle modification would be as effective as medication at lowering cholesterol. Nearly 70% believed that long term statin could lead to kidney or liver damage, and 56% thought that statin was associated with higher risk of cancer. A third saw herbal medicine or supplements as healthier and safer. About 45% believed that statin therapy should not be taken long term and that one could stop taking cholesterol medication when cholesterol is under control. Malays were more likely to have poor knowledge (adjusted OR 0.68; 95% CI 0.47–0.98; P = 0.039) compared to Chinese. Participants with intermediate education were more likely to have good knowledge of cholesterol and its management (adjusted OR 1.67; 95% CI 1.11–2.51; P = 0.013) compared to those with primary education. Conclusion Public knowledge and awareness of high cholesterol and its management remains poor in Asian multi-ethnic population. Understanding gaps in public knowledge can inform the implementation of health promotion programs to effectively raise awareness of cholesterol and its management.

IntroductionInsulin-like growth factor-1 (IGF-1) has been implicated in fetal and early-life growth and development of type 2 diabetes (T2D). We aimed to examine the interaction between circulating IGF-1 and birth weight in relation to risk of T2D.Research design and methodsWe included 181 090 adults, aged 39–70 years in the UK Biobank Study, who were free of diabetes or major cardiovascular diseases at baseline. Serum IGF-1 levels were determined using chemiluminescent immunoassay method. Birth weight was self-reported; a Genetic Risk Score (GRS) was calculated to define the genetically determined birth weight. The outcome was the incidence of T2D.ResultsWe identified 3299 incident T2D cases over an average of 9.9 years of follow-up. Among the participants with birth weight of ≥2.5 kg, IGF-1 levels were inversely associated with T2D risk in a dose-dependent manner (p-trendConclusionsOur results indicate that birth weight significantly modifies the relation between adulthood levels of circulating IGF-1 and the risk of T2D. Our findings highlight the importance of early-life risk factors in the development of the lifecourse prevention strategies targeting IGF-1 and T2D.

BACKGROUND: Combinations of circulating fatty acids may affect the risk of type 2 diabetes (T2D) and coronary artery disease (CAD). No previous studies have identified a dietary pattern predicting fatty acid profiles using reduced rank regression (RRR) and evaluated its associations with the risk of T2D and CAD. OBJECTIVE: The aim of this study was to derive a dietary pattern to explain variation in plasma fatty acid concentrations using RRR and evaluate these in relation to risk of T2D and CAD. METHODS: We derived a dietary pattern using fatty acid concentrations from 711 controls of a nested case-control study in the Singapore Chinese Health Study using RRR with 36 food and beverages as predictors and 19 fatty acid biomarkers as responses. Dietary pattern scores were then calculated for the full cohort of men and women (mean age: 56 y). We followed up 45,411 and 58,065 participants for incident T2D and CAD mortality, respectively. Multivariable Cox regression models were used to estimate HRs and 95% CIs. RESULTS: We identified a dietary pattern high in soy, vegetables, fruits, tea, tomato products, bread, fish, margarine and dairy, and low in rice, red meat, coffee, alcohol, sugar-sweetened beverages, and eggs. This pattern predicted higher circulating n–3 (ω-3) PUFAs (18:3n–3, 20:3n–3, 20:5n–3), odd-chain fatty acids (15:0, 17:0), 18:2n–6 and 20:1, and lower 20:4n–6 and 16:1. During a mean follow-up of 11 y and 19 y, 5207 T2D and 3016 CAD mortality events, respectively, were identified. Higher dietary pattern scores were associated with a lower risk of T2D [multivariable-adjusted HR comparing extreme quintiles, 0.86 (95% CI: 0.79, 0.95); P-trend

Aims Galectin‐3 (Gal‐3) is implicated in the pathogenesis of heart failure and is also influenced by ageing. This study aims to determine the extent to which Gal‐3 levels estimate odds of myocardial dysfunction in ageing cohorts, ‘upstream’ prior to clinical disease. Methods and results Four hundred seventy‐five asymptomatic subjects underwent simultaneous assessments of cardiovascular structure and function, with measurements of circulating Gal‐3. Myocardial dysfunction was defined as impaired myocardial relaxation (ratio of peak velocity flow in early diastole E (m/s) to peak velocity flow in late diastole by atrial contraction A (m/s)