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Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci (P < 5 × 10 -8 ). Several of these contain candidate genes (TINF2, PARP1, TERF1, ATM and POT1) with potential roles in telomere biology and DNA repair mechanisms. Meta-analyses with additional 37,505 European individuals reveals six more genome-wide loci, including associations at MPHOSPH6, NKX2-3 and TYMS. We demonstrate that longer LTL associates with protection against respiratory disease mortality [HR = 0.854(0.804-0.906), P = 1.88 × 10 -7 ] in the Singaporean Chinese samples. We further show that the LTL reducing SNP rs7253490 associates with respiratory infections (P = 7.44 × 10 -4 ) although this effect may not be strongly mediated through LTL. Our data expands on the genetic basis of LTL and may indicate on a potential role of LTL in immune competence.

Singapore has experienced a marked increase in colorectal cancer incidence over the past 40 years. Evidence from prospective studies in Western Europe and the USA suggests that low physical activity and high amounts of sedentary time are associated with increased colorectal cancer risk. The aim of this study is to evaluate these relationships in an Asian population. The Singapore Chinese Health Study enrolled 63 257 adults between 1993 and 1998. At enrollment, participants reported past year physical activity and time spent sitting. Incident colorectal cancers (n=1994) were identified through 31 December 2014. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for potential confounders. Any strenuous-vigorous or moderate physical activity was reported by 13.7 and 22.1% of the cohort, respectively. Strenuous-vigorous physical activity was associated with statistically significant reduced colorectal cancer risk (HR=0.85; 95% CI: 0.74-0.99 for ≥0.5 h/week vs. none), but moderate was not. In analysis stratified by time spent watching television, an inverse relationship between moderate physical activity and colorectal cancer risk (HR=0.86; 95% CI: 0.72-1.01 for ≥0.5 h/week vs. none) was observed for those who reported at least 3 h/day sitting watching television (Pinteraction=0.042). Participation in strenuous-vigorous physical activity, such as jogging, swimming, or heavy manual labor, was associated with reduced colorectal cancer risk among Singapore Chinese. Further research on physical activity and sedentary behaviors, independently and in combination, and colorectal cancer risk in Asian populations is needed.

Background: While elevated systolic blood pressure (SBP) is related to cardiovascular disease (CVD) mortality, it is unclear if the optimal SBP level may differ by age or the presence of underlying CVD., Objective: We investigated the association between SBP categories and CVD mortality among middle-aged and elderly adults with and without CVD history., Methods: We used data from 30,692 participants of the population-based Singapore Chinese Health Study who had blood pressures measured using a standard protocol at ages 48-85years between 1994 and 2005. Information on lifestyle factors were collected at recruitment (1993-1998) and during follow-up interviews (1999 and 2004). Mortality was identified via nationwide registry linkage up to 31 December 2014., Results: SBP 120-139mmHg category was associated with lowest risk of CVD mortality in both age-groups of <60 and 60+years, as well as in those with and without underlying coronary heart disease or stroke. Overall, compared to this category, CVD risk was non-significantly increased in lower SBP categories and significantly increased in the higher SBP categories. The risk estimates associated with elevated SBP were higher among those <60years compared to their older counterparts, but less distinct between those with and without underlying CVD., Conclusion: SBP 120-139mmHg was associated with the lowest risk of CVD mortality in middle aged and elderly adults, regardless of underlying CVD. Although risks in both adult groups were similar, there is a greater risk associated with higher SBP among those aged below 60years, highlighting a greater urgency of treatment in this younger group., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Cytochrome P450 2A6 (CYP2A6) catalyzes nicotine metabolism and contributes to the metabolism of the tobacco-specific lung carcinogen, NNK. Genetic variation in CYP2A6 may affect smoking behavior and contribute to lung cancer risk. A nested case-control study of 325 lung cancer cases and 356 controls was conducted within a prospective cohort of 18,244 Chinese men in Shanghai, China. Quantified were 4 allelic variants of CYP2A6 [*1(+51A), *4, *7, and *9] and urinary total nicotine, total cotinine, total trans-3'-hydroxycotinine (3HC) and total NNAL (an NNK metabolite). Calculated were total nicotine equivalents (TNE), the sum of total nicotine, total cotinine and total 3HC and the total 3HC:total cotinine ratio as a measure of CYP2A6 activity. The nicotine metabolizer status (normal, intermediate, slow and poor) was determined by CYP2A6 genotypes. The smoking-adjusted odds ratios (95% confidence intervals) of lung cancer for the highest vs lowest quartile of total nicotine, total cotinine, total 3HC, TNE and total NNAL were 3.03 (1.80-5.10), 4.70 (2.61-8.46), 4.26 (2.37-7.68), 4.71 (2.61-8.52), and 3.15 (1.86-5.33) (all Ptrend  < 0.001), respectively. Among controls CYP2A6 poor metabolizers had a 78% lower total 3HC:total cotinine ratio and 72% higher total nicotine (Ptrend ≤ 0.002). Poor metabolizers had an odds ratio of 0.64 (95% confidence interval = 0.43-0.97) for lung cancer, which was statistically nonsignificant (odds ratio = 0.74, 95% confidence interval = 0.48-1.15) after adjustment for urinary TNE and smoking intensity and duration. The lower lung cancer risk observed in CYP2A6 poor metabolizers is partially explained by the strong influence of CYP2A6 genetic polymorphisms on nicotine uptake and metabolism., (© 2015 UICC.)

Identifying risk factors for future change in sleep duration can clarify whether, and if so how, sleep and morbidity are bidirectionally related. To date, only limited longitudinal evidence exists characterizing changes to sleep duration among older adults. This study aimed to identify factors associated with change in sleep duration in a large sample of older adults (≥ 60 years) residing in Singapore (n = 10 335). These adults were monitored as part of the Singapore Chinese Health Study, which collected information regarding daily sleep duration at baseline (assessed in 1993-1998) and at a follow-up wave conducted over a mean of 12.7 years later (assessed in 2006-2010). Among adults sleeping 6-8 h at baseline (n = 8265), most participants (55.6%) remained 6-8 h sleepers at follow-up, while 8.4% became short (< 6 h) and 36.0% became long (> 8 h) sleepers. A history of stroke, diabetes, cancer, hip fracture and greater age all independently increased the odds of having long sleep duration at follow-up, while greater educational attainment and weekly physical activity were both associated with reduced odds of becoming a long sleeper. Other than greater baseline age, the only factor related to higher odds of becoming a short sleeper was concurrent stomach/duodenal ulcer at follow-up. Long sleep duration among older adults may therefore reflect longstanding disease processes, whereas the aetiology of short sleep may predominately involve factors other than those examined. Future research is needed to distinguish if/when long sleep duration serves the disease recovery process, and when long sleep duration complicates disease and requires sleep medicine interventions., (© 2015 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

While epidemiologic studies suggest that bone turnover biomarkers may predict hip fracture risk, findings are inconsistent and Asian data are lacking. We conducted a matched case-control (1:1) study nested in the Singapore Chinese Health Study, a population-based prospective cohort of Chinese men and women (45-74years) recruited from 1993 to 1998 in Singapore. One hundred cases with incident hip fracture and 100 individually matched controls were randomly selected from 63,257 participants. Serum bone turnover biomarkers, namely bone alkaline phosphatase (bone ALP), osteocalcin (OC), procollagen type I N propeptide (PINP), N-terminal and C-terminal crosslinking telopeptide of type I collagen (NTX-I and CTX-I) were measured using immunoassays. Hip fracture cases had significantly higher serum levels of OC, PINP, CTX-I and NTX-I than controls (p<0.05). There was a dose-dependent positive relationship between OC, PINP, CTX-I and NTX-I and risk of hip fracture (all Ps for trend≤0.006), where the risk was significantly increased by 4.32-8.23 folds for the respective BTM [Quartile (Q) 4 vs. Q1]. The odds ratio [OR (95% CI)] at the highest quartile (Q4) was 6.63 (2.02-21.18) for PINP and 4.92 (1.67-14.51) for CTX-I. The joint effect of PINP and CTX-I showed a 7-fold increase in risk (OR: 7.36; 95% CI: 2.53-21.41) comparing participants with higher levels of PINP (Q4) and CTX-I (Q3-Q4) to those with low levels of PINP (Q1-Q3) and CTX-I (Q1-Q2). Our data demonstrated that higher serum levels of bone turnover biomarkers were associated with increased risk of hip fracture in an Asian population., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Genome-wide association studies (GWAS) have identified genetic factors in type 2 diabetes (T2D), mostly among individuals of European ancestry. We tested whether previously identified T2D-associated single nucleotide polymorphisms (SNPs) replicate and whether SNPs in regions near known T2D SNPs were associated with T2D within the Singapore Chinese Health Study., Methods: 2338 cases and 2339 T2D controls from the Singapore Chinese Health Study were genotyped for 507,509 SNPs. Imputation extended the genotyped SNPs to 7,514,461 with high estimated certainty (r(2)>0.8). Replication of known index SNP associations in T2D was attempted. Risk scores were computed as the sum of index risk alleles. SNPs in regions ± 100 kb around each index were tested for associations with T2D in conditional fine-mapping analysis., Results: Of 69 index SNPs, 20 were genotyped directly and genotypes at 35 others were well imputed. Among the 55 SNPs with data, disease associations were replicated (at p<0.05) for 15 SNPs, while 32 more were directionally consistent with previous reports. Risk score was a significant predictor with a 2.03 fold higher risk CI (1.69-2.44) of T2D comparing the highest to lowest quintile of risk allele burden (p = 5.72 × 10(-14)). Two improved SNPs around index rs10923931 and 5 new candidate SNPs around indices rs10965250 and rs1111875 passed simple Bonferroni corrections for significance in conditional analysis. Nonetheless, only a small fraction (2.3% on the disease liability scale) of T2D burden in Singapore is explained by these SNPs., Conclusions: While diabetes risk in Singapore Chinese involves genetic variants, most disease risk remains unexplained. Further genetic work is ongoing in the Singapore Chinese population to identify unique common variants not already seen in earlier studies. However rapid increases in T2D risk have occurred in recent decades in this population, indicating that dynamic environmental influences and possibly gene by environment interactions complicate the genetic architecture of this disease.

Objective: To evaluate the association between body mass index and mortality from overall cardiovascular disease and specific subtypes of cardiovascular disease in east and south Asians., Design: Pooled analyses of 20 prospective cohorts in Asia, including data from 835,082 east Asians and 289,815 south Asians. Cohorts were identified through a systematic search of the literature in early 2008, followed by a survey that was sent to each cohort to assess data availability., Setting: General populations in east Asia (China, Taiwan, Singapore, Japan, and Korea) and south Asia (India and Bangladesh)., Participants: 1,124,897 men and women (mean age 53.4 years at baseline)., Main Outcome Measures: Risk of death from overall cardiovascular disease, coronary heart disease, stroke, and (in east Asians only) stroke subtypes., Results: 49,184 cardiovascular deaths (40,791 in east Asians and 8393 in south Asians) were identified during a mean follow-up of 9.7 years. East Asians with a body mass index of 25 or above had a raised risk of death from overall cardiovascular disease, compared with the reference range of body mass index (values 22.5-24.9; hazard ratio 1.09 (95% confidence interval 1.03 to 1.15), 1.27 (1.20 to 1.35), 1.59 (1.43 to 1.76), 1.74 (1.47 to 2.06), and 1.97 (1.44 to 2.71) for body mass index ranges 25.0-27.4, 27.5-29.9, 30.0-32.4, 32.5-34.9, and 35.0-50.0, respectively). This association was similar for risk of death from coronary heart disease and ischaemic stroke; for haemorrhagic stroke, the risk of death was higher at body mass index values of 27.5 and above. Elevated risk of death from cardiovascular disease was also observed at lower categories of body mass index (hazard ratio 1.19 (95% confidence interval 1.02 to 1.39) and 2.16 (1.37 to 3.40) for body mass index ranges 15.0-17.4 and <15.0, respectively), compared with the reference range. In south Asians, the association between body mass index and mortality from cardiovascular disease was less pronounced than that in east Asians. South Asians had an increased risk of death observed for coronary heart disease only in individuals with a body mass index greater than 35 (hazard ratio 1.90, 95% confidence interval 1.15 to 3.12)., Conclusions: Body mass index shows a U shaped association with death from overall cardiovascular disease among east Asians: increased risk of death from cardiovascular disease is observed at lower and higher ranges of body mass index. A high body mass index is a risk factor for mortality from overall cardiovascular disease and for specific diseases, including coronary heart disease, ischaemic stroke, and haemorrhagic stroke in east Asians. Higher body mass index is a weak risk factor for mortality from cardiovascular disease in south Asians.

Mitochondrial DNA (mtDNA) copy number in peripheral blood is associated with increased risk of several cancers. However, data from prospective studies on mtDNA copy number and breast cancer risk are lacking. We evaluated the association between mtDNA copy number in peripheral blood and breast cancer risk in a nested case-control study of 183 breast cancer cases with pre-diagnostic blood samples and 529 individually matched controls among participants of the Singapore Chinese Health Study. The mtDNA copy number was measured using real time PCR. Conditional logistic regression analyses showed that there was an overall positive association between mtDNA copy number and breast cancer risk (P(trend) = 0.01). The elevated risk for higher mtDNA copy numbers was primarily seen for women with <3 years between blood draw and cancer diagnosis; ORs (95% CIs) for 2(nd), 3(rd), 4(th), and 5(th) quintile of mtDNA copy number were 1.52 (0.61, 3.82), 2.52 (1.03, 6.12), 3.12 (1.31, 7.43), and 3.06 (1.25, 7.47), respectively, compared with the 1(st) quintile (P(trend) = 0.004). There was no association between mtDNA copy number and breast cancer risk among women who donated a blood sample ≥3 years before breast cancer diagnosis (P(trend) = 0.41). This study supports a prospective association between increased mtDNA copy number and breast cancer risk that is dependent on the time interval between blood collection and breast cancer diagnosis. Future studies are warranted to confirm these findings and to elucidate the biological role of mtDNA copy number in breast cancer risk.

Cigarette smoking is a risk factor for colorectal cancer. Putative colorectal procarcinogens in tobacco smoke include polycyclic aromatic hydrocarbons and heterocyclic aromatic amines that are known substrates of glutathione S-transferases (GSTs). This study examined the influence of functional GST gene polymorphisms on the smoking-colorectal cancer association in a population known to be minimally exposed to dietary sources of these procarcinogens. Incident cases of colorectal cancer (n = 480) and matched controls (n = 1167) were selected from the Singapore Chinese Health Study, a population-based prospective cohort of 63 257 men and women who have been followed since 1993. We determined the deletion polymorphisms of GSTM1 and GSTT1 and the functional polymorphism at codon 105 of GSTP1 for each subject. A three level composite GST index was used to examine if GST profile affected a smoker's risk of developing colorectal cancer. While there was no statistically significant association between cigarette smoking and colorectal cancer risk among subjects absent of any at-risk GST genotypes, smokers possessing two to three at-risk GST genotypes exhibited a statistically significant increased risk of colorectal cancer compared with non-smokers (P = 0.0002). In this latter stratum, heavy smokers exhibited a >5-fold increased risk relative to never-smokers (odds ratio, 5.43; 95% confidence interval, 2.22-13.23). Subjects with one at-risk GST genotype displayed a statistically significant but weaker association with smoking. These findings suggest that GST gene polymorphisms influence interindividual susceptibility to smoking-associated colorectal cancer. Our data indicate an important role for GST enzymes in the detoxification of colorectal carcinogens in tobacco smoke.

Background: Coffee consumption has been associated with reduced markers of hepatic cell damage, reduced risk of chronic liver disease, and cirrhosis across a variety of populations. Data on the association between coffee consumption and risk of hepatocellular carcinoma (HCC), especially in high-risk populations, are sparse., Methods: This study examines the relationship between coffee and caffeine consumption, and the risk of developing HCC within the Singapore Chinese Health Study, a prospective cohort of 63,257 middle-aged and older Chinese men and women, a relatively high-risk population for HCC. Baseline data on coffee consumption and other dietary and lifestyle factors were collected through in-person interviews at enrollment between 1993 and 1998., Results: As of 31 December 2006, 362 cohort participants had developed HCC. High levels of coffee or caffeine consumption were associated with reduced risk of HCC (p for trend < 0.05). Compared with non-drinkers of coffee, individuals who consumed three or more cups of coffee per day experienced a statistically significant 44% reduction in risk of HCC (hazard ratio 0.56, 95% confidence interval, 0.31-1.00, p = .049) after adjustment for potential confounders and tea consumption., Conclusion: These data suggest that coffee consumption may reduce the risk of developing HCC in Chinese in Singapore.

Background: Most studies that have evaluated the association between the body-mass index (BMI) and the risks of death from any cause and from specific causes have been conducted in populations of European origin., Methods: We performed pooled analyses to evaluate the association between BMI and the risk of death among more than 1.1 million persons recruited in 19 cohorts in Asia. The analyses included approximately 120,700 deaths that occurred during a mean follow-up period of 9.2 years. Cox regression models were used to adjust for confounding factors., Results: In the cohorts of East Asians, including Chinese, Japanese, and Koreans, the lowest risk of death was seen among persons with a BMI (the weight in kilograms divided by the square of the height in meters) in the range of 22.6 to 27.5. The risk was elevated among persons with BMI levels either higher or lower than that range--by a factor of up to 1.5 among those with a BMI of more than 35.0 and by a factor of 2.8 among those with a BMI of 15.0 or less. A similar U-shaped association was seen between BMI and the risks of death from cancer, from cardiovascular diseases, and from other causes. In the cohorts comprising Indians and Bangladeshis, the risks of death from any cause and from causes other than cancer or cardiovascular disease were increased among persons with a BMI of 20.0 or less, as compared with those with a BMI of 22.6 to 25.0, whereas there was no excess risk of either death from any cause or cause-specific death associated with a high BMI., Conclusions: Underweight was associated with a substantially increased risk of death in all Asian populations. The excess risk of death associated with a high BMI, however, was seen among East Asians but not among Indians and Bangladeshis.

Consumption of dairy products, the primary source of calcium in Western diets, has been found to be positively associated with prostate cancer. In an Asian diet, nondairy foods are the major contributors of calcium. Thus, a study of dietary calcium and prostate cancer in Asians can better inform on whether calcium, as opposed to other dairy components, is responsible for the dairy foods-prostate cancer association. We examined calcium intake and prostate cancer risk among 27,293 men in the Singapore Chinese Health Study that was established between 1993 and 1998. As of December 31, 2007, 298 incident prostate cancer cases had been diagnosed among the cohort members. Diet was assessed at baseline with a validated 165-item food-frequency questionnaire. It is hypothesized that there is greater net absorption of calcium in smaller individuals. Therefore, the calcium-prostate cancer association was also assessed in stratified analyses by median body mass index. Vegetables were the largest contributor of daily calcium intake in the study population. Overall, we observed a modest, statistically nonsignificant 25% increase in prostate cancer risk for the 4th (median = 659 mg/d) versus 1st (median = 211 mg/d) quartiles of calcium intake after adjustment for potential confounders. The association became considerably stronger and achieved statistical significance (hazard ratio, 2.03; 95% confidence interval, 1.23-3.34; P for trend = 0.01) for men with a below median body mass index (22.9 kg/m(2)). Dietary calcium might be a risk factor for prostate cancer even at relatively low intake.

Prospective epidemiologic studies conducted in Western populations support an association between current smoking and aggressive subtypes of prostate cancer. In Singapore, where prostate-specific antigen is not used for population-wide screening, prostate cancer incidence has tripled within the past two decades. Using Cox regression methods, we examined the relationship between smoking and prostate cancer established between 1993 and 1998 in a cohort of 27,293 Singapore Chinese men. As of December 2006, 250 incident prostate cancer cases were diagnosed. In our cohort, 42.2% reported never smoking cigarettes, 15.7% quit over 5 years ago (long-term former), 5.7% quit within the past 5 years (recent former), and 36.4% were current smokers. From multivariable models, we observed no association with smoking status, age at starting to smoke, years smoked, or number of cigarettes per day. Among recent former and current smokers combined, we observed a small positive association for earlier age at starting to smoke that was somewhat stronger for nonadvanced disease (hazard ratio = 1.63, 95% confidence interval: 0.85, 3.12, for <15 years versus nonsmokers). Smoking was not a major risk factor for prostate cancer in our Singapore Chinese cohort, a traditionally low risk population with parallel increases in incidence and mortality.

Although there is some epidemiologic evidence that soy may reduce risk of osteoporotic fracture in women, it is not known whether this risk reduction also occurs for men. The authors examined gender-specific associations between soy intake and hip fracture risk in the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese living in Singapore. At recruitment between 1993 and 1998, each subject was administered a food frequency questionnaire and questions on medical history and lifestyle factors. As of December 31, 2006, 276 incident cases of hip fracture in men and 692 cases in women were identified via linkage with hospital discharge databases. For both genders, hip fracture risk was positively associated with cigarette smoking and was inversely associated with body mass index. There was a statistically significant association of tofu equivalents, soy protein, and isoflavones with hip fracture risk among women but not among men. Compared with women in the lowest quartile of intakes for tofu equivalents (<49.4 g/day), soy protein (<2.7 g/day), and isoflavones (<5.8 mg/1,000 kcal/day), those in the second-fourth quartiles exhibited 21%-36% reductions in risk (all P < 0.036). Risk levels were comparable across the second, third, and fourth quartiles of soy intake categories.

BackgroundAlthough studies suggest that omega-3 fatty acids intake may reduce cardiovascular disease (CVD) mortality risk, few studies have differentiated dietary eicosapentaenoic/docosahexaenoic acid (EPA/DHA) from alpha-linolenic acid (ALA), and epidemiological research in Asian populations is limited.MethodsThe Singapore Chinese Health Study is a population-based cohort that recruited 63,257 Chinese adults aged 45-74 years from 1993 to 1998. Usual diet was measured at recruitment using a validated semiquantitative food-frequency questionnaire, and mortality information was identified via registry linkage up to 31 December 2011. Cox proportional hazard models were used to calculate hazard ratios (HRs) with adjustment for potential confounders.ResultsWe documented 4780 cardiovascular deaths (including 2697 coronary heart disease (CHD) deaths and 1298 stroke deaths) during 890,473 person-years of follow up. Omega-3 fatty acids intake was monotonically associated with reduced risk of cardiovascular mortality. Compared to the lowest quartile, the HR was 0.88 (95% confidence interval, CI, 0.81-0.96), 0.88 (95% CI 0.80-0.97), and 0.83 (95% CI 0.74-0.92) for the second, third, and highest quartile, respectively (p-trend = 0.003). Both EPA/DHA and ALA were independently associated with reduced risk of cardiovascular mortality: HR comparing extreme quartiles was 0.86 (95% CI 0.77-0.96, p-trend = 0.002) and 0.81 (95% CI 0.73-0.90, p-trend