Singapore Chinese Health Study Research Articles

Association between sleep duration from midlife to late life and the risk of depressive symptoms: the Singapore Chinese Health Study.

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

Consumption of different types of meat and the risk of chronic limb-threatening ischemia: the Singapore Chinese Health Study

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

Comparison of race- and ethnicity-specific BMI cutoffs for categorizing obesity severity: a multicountry prospective cohort study.

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

The Causal Effect of Adult Height on Late-Life Handgrip Strength: The Singapore Chinese Health Study.

Adult height has been associated with handgrip strength, which is a surrogate marker of physical frailty. However, it is uncertain if this association is causative or due to confounding bias. We evaluated pairwise associations among handgrip strength, adult height, and genetically determined height (using a polygenic score [PGS] for height in a mediation framework and a 2-sample Mendelian randomization approach) by means of a multivariable regression model using a prospective cohort of Chinese living in Singapore. We additionally evaluated pathway enrichments of height-related genes in relation to increased handgrip strength to discover common biological mechanisms underlying associations of genetically determined height with handgrip strength. Height PGS exhibited a positive association with handgrip strength at late life after adjusting for midlife body weight and other baseline exposures (cigarette smoking, education, and physical activity status, p = 1.2 × 10-9). Approximately 66.4% of the total effect of height PGS on handgrip strength was mediated through adult height (βindirect-effect = 0.034, pindirect-effect = 1.4 × 10-40). Two-sample Mendelian randomization evaluations showed a consistent causal relationship between increased height and increased handgrip strength in late life (p between 6.6 × 10-4 and 3.9 × 10-18), with insignificant horizontal pleiotropic effects (pMR-Egger intercept = 0.853). Pathway analyses of genes related to both increased adult height and handgrip strength revealed enrichment in ossification and adipogenesis pathways (padj between .034 and 6.8 × 10-4). The study highlights a potentially causal effect between increased adult height and increased handgrip strength in late life, which may be explained by related biological processes underlying the preservation of muscle mass and strength in aging.

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

BackgroundIt 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.MethodsDiet 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.ResultsComparing 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.ConclusionsMaintaining a high diet quality or a substantial improvement in diet quality after midlife could lower the risk of physical frailty at late life.

Association between Dietary Antioxidant Capacity in Midlife and Depressive Symptoms in Late Life: The Singapore Chinese Health Study.

Preclinical and limited epidemiological studies suggest that oxidative stress may be implicated in geriatric depression. Our study investigated the association between midlife dietary total antioxidant capacity (TAC) and depressive symptoms in late life among 13,712 participants in a population-based cohort of Chinese in Singapore. At baseline (1993-1998), intake of antioxidants from diet and supplements at a mean age of 52.4 years was estimated using a validated food frequency questionnaire to derive two dietary TAC indices from vitamins C and E, carotenoids and flavonoids: the Comprehensive Dietary Antioxidant Index (CDAI) and Vitamin C Equivalent Antioxidant Capacity (VCEAC). At follow-up 3 (2014-2016), when participants were at a mean age of 72.5 years, depressive symptoms were assessed using the Geriatric Depression Scale, and depression, defined as having ≥5 symptoms, was presented in 3173 (23.1%) participants. Both CDAI and VCEAC indices were inversely associated with odds of depressive symptoms in a stepwise manner: the OR (95% CI) comparing the extreme quartiles was 0.73 (0.64-0.83; Ptrend < 0.01) for the CDAI and 0.77 (0.68-0.87; Ptrend < 0.01) for the VCEAC. Specifically, higher intakes of vitamin C, carotenoids, and flavonoids were associated with a lower likelihood of depressive symptoms. Our findings support the recommendation of an antioxidant-rich diet for the prevention of depression.

Healthcare burden of cognitive impairment: Evidence from a Singapore Chinese health study.

Cognitive impairment (CI) raises risks for unplanned healthcare utilisation and expenditures and for premature mortality. It may also reduce risks for planned expenditures. Therefore, the net cost implications for those with CI remain unknown. We examined differences in healthcare utilisation and cost between those with and without CI. Using administrative healthcare utilisation and cost data linked to the Singapore Chinese Health Study cohort, we estimated regression-adjusted differences in annual healthcare utilisation and costs by CI status determined by modified Mini-Mental State Exam. Estimates were stratified by ex ante mortality risk constructed from out-of-sample Cox model predictions applied to the full sample, with a separate analysis restricted to decedents. These estimates were used to project differential healthcare costs by CI status over 5 years. Patients with CI had 17% higher annual cost compared to those without CI (SGD4870 versus SGD4177, P<0.01). Accounting for the greater mortality risk, individuals with CI cost 9% to 17% more over 5 years, or SGD2500 (95% confidence interval 1000-4200) to SGD3600 (95% confidence interval 1300-6000) more, depending on their age. Higher cost was mainly due to more emergency department visits and subsequent admissions (i.e. unplanned). Differences attenuated in the last year of life when costs increased dramatically for both groups. Ageing populations and higher rates of CI will further strain healthcare resources primarily through greater use of emergency department visits and unplanned admissions. Efforts should be made to identify at risk patients with CI and take appropriate remediation strategies.

Low-Carbohydrate Diet Score and Risk of Hepatocellular Carcinoma: Findings from a Prospective Cohort Study.

In a large cohort study of more than 63,000 Chinese Singaporeans, we found that a diet with lower carbohydrate and higher animal fat and protein was associated with increased risk of HCC, suggesting that dietary modification could be an effective strategy in primary prevention to reduce the HCC burden.

Abstract 2199: Low-carbohydrate diet score and risk of bladder cancer: Findings from the Singapore Chinese Health Study

Abstract Background. Bladder cancer is a leading tumor of urinary tract with annually 570,000+ new cases and 200,000+ deaths worldwide. In the United States, the current incidence rate of bladder cancer is 15.8 per 100,000 population with more than 82,000 new cases and more than 16,000 deaths each year. Although smoking is established as a major risk factor for bladder cancer development, accounting for 30-50% cases, the role of other modifiable risk factors, including dietary in bladder cancer remains unclear. Low-carbohydrate diet (LCD) is a dietary pattern to restrict carbohydrate and to favor protein and/or fat intakes that has recently been well-accepted for weight loss. While its short-term effect to support the weight loss has been popular, its long-term effect on chronic diseases, including cancer, needs to be elucidated. In the current analysis, we sought to determine the association between LCD scores and bladder cancer risk in the Singapore Chinese Health Study (SCHS), an ongoing prospective cohort study consisting of more than 63,000 Chinese Singaporeans, 45- 74 years of age at baseline enrollment period 1995-1998. Methods. Total, animal-based and plant-based LCD scores were derived from the baseline dietary survey data, representing summed intake of carbohydrates, fats and proteins from all dietary, animal- and plant-food sources, respectively. Bladder cancer cases were ascertained using cancer registry. Cox proportional hazard regression model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for different LCD score levels with risk of bladder cancer. Results. By December 31, 2015, or after 17.6 years of follow-up, 250 bladder cancer cases were developed within the SCHS. Total LCD score was marginally associated with increased risk of bladder cancer (HRQ4vs.Q1=1.43, 95% CI: 0.98-2.09, Ptrend = 0.06). Animal-based LCD score was significantly associated with risk of bladder cancer. The HRs and respective 95% CIs of bladder cancer for quartiles 2, 3, and 4, compared with the lowest quartile, were 1.09 (0.76-1.56), 1.17 (0.81-1.70), and 1.53 (1.09-2.17) (Ptrend=0.01). The positive association was only present in men, ever smokers, never drinkers and individuals without history of type 2 diabetes (All P’sheterogeneity&amp;gt;0.05). Conclusions. In a prospective cohort study of more than 63,000 Chinese Singaporeans, we found that animal-based LCD score, representing a diet with lower carbohydrate and higher animal fat and protein, was significantly associated with increased risk of bladder cancer. Dietary modification is therefore suggested as an effective strategy for primary prevention of bladder cancer. Citation Format: Yen Thi-Hai Pham, Renwei Wang, Aizhen Jin, Woon-Puay Koh, Jian-Min Yuan, Hung N. Luu. Low-carbohydrate diet score and risk of bladder cancer: Findings from the Singapore Chinese Health Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2199.

Abstract 3461: Shorter leukocyte telomere length and higher risk of primary liver cancer in a prospective cohort study

Abstract Background: Telomeres are conserved tandem repeats at chromosome ends that are vital to maintaining chromosomal stability and preventing degradation. Shorter telomere lengths (TL) are typically associated with older biological age or poor health status and can activate programmed cell death, whereas longer telomere lengths can be indicative of younger age or abnormal replication processes with oncogenic mutations. Previous research has identified a link between telomere length and carcinogenesis, but relatively few studies have investigated TL and primary liver cancer (PLC) risk despite it being one of the leading causes of cancer worldwide. The goal of this analysis was to study this association in a large prospective cohort. Methods: Data was extracted from the Singapore Chinese Cohort Health Study, a cohort of 63,257 men and women aged 45-74 years at enrollment during 1993-1998. Telomere length was measured in peripheral leukocytes of 26,540 participants who provided baseline blood samples, using a validated quantitative polymerase chain reaction (qPCR) method. PLC incidence and death among cohort participants was annually surveilled using the nationwide Singapore Cancer Registry and the National Birth and Death Registry from study enrollment to 2015. For statistical analysis, a t test was performed to examine the differences in TL between participants who developed incident PLC and those who remained free of PLC. Cox proportional hazard method was used to estimate the hazard ratios (HRs) and their 95% confidence interval (CI) of PLC incidence according to TL quartiles. Results: Over a 12-year follow-up, 199 participants developed incident PLC. The relative TL was significantly lower in participants with incident PLC than those without (-6.7%, p &amp;lt; 0.001). Multivariate Cox regression model showed an inverse association between TL quartile and risk of PLC (p for trend = 0.009). Compared with the lowest quartile, HRs (95% CIs) of PLC for the 2nd, 3rd, and highest quartile of TL were 0.78 (0.54-1.12), 0.75 (0.51-1.11), and 0.57 (0.37-0.88), respectively, after adjustment for age, sex, alcohol use, body mass index, and smoking status. Conclusion: The present analysis demonstrated a statistically significant association between shorter telomere length and increased risk of PLC in a large prospective cohort of Singaporean Chinese. This inverse association for PLC is different from those for other cancer types in the same cohort. These results warrant further studies such as using Mendelian randomization to quantify genetic variation in TL with PLC development. Citation Format: Sindhu Karnam, Kathryn Demanelis, Kenneth B. Beckman, Renwei Wang, Jennifer Adams-Haduch, Woon-Puay Koh, Jian-Min Yuan. Shorter leukocyte telomere length and higher risk of primary liver cancer in a prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3461.

A Pre-Leukemic DNA Methylation Signature in Healthy Individuals at Higher Risk for Developing Myeloid Malignancy.

DNA methylation alterations are widespread in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), some of which appear to have evolved independently of somatic mutations in epigenetic regulators. Although the presence of somatic mutations in peripheral blood can predict the risk of development of AML and MDS, its accuracy remains unsatisfactory. We performed global DNA methylation profiling in a case control study nested within the Singapore Chinese Health Study to evaluate whether DNA methylation alterations were associated with AML/MDS development. Targeted deep sequencing and methylated DNA immunoprecipitation sequencing (MeDIP-seq) were performed on peripheral blood collected a median of 9.9 years before diagnosis of AML or MDS, together with age-matched still-healthy individuals as controls. Sixty-six individuals who developed AML or MDS displayed significant DNA methylation changes in the peripheral blood compared with 167 age- and gender-matched controls who did not develop AML/MDS during the follow-up period. Alterations in methylation in the differentially methylation regions were associated with increased odds of developing AML/MDS. The epigenetic changes may be acquired independently and before somatic mutations that are relevant for AML/MDS development. The association between methylation changes and the risk of pre-AML/MDS in these individuals was considerably stronger than somatic mutations, suggesting that methylation changes could be used as biomarkers for pre-AML/MDS screening.

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.

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

BackgroundIt 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. ObjectivesWe 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. MethodsThe 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. ResultsWe 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). ConclusionsMidlife 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.

Adherence to a Planetary Health Diet, Environmental Impacts, and Mortality in Chinese Adults

Although the EAT-Lancet Commission has recently proposed a planetary health diet (PHD) to promote human and environmental health, little is known about how PHD affects environment and mortality risk among an Asian population. To investigate whether a PHD score is associated with environmental impacts and mortality outcomes in a Chinese cohort living in Singapore. This cohort study used data from the Singapore Chinese Health Study. Eligible participants were without known cardiovascular disease and cancer at baseline; they were recruited between 1993 and 1998 and followed up using record linkage data until 2020. Data were analyzed from September 2022 to April 2023. PHD score was calculated based on the reference consumption of 14 dietary components in PHD and individual energy intake assessed using a validated food frequency questionnaire in this cohort. Diet-related environmental impacts were estimated using a food frequency questionnaire. Mortality outcomes (all-cause, cardiovascular disease, cancer, and respiratory disease) were identified via linkage with a nationwide registry. A total of 57 078 participants were included in this study (mean [SD] age, 56.1 (7.9) years; 31 958 women [56.0%]). During a median (IQR) follow-up of 23.4 (18.7-26.2) years, 22 599 deaths occurred. Comparing the highest and lowest quintiles, higher PHD scores were associated with lower greenhouse gas emissions (β = -0.13 kg CO2 equivalent; 95% CI, -0.14 to -0.12 kg CO2 equivalent), but with higher total water footprint (β = 0.12 m3; 95% CI, 0.11-0.13 m3) and land use (β = 0.29 m2; 95% CI, 0.28-0.31 m2). In the adjusted multivariable model, compared with the lowest quintile, participants in the highest quintile of PHD score had lower risk of all-cause mortality (hazard ratio [HR], 0.85; 95% CI, 0.81-0.89), cardiovascular disease mortality (HR, 0.79; 95% CI, 0.73-0.85), cancer mortality (HR, 0.93; 95% CI, 0.86-1.00), and respiratory disease mortality (HR, 0.81; 95% CI, 0.74-0.89). In this study of Singapore Chinese adults, higher adherence to PHD was associated with reduced risk of chronic disease mortality. However, environmental impacts were uncertain, as higher adherence was associated with lower greenhouse gas emissions but higher total water footprint and land use.

Consumption of Coffee, Tea, and Caffeine at Midlife, and the Risk of Physical Frailty in Late Life

ObjectivesOur study evaluated the prospective association between the consumption of caffeine-containing beverages at midlife and the risk of physical frailty at late life within a population-based cohort of Chinese adults living in Singapore over a follow-up period of 20 years. DesignProspective cohort study. Setting and ParticipantsWe used data from 12,583 participants from the baseline and third follow-up interviews of the Singapore Chinese Health Study (SCHS). Participants had a mean age of 53 years at baseline (1993–1998), and a mean age of 73 years during the third follow-up (2014–2017). MethodsAt baseline, habitual consumption of caffeine-containing beverages was evaluated using a validated semi-quantitative food-frequency questionnaire. During the third follow-up, physical frailty was assessed using the modified Cardiovascular Health Study phenotype. ResultsCompared with non-daily drinkers, those who drank 4 or more cups of coffee daily had reduced odds of physical frailty [odds ratio (OR), 0.54; 95% CI, 0.38–0.76]. Similarly, compared with those who hardly drank tea, participants who drank tea everyday also had reduced odds (OR, 0.82; 95% CI, 0.71–0.95). Total daily caffeine intake at midlife was associated with reduced likelihood of frailty at late life in a dose-response relationship (Ptrend < .001). Relative to their counterparts in the lowest quartile of daily caffeine intake (0–67.6 mg/d), participants in the highest quartile (223.0–910.4 mg/d) had an OR of 0.77 (95% CI, 0.66–0.91). Higher caffeine consumption was associated with lower likelihood of being in the slowest quintile for timed up-and-go (TUG) and weakest quintile for handgrip strength. Conclusions and ImplicationsIn this cohort of Chinese adults, higher consumption of caffeine at midlife, via coffee and tea, was associated with a reduced likelihood of physical frailty in late life.

Longitudinal Dietary Trajectories With Cognitive and Psychosocial Well-Being in Chinese Adults Aged 85 Years and Older in Singapore.

Studies on longitudinal trajectories of diet and the influence on aging in older adults are limited. We characterized diet quality trajectories over the past 2 decades among adults aged ≥85 years and examined their associations with cognitive and psychosocial outcomes. We used data from 861 participants in the population-based Singapore Chinese Health Study. Dietary intakes were assessed at baseline (mean age [range]: 65 [60-74] years) and at follow-ups 3 (85 [81-95]) and 4 (88 [85-97]) years. Diet quality was measured by adherence to the Dietary Approaches to Stop Hypertension pattern, and group-based trajectory modeling was used to derive diet quality trajectories. At Follow-up 4, we assessed cognition using the Singapore-modified Mini-Mental State Examination, depressive symptoms using the 15-item Geriatric Depression Scale, social engagement, and self-rated health. Multivariable logistic regression models examined associations of diet quality trajectories with these outcomes. About 49.7% had a trajectory with consistently low diet quality scores, whereas 50.3% had a trajectory with consistently high diet quality scores. Compared to the "consistently low" trajectory, the "consistently high" trajectory had 29% and 26% lower likelihoods of cognitive impairment and depressive symptoms, respectively (odds ratio, 95% confidence interval: 0.71 [0.51, 0.99] and 0.74 [0.55, 0.99], respectively); as well as 47% higher likelihood of social engagement (1.47 [1.09, 1.98]). No statistically significant association was observed between the trajectories and self-rated health. Maintaining high diet quality throughout the older adult life course was associated with better cognitive and psychosocial well-being in adults aged ≥85 years.

Abstract 3015: Soluble CD137 and risk of hepatocellular carcinoma: nested case-control studies in cohorts in Shanghai and Singapore

Abstract Background: Chronic inflammation plays a significant role in hepatocellular carcinoma (HCC). With rising incidence and poor prognosis of HCC, identifying relatively less invasive biomarkers, especially inflammatory ones, may improve the assessment and stratification of HCC risk. The objective of our studies was to assess if CD8+ T cell cytokines in pre-diagnostic serum are associated with risk of HCC development. Methods: We conducted two parallel case-control studies of HCC nested within the Shanghai Cohort Study (SCS) and the Singapore Chinese Health Study (SCHS), two prospective cohorts of 81,000 individuals with 25+ years of follow-up. The serum concentrations of five CD8+ T cell cytokines ─ soluble CD137 (sCD137), soluble Fas (sFas), perforin, macrophage inflammatory protein 1-beta (MIP-1β), and tumor necrosis factor alpha (TNF-α) ─ were determined using Luminex bead-based immunoassay on 315 HCC cases and 315 individually matched controls in the SCS, and on 197 HCC case-control pairs in the SCHS. Conditional logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) for HCC with elevated levels of cytokines with adjustment for body mass index, alcohol drinking, cigarette smoking, seropositivity of hepatitis surface antigen (HBsAg), and history of diabetes. Results: sCD137 levels were statistically significantly higher in HCC cases than controls in both cohorts. Compared with the 1st quartile (Q1) of sCD137, multivariable-adjusted ORs (95% CI) of HCC for the 4th quartile (Q4) were 3.8 (1.7-8.3) in the SCS and 3.5 (1.4 -8.5) in the SCHS (both Ptrend’s &amp;lt; 0.001). Among HBsAg-negative individuals, ORs (95% CIs) for Q2, Q3, &amp; Q4 of sCD137 were 2.7 (1.5-4.9), 2.7 (1.4-5.0), and 4.5 (2.4-8.5), respectively, compared with Q1 (Ptrend &amp;lt; 0.001) in both SCS and SCHS combined. The corresponding ORs (95% CIs) among HBsAg- positive individuals were 21.0 (9.3-47.6), 34.1 (13.8-84.2), and 56.7 (23.3-137.9), respectively, with a P=0.095 for multiplicative interaction. The sCD137-HCC risk association remained constant over different time periods from blood draw to HCC diagnosis: ORs (95% CIs) for Q4 vs. Q1 were 4.7 (1.2-17.5) for &amp;lt;5 years, 3.7 (1.3-10.6) for 5-10 years, and 3.94 (1.6-9.5) for more than 10 years between blood collection and cancer diagnosis. sFas was positively associated with HCC risk in the SCHS but not in the SCS. There was no statistically significant association for perforin, MIP-1β, or TNF-α with HCC risk in either cohort. Conclusion: These novel and validated findings demonstrated that serum sCD137 levels were significantly elevated many years prior to HCC diagnosis, and had a potential synergistic effect with chronic viral infection on the HCC risk. sCD137 may be developed as a immune monitoring biomarker for risk stratification and assessment, which can lead to early diagnosis and improve prognosis of HCC patients. Citation Format: Claire E. Thomas, Jennifer J. Adibi, Allison L. Kuipers, Brenda Diergaarde, Hung N. Luu, Aizhen Jin, Woon-Puay Koh, Yu-Tang Gao, Jennifer Adams-Haduch, Renwei Wang, Anna Lokshin, Jaideep Behari, Jian-Min Yuan. Soluble CD137 and risk of hepatocellular carcinoma: nested case-control studies in cohorts in Shanghai and Singapore [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3015.

Abstract 6449: Association between dietary one-carbon metabolism-related nutrients and the risk of colorectal cancer: Findings from the Singapore Chinese Health Study

Abstract Background. Colorectal cancer (CRC) is a commonly diagnosed subtype of cancer with a high mortality rate. One-carbon metabolism is a set of complex pathways, responsible for providing methyl group for DNA synthesis, repair and methylation. Adequate DNA methylation maintains chromosome stability and prevents gene disruption. Diet is a major source for key substrates and co-factors (i.e., vitamin B6, choline and folate) involved in one-carbon metabolism. A majority of epidemiologic studies that have evaluated one-carbon metabolism-related nutrients in relation to CRC risk have focused on the potential role of folate only. Due to the involvement of multiple nutrients and the complexity of one-carbon metabolism pathways, a comprehensive assessment of the nutrients involved and their associations with CRC risk is needed. The purpose of the current analysis was therefore to evaluate the association between one-carbon metabolism-related nutrients with the risk of developing CRC using the Singapore Chinese Health Study (SCHS). Methods. The SCHS is an on-going population-based prospective cohort study that includes 61,321 Chinese men and women in Singapore who were 45-74 years of age at baseline. A 165-item semi-quantitative food frequency questionnaire was used to obtain information of dietary intake. Cox proportional hazard regression models were used to estimate the hazard ratios (HRs) and respective 95% confidence intervals (CIs) for CRC associated with one-carbon metabolism-related nutrients, including thiamine, riboflavin, niacin, vitamin B6, folate acid, vitamin B12, choline, methionine, and betaine, adjusting for potential confounders. Results. After an average of 17.5 years of follow-up, 2,140 participants developed CRC. An inverse association between folate acid and colon cancer. The HRs and respective 95% CIs for quarters 2, 3 and 4 vs. quarter 1 (the lowest quartile) was 0.98 (0.84-1.14), 0.93 (0.79-1.10) and 0.80 (0.64-0.98) (Ptrend=0.04). Similar pattern was observed between folate acid intake and colon cancer risk among never smokers (HRQ4vsQ1=0.67, 95% CI: 0.51-0.86; Ptrend=0.005). No association was found between other one-carbon metabolism-related nutrients and the risk of colorectal cancer Conclusions. In a large on-going prospective cohort study of more than 61,000 Chinese Singaporeans, we found inverse associations between dietary folate acid and the risk of colon cancer. This association was more obvious among never smokers. Our findings provide critical implication for primary prevention and control of colorectal cancer. Citation Format: Yen Thi-Hai Pham, Aizhen Jin, Renwei Wang, Woon-Puay Koh, Jian-Min Yuan, Hung N. Luu. Association between dietary one-carbon metabolism-related nutrients and the risk of colorectal cancer: Findings from the Singapore Chinese Health Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6449.

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

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. 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-1β), and tumour necrosis factor alpha (TNF-α). 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. 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.

Polygenic risk scores for the prediction of common cancers in East Asians: A population-based prospective cohort study.

To evaluate the utility of polygenic risk scores (PRSs) in identifying high-risk individuals, different publicly available PRSs for breast (n=85), prostate (n=37), colorectal (n=22), and lung cancers (n=11) were examined in a prospective study of 21,694 Chinese adults. We constructed PRS using weights curated in the online PGS Catalog. PRS performance was evaluated by distribution, discrimination, predictive ability, and calibration. Hazard ratios (HR) and corresponding confidence intervals (CI) of the common cancers after 20 years of follow-up were estimated using Cox proportional hazard models for different levels of PRS. A total of 495 breast, 308 prostate, 332 female-colorectal, 409 male-colorectal, 181 female-lung, and 381 male-lung incident cancers were identified. The area under receiver operating characteristic curve for the best-performing site-specific PRS were 0.61 (PGS000873, breast), 0.70 (PGS00662, prostate), 0.65 (PGS000055, female-colorectal), 0.60 (PGS000734, male-colorectal), 0.56 (PGS000721, female-lung), and 0.58 (PGS000070, male-lung), respectively. Compared to the middle quintile, individuals in the highest cancer-specific PRS quintile were 64% more likely to develop cancers of the breast, prostate, and colorectal. For lung cancer, the lowest cancer-specific PRS quintile was associated with 28-34% decreased risk compared to the middle quintile. In contrast, the HR observed for quintiles 4 (female-lung: 0.95 [0.61-1.47]; male-lung: 1.14 [0.82-1.57]) and 5 (female-lung: 0.95 [0.61-1.47]) were not significantly different from that for the middle quintile. Site-specific PRSs can stratify the risk of developing breast, prostate, and colorectal cancers in this East Asian population. Appropriate correction factors may be required to improve calibration. This work is supported by the National Research Foundation Singapore (NRF-NRFF2017-02), PRECISION Health Research, Singapore (PRECISE) and the Agency for Science, Technology and Research (A*STAR). WP Koh was supported by National Medical Research Council, Singapore (NMRC/CSA/0055/2013). CC Khor was supported by National Research Foundation Singapore (NRF-NRFI2018-01). Rajkumar Dorajoo received a grant from the Agency for Science, Technology and Research Career Development Award (A*STAR CDA - 202D8090), and from Ministry of Health Healthy Longevity Catalyst Award (HLCA20Jan-0022).The Singapore Chinese Health Study was supported by grants from the National Medical Research Council, Singapore (NMRC/CIRG/1456/2016) and the U.S. National Institutes of Health (NIH) (R01 CA144034 and UM1 CA182876).