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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., Competing Interests: The authors have declared that no competing interests exist.

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., (© 2019 The Authors. Health Economics published by John Wiley & Sons Ltd.)

Background: Little 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., Methods: In this pooled analysis of 738 013 Asians from 16 prospective cohorts, we quantified the associations of low-intensity (<5 cigarettes/day) and late initiation (≥35 years) of smoking with mortality outcomes. HRs and 95% CIs were estimated for each cohort by Cox regression. Cohort-specific HRs were pooled using random-effects meta-analysis., Findings: During a mean follow-up of 11.3 years, 92 068 deaths were ascertained. Compared with never smokers, current smokers who consumed <5 cigarettes/day or started smoking after age 35 years had a 16%-41% increased risk of all-cause, cardiovascular disease (CVD), respiratory disease mortality and a >twofold risk of lung cancer mortality. Furthermore, current smokers who started smoking after age 35 and smoked <5 cigarettes/day had significantly elevated risks of all-cause (HRs (95% CIs)=1.14 (1.05 to 1.23)), CVD (1.27 (1.08 to 1.49)) and respiratory disease (1.54 (1.17 to 2.01)) mortality. Even smokers who smoked <5 cigarettes/day but quit smoking before the age of 45 years had a 16% elevated risk of all-cause mortality; however, the risk declined further with increasing duration of abstinence., Conclusions: Our 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear., Methods: We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided., Results: Over a period of 38 369 156 person-years of follow-up, 1391 gallbladder, 758 intrahepatic bile duct, 1208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all Ptrend < .01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (eg, >40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; Ptrend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; Ptrend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers., Conclusions: Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract., (Published by Oxford University Press 2019. This work is written by US Government employees and is in the public domain in the United States.)

Background: To date, few epidemiologic studies have been conducted to elucidate lifestyle-related risk factors for multiple myeloma in Asia. We investigated the association of body mass index (BMI), smoking, and alcohol intake with the risk of multiple myeloma mortality through a pooled analysis of more than 800,000 participants in the Asia Cohort Consortium., Methods: The analysis included 805,309 participants contributing 10,221,623 person-years of accumulated follow-up across Asia Cohort Consortium cohorts. HRs and 95% confidence intervals (95% CI) for the association between BMI, smoking, and alcohol at baseline and the risk of multiple myeloma mortality were assessed using a Cox proportional hazards model with shared frailty., Results: We observed a statistically significant dose-dependent association between BMI categories and the risk of multiple myeloma mortality (<18.5 kg/m 2 : HR = 0.80, 95% CI: 0.52-1.24; 18.5-24.9 kg/m 2 : reference; 25.0-29.9 kg/m 2 : HR = 1.17, 95% CI: 0.94-1.47; ≥30 kg/m 2 : HR = 1.61, 95% CI: 0.99-2.64, P = 0.014). By sex, this association was more apparent in women than in men (P for heterogeneity between sexes = 0.150). We observed no significant associations between smoking or alcohol consumption and risk of multiple myeloma mortality.trend = 0.014). By sex, this association was more apparent in women than in men (P for heterogeneity between sexes = 0.150). We observed no significant associations between smoking or alcohol consumption and risk of multiple myeloma mortality., Conclusions: This study showed that excess body mass is associated with an increased risk of multiple myeloma mortality among Asian populations. In contrast, our results do not support an association between smoking or alcohol consumption and the risk of multiple myeloma mortality in Asian populations., Impact: This study provides important evidence on the association of BMI, smoking, and alcohol with the risk of multiple myeloma mortality in Asian populations., (©2019 American Association for Cancer Research.)

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The concentrations of high- and low-density-lipoprotein cholesterol and triglycerides are influenced by smoking, but it is unknown whether genetic associations with lipids may be modified by smoking. We conducted a multi-ancestry genome-wide gene-smoking interaction study in 133,805 individuals with follow-up in an additional 253,467 individuals. Combined meta-analyses identified 13 new loci associated with lipids, some of which were detected only because association differed by smoking status. Additionally, we demonstrate the importance of including diverse populations, particularly in studies of interactions with lifestyle factors, where genomic and lifestyle differences by ancestry may contribute to novel findings.

Background: the relations of cigarette smoking and alcohol drinking with risk of cognitive impairment remain inconsistent., Methods: to examine the independent and joint relations of smoking and alcohol drinking with cognitive impairment, we used data from 16,948 men and women, who had been followed-up for 16-23 (mean of 20) years as participants of the Singapore Chinese Health Study, a population-based prospective cohort. Data on smoking and alcohol drinking were collected at baseline (1993-98), when participants were aged 45-74 (mean 53) years. Cognition was assessed using a 30-item Mini-Mental State Examination during follow-up three visits (2014-16), when participants were aged 61-96 (mean 73) years. Multivariable logistic regression models were used to estimate the odd ratios (ORs) and 95% confidence intervals (CIs)., Results: cognitive impairment was present in 2,443 (14.4%) participants. Compared with non-current smokers, current smokers had 20% increased risk (OR = 1.20, 95% CI = 1.04-1.39). Compared with those who drank less than weekly, regular alcohol drinking (at least weekly) had 17% increased risk (OR = 1.17, 95% CI = 1.01-1.36). Compared with those who were neither smokers nor drinkers, those who were either current smokers or regular drinkers alone had no significantly increased risk, while the risk was highest in those who were both current smokers and regular drinkers (OR = 1.77, 95% CI = 1.39-2.26, Pinteraction = 0.003)., Conclusions: co-existence of smoking and regular alcohol drinking at midlife had a much stronger impact than the individual factors on risk of cognitive impairment in late life.

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10 -8 ) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10 -8 ). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2)., (Copyright © 2018 American Society of Human Genetics. All rights reserved.)

Background: Incidence of gastric cancer is the highest in Eastern Asia. Multiple modifiable lifestyle factors have been identified as risk factors for gastric cancer. However, their aggregated effect on the risk of gastric cancer has not been examined among populations with high prevalence of Helicobacter pylori., Methods: A study was conducted to examine the association between multiple lifestyle factors together and the risk of developing gastric adenocarcinoma in the Singapore Chinese Health Study, a prospective cohort of 63 257 men and women between 45 and 74 years enroled during 1993-1998. Composite score of cigarette smoking, alcohol consumption, obesity, dietary pattern, and sodium intake at baseline was assessed with hazard ratio (HR) and 95% confidence interval (CI) of gastric adenocarcinoma using Cox regression method., Results: Higher healthy composite lifestyle scores were significantly associated with reduced risk of gastric adenocarcinoma in a dose-dependent manner. Hazard ratios (95% CIs) for total, cardia, and non-cardia gastric adenocarcinoma for the highest (score 5) vs lowest composite score (score 0/1/2) were 0.42 (0.31-0.57), 0.22 (0.10-0.47), and 0.55 (0.39-0.78), respectively (all P trend <0.001). These lifestyles together accounted for 48% of total gastric adenocarcinoma cases in the study population. The inverse association was observed in both genders, and remained after exclusion of first 5 years of follow-up., Conclusions: The inverse association between the aggregated healthy lifestyle factors and the risk of gastric adenocarcinoma is in dose-dependent manner in this highly H. pylori-exposed population. These lifestyle factors together may account for up to half of disease burden in this study population.

Objective: Cigarette smoking is shown to reduce serum urate. However, its impact on risk of gout is unknown. We prospectively examined the relationship between cigarette smoking and gout risk in this Asian cohort., Methods: We analyzed the data from the Singapore Chinese Health Study, a cohort of 63,257 Chinese ages 45-74 years at recruitment in 1993-1998. Information on cigarette smoking and other lifestyle factors was collected through in-person interviews at recruitment. This analysis included 53,213 participants who took part in either the first followup (1999-2004) and/or the second followup interviews (2006-2010). Cox proportional hazards models were used to assess the relationship between cigarette smoking and gout risk., Results: A total of 2,244 incident cases of physician-diagnosed gout were identified after a mean followup of 11.1 years. Among men, compared to never smokers, the risk of gout in current smokers was decreased by 27% (hazard ratio [HR] 0.73 [95% confidence interval (95% CI) 0.63-0.84]). This risk reduction was greater in lean male smokers (HR 0.69 [95% CI 0.57-0.83]) than overweight smokers (HR 0.87 [95% CI 0.67-1.13]) (P = 0.09 for interaction). This inverse association with smoking was rapidly attenuated to become null even in former smokers who had recently quit smoking. Conversely, there was no association between smoking and gout risk in women. In a companion cross-sectional study, current smokers had significantly lower levels of serum urate than former and never smokers, and this observation was present in men and not women., Conclusion: Current smoking is associated with lower risk of gout in men in this Asian cohort., (© 2016, American College of Rheumatology.)

Many potentially modifiable risk factors for prostate cancer are also associated with prostate cancer screening, which may induce a bias in epidemiologic studies. We investigated the associations of body mass index (weight (kg)/height (m)(2)), smoking, and alcohol consumption with risk of fatal prostate cancer in Asian countries where prostate cancer screening is not widely utilized. Analysis included 18 prospective cohort studies conducted during 1963-2006 across 6 countries in southern and eastern Asia that are part of the Asia Cohort Consortium. Body mass index, smoking, and alcohol intake were determined by questionnaire at baseline, and cause of death was ascertained through death certificates. Analysis included 522,736 men aged 54 years, on average, at baseline. During 4.8 million person-years of follow-up, there were 634 prostate cancer deaths (367 prostate cancer deaths across the 11 cohorts with alcohol data). In Cox proportional hazards analyses of all cohorts in the Asia Cohort Consortium, prostate cancer mortality was not significantly associated with obesity (body mass index >25: hazard ratio (HR) = 1.08, 95% confidence interval (CI): 0.85, 1.36), ever smoking (HR = 1.00, 95% CI: 0.84, 1.21), or heavy alcohol intake (HR = 1.00, 95% CI: 0.74, 1.35). Differences in prostate cancer screening and detection probably contribute to differences in the association of obesity, smoking, or alcohol intake with prostate cancer risk and mortality between Asian and Western populations and thus require further investigation., (© The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Paraoxonase 1 (PON1) plays an important role in reducing the risk of coronary heart disease (CHD). Smoking is known to reduce PON1 activity. We aimed to investigate the effects of interactions between PON1 variants and smoking on CHD in the Singaporean Chinese population., Methods: In a case-control study nested within Singapore Chinese Health Study (N=1914), subjects with and without CHD were classified into never-smokers and ever-smokers (ever smoked at least one cigarette a day for 1 year or longer). Associations at four independent SNPs at the PON1 locus (rs3735590, rs3917550, rs662, rs3917481) with CHD were evaluated using logistic regression, before/after stratification on smoking status. Interactions between smoking and PON1 variants were analyzed with likelihood ratio tests, by including the SNP*smoking interaction term in regression analyses., Results: The T allele at the coding SNP, rs662, was associated with higher risk of CHD in ever-smokers only (OR=1.35, 95% CI 1.08-1.68; adjusted P=0.036). At the miR-SNP, rs3735590, carrying at least one copy of minor allele T was associated with increased risk of CHD in a dominant manner in never-smokers only (OR=1.53, 95% CI 1.11-2.11; adjusted P=0.036). Significant interactions between two PON1 SNPs and smoking in relation to CHD risk were identified (adjusted P=0.012 for rs662; adjusted P=0.044 for rs3735590). These associations remained significant after adjustment for known CHD risk factors and upon correction for multiple tests., Conclusions: Two PON1 SNPs, rs662 and rs3735590, were found to significantly interact with cigarette smoking to modulate the risk of CHD in the Singaporean Chinese population., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Tobacco smoking is a major risk factor for many diseases. We sought to quantify the burden of tobacco-smoking-related deaths in Asia, in parts of which men's smoking prevalence is among the world's highest., Methods and Findings: We performed pooled analyses of data from 1,049,929 participants in 21 cohorts in Asia to quantify the risks of total and cause-specific mortality associated with tobacco smoking using adjusted hazard ratios and their 95% confidence intervals. We then estimated smoking-related deaths among adults aged ≥45 y in 2004 in Bangladesh, India, mainland China, Japan, Republic of Korea, Singapore, and Taiwan-accounting for ∼71% of Asia's total population. An approximately 1.44-fold (95% CI = 1.37-1.51) and 1.48-fold (1.38-1.58) elevated risk of death from any cause was found in male and female ever-smokers, respectively. In 2004, active tobacco smoking accounted for approximately 15.8% (95% CI = 14.3%-17.2%) and 3.3% (2.6%-4.0%) of deaths, respectively, in men and women aged ≥45 y in the seven countries/regions combined, with a total number of estimated deaths of ∼1,575,500 (95% CI = 1,398,000-1,744,700). Among men, approximately 11.4%, 30.5%, and 19.8% of deaths due to cardiovascular diseases, cancer, and respiratory diseases, respectively, were attributable to tobacco smoking. Corresponding proportions for East Asian women were 3.7%, 4.6%, and 1.7%, respectively. The strongest association with tobacco smoking was found for lung cancer: a 3- to 4-fold elevated risk, accounting for 60.5% and 16.7% of lung cancer deaths, respectively, in Asian men and East Asian women aged ≥45 y., Conclusions: Tobacco smoking is associated with a substantially elevated risk of mortality, accounting for approximately 2 million deaths in adults aged ≥45 y throughout Asia in 2004. It is likely that smoking-related deaths in Asia will continue to rise over the next few decades if no effective smoking control programs are implemented. Please see later in the article for the Editors' Summary.

Objective: This study determines if recent smoking cessation, compared with long-term cessation, can reduce mortality risk associated with smoking., Methods: Data from the Singapore Chinese Health Study, a cohort study of middle-aged and elderly Chinese in Singapore, were analysed (n=48 251). Smoking status was evaluated at recruitment between 1993 and 1998 and reassessed between 1999 and 2004. Participants were classified as never-smokers, long-term quitters (quit before recruitment, mean 17.0 years), new quitters (quit between recruitment and second interview, mean 4.3 years) and current smokers. Mortality was ascertained by linkage with the nationwide death registry., Results: After a mean follow-up of 8.1 years, 6003 deaths had occurred by 31 December 2009. Compared with current smokers, the adjusted HR (95% CI) for total mortality was 0.84 (0.76 to 0.94) for new quitters, 0.61 (0.56 to 0.67) for long-term quitters and 0.49 (0.46 to 0.53) for never-smokers. New quitters had 24% reduction in lung cancer mortality (HR: 0.76, 95% CI 0.57 to 1.00) and long-term quitters had 56% reduction (HR: 0.44, 95% CI 0.35 to 0.57). Risk for coronary heart disease mortality was reduced in new quitters (HR: 0.84, 95% CI 0.66 to 1.08) and long-term quitters (HR: 0.63, 95% CI 0.52 to 0.77), although the result for new quitters was of borderline significance due to relatively small number of cardiovascular deaths. Risk for chronic pulmonary disease mortality was reduced in long-term quitters but increased in new quitters., Conclusion: Significant reduction in risk of total mortality, specifically for lung cancer mortality, can be achieved within 5 years of smoking cessation.

Background: The relationship between smoking and risk of kidney failure, especially in people of Chinese origin, is not clear. We analyzed data from the Singapore Chinese Health Study to investigate whether smoking increases the risk of kidney failure., Methods: The Singapore Chinese Health Study is a population-based cohort of 63,257 Chinese adults enrolled between 1993 and 1998. Information on smoking status was collected at baseline. Incidence of kidney failure was identified via record linkage with the nationwide Singapore Renal Registry until 2008. Kidney failure was defined by one of the following: 1) serum creatinine level of more than or equal to 500 µmol/l (5.7 mg/dl), 2) estimated glomerular filtration rate of less than 15 ml/min/1.73 m(2), 3) undergoing hemodialysis or peritoneal dialysis, 4) undergone kidney transplantation. Cox proportional hazard regression analysis was performed for the outcome of kidney failure after adjusting for age, education, dialect, herbal medications, body mass index, sex, physician-diagnosed hypertension and diabetes mellitus., Results: The mean age of subjects was 55.6 years at baseline, and 44% were men. Overall 30.6% were ever smokers (current or former) at baseline. A total of 674 incident cases of kidney failure occurred during a median follow-up of 13.3 years. Among men, smokers had a significant increase in the adjusted risk of kidney failure [hazard ratio (HR): 1.29; 95% CI: 1.02-1.64] compared to never smokers. There was a strong dose-dependent association between number of years of smoking and kidney failure, (p for trend = 0.011). The risk decreased with prolonged cessation (quitting ≥10 years since baseline). The number of women smokers was too few for conclusive relationship., Limitation: Information on baseline kidney function was not available., Conclusions: Cigarette smoking is associated with increased risk of kidney failure among Chinese men. The risk appears to be dose- and duration-dependent and modifiable after long duration of cessation.

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.

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.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (sum of which is denoted as total NNAL) are metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). NNK and NNAL can induce lung cancer in laboratory animals but human data are limited. The association between prediagnostic levels of urinary total NNAL and risk of lung cancer development was evaluated in two prospective cohorts of Chinese cigarette smokers. We conducted a nested case-control study involving 246 cases of incident lung cancer and 245 cohort controls who were individually matched to the index cases by age, gender, neighborhood of residence at cohort enrollment, and date of urine collection. Urinary levels of total NNAL were significantly associated with risk of lung cancer in a dose-dependent manner. Relative to the lowest tertile, risks associated with the second and third tertiles of total NNAL were 1.43 [95% confidence interval (95% CI), 0.86-2.37] and 2.11 (95% CI, 1.25-3.54), respectively (P for trend=0.005) after adjustment for self-reported smoking history and urinary total cotinine. Smokers in the highest tertiles of urinary total NNAL and total cotinine exhibited a 8.5-fold (95% CI, 3.7-19.5) increased risk for lung cancer relative to smokers with comparable smoking history but possessing the lowest tertiles of urinary total NNAL and total cotinine. Findings of the present study directly link NNK exposure to lung cancer development in humans.

Objectives: We examined the association among cigarette smoking, smoking cessation and a broad range of cancer incidence and all cause and cause-specific mortality in a population-based cohort of adults of Chinese ethnicity in Singapore., Methods: Subjects were 61,320 participants of the Singapore Chinese Health Study (44.5% men, aged 45-74 years, recruitment from 1993-1998) who were free of cancer at the baseline examination. Main outcomes-of-interest included cancer incidence, all cause and cause-specific mortality as of December 31, 2005., Results: Cigarette smoking was positively associated with overall cancer incidence, including cancers at the following specific sites: head and neck region, upper gastrointestinal tract, hepatobiliary and pancreas cancer, lung, and bladder/renal pelvis cancer. Compared to never smokers, the relative risk (RR) (95% confidence interval [CI]) of cancer incidence (all cancer sites) among current smokers smoking >22 cigarettes/day was 1.9 (1.7-2.1), p-trend<0.0001. Similarly, cigarette smoking was associated with all cause and cause-specific mortality, including deaths due to cancer, ischemic heart disease, other heart diseases, and chronic obstructive pulmonary disease. Compared to never smokers, RR (95%CI) of all cause mortality among current smokers smoking >22 cigarettes/day was 1.8 (1.6-2.0), p-trend<0.0001. Also, relative to current smokers, ex-smokers experienced reduced cancer incidence and total mortality. The population attributable risk of smoking in men for cancer incidence as well as all-cause mortality was 23%, whereas in women it ranged from 4-5%., Conclusions: Cigarette smoking is an important risk factor for cancer incidence and major causes of mortality in Chinese men and women of Singapore.

Recently, we reported that among Singapore Chinese, cigarette smoking and alcohol drinking were independent risk factors for colorectal cancer. Both tobacco smoking and alcohol use are plausible colorectal cancer risk factors, partly due to their ability to induce mutations in the colorectal lumen. In the present study, we investigated the role in colorectal cancer of single-nucleotide polymorphisms in five DNA repair genes: XRCC1 (Arg(194)Trp and Arg(399)Gln), PARP (Val(762)Ala, Lys(940)Arg), XPD (Asp(312)Asn, Lys(751)Gln), OGG1 (Ser(326)Cys), and MGMT (Leu(84)Phe). We conducted this study within the Singapore Chinese Health Study, a population-based cohort of 63,257 middle-aged and older Singapore Chinese men and women enrolled between 1993 and 1998. Our study included 1,176 controls and 310 cases (180 colon and 130 rectum cancer). We observed a positive association between the PARP codon 940 Lys/Arg and Arg/Arg genotypes and colorectal cancer risk [odds ratio (OR), 1.8; 95% confidence interval (95% CI), 1.1-3.1], and an inverse association between the MGMT codon 84 Leu/Phe or Phe/Phe genotypes and colon cancer risk (OR, 0.6; 95% CI, 0.3-0.9), but not rectal cancer (test of heterogeneity by tumor site, P=0.027). We observed evidence that XRCC1 may modify the effects of smoking (interaction P=0.012). The effect of smoking among carriers of the Arg(194)-Gln(399) haplotype was OR=0.7 (95% CI, 0.4-1.1), whereas, among carriers of the Trp(194)-Arg(399) haplotype, it was OR=1.6 (95% CI, 1.1-2.5). We also observed a nonstatistically significant modification of XRCC1 on the effects of alcohol (P=0.245). Whereas alcohol had no effect among carriers of the codon 194 Arg/Arg (OR, 1.0; 95% CI, 0.6-1.7) or Arg/Trp genotypes (OR, 1.1; 95% CI, 0.6-1.9), there was a positive association among carriers of the Trp/Trp genotype (OR, 2.8; 95% CI, 1.0-8.1). Our results support a role for reactive oxygen species as relevant genotoxins that may account for the effects of both smoking and alcohol on colorectal cancer risk.

Although studies in Western populations have shown that smokers have decreased dietary intakes of antioxidants and other health-related nutrients, this has not been established in oriental populations. This study aimed to identify differences in dietary and lifestyle characteristics between current, former, and never-smokers among middle-aged and older Chinese in Singapore. The subjects, 45-74 y old, were participants in the Singapore Chinese Health Study, a prospective cohort that enrolled 63,257 (27,959 men and 35,298 women) Chinese in Singapore between 1993 and 1998. Data on current dietary habits (using a validated, semiquantitative FFQ) and other lifestyle factors were collected through face-to-face interviews. Mean daily intakes of various nutrients were estimated using a food composition table that was specifically developed for this population. The current smoking rates were 36% in men and 6% in women; an additional 22% of men and 3% of women were former smokers. In both sexes, current smokers were less educated, had lower BMI, led a more sedentary lifestyle, and drank more alcohol and coffee than those who never smoked. Current smokers had dose-dependent decreases in the intakes of a wide range of antioxidants, vitamins, fiber, and calcium, but increases in the intakes of cholesterol and nitrosamines compared with people who never smoked. Former smokers had dietary intakes that either were similar to never-smokers or intermediate between current and never-smokers. Our results are consistent with findings among Western populations, and suggest that the unhealthy diet and lifestyle in smokers occur across diverse cultures.

BackgroundLimited research has examined the association between dietary patterns and mortality, especially in non-Western populations.ObjectiveWe examined the association of dietary patterns with all-cause mortality and cause-specific mortality in the Singapore Chinese Health Study, which included a unique ethnic population with strong Western and South Asian cultural influences.DesignWe conducted a prospective data analysis of the Singapore Chinese Health Study, which included 52,584 Chinese men and women (aged 45-74 y) who were free of diabetes, cardiovascular disease (CVD), and cancer at baseline (1993-1998) and followed through 2011 with 10,029 deaths. The following 2 major dietary patterns were identified by using a principal components analysis: a vegetable-, fruit-, and soy-rich (VFS) pattern and a dim sum- and meat-rich (DSM) dietary pattern. Pattern scores for each participant were calculated and examined with all-cause and cause-specific mortality risks by using a Cox proportional hazards regression.ResultsThe VFS pattern was inversely associated with all-cause mortality and each cause-specific category (CVD, cancer, and respiratory) of mortality during the follow-up period. Compared with the lowest quintile of the VFS pattern, HRs for quintiles 2-5 for all-cause mortality were 0.90, 0.79, 0.80, and 0.75, respectively (P-trend < 0.0001). The DSM pattern was positively associated with CVD mortality in the whole population (HR for fifth quintile compared with first quintile: 1.23; 95% CI: 1.07, 1.40; P-trend = 0.001). Positive associations between the DSM pattern and cancer and all-cause mortality were only present in ever-smokers. In ever-smokers, relative to the first quintile, HRs for quintiles 2-5 of the DSM pattern for all-cause mortality were 1.04, 1.04, 1.13, and 1.24, respectively (P-trend < 0.0001). Similarly, HRs for quintiles 2-5 for cancer mortality were 1.08, 1.03, 1.25, and 1.34, respectively (P-trend < 0.0001). The DSM pattern was not associated with respiratory mortality.ConclusionDietary patterns are strongly associated with mortality in Chinese Singaporeans.

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. [ABSTRACT FROM AUTHOR]

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 (P trend < .0001). The HR for those with 5 factors was ~1.5 times the product of individual risk estimates from the 5 factors on a multiplicative scale. The stepwise increase in risk of active tuberculosis with increasing number of lifestyle risk factors was significantly stronger in participants with diabetes than their counterparts without diabetes at recruitment (P interaction = .01). Conclusions Multiple lifestyle risk factors were associated with risk of active tuberculosis in a synergistic manner. Our findings highlight the importance of public health programs and interventions targeting these factors simultaneously to reduce the tuberculosis burden among the general population. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background Whether genetic susceptibility to type 2 diabetes is modified by a healthy lifestyle among Chinese remains unknown. Objectives The aim of the study was to determine whether genetic risk and adherence to a healthy lifestyle contribute independently to the risk of developing type 2 diabetes. Methods We defined a lifestyle score using BMI, alcohol intake, smoking, physical activities, and diets in 461,030 participants from the China Kadoorie Biobank and 38,434 participants from the Singapore Chinese Health Study. A genetic risk score was constructed based on type 2 diabetes loci among 100,175 and 16,172 participants in each cohort, respectively. A Cox proportional-hazards model was used to estimate the interaction between genetic and lifestyle factors on the risk of type 2 diabetes. Results In 2 independent Asian cohorts, we consistently found a healthy lifestyle (the bottom quintile of lifestyle score) was associated with a substantially lower risk of type 2 diabetes than an unhealthy lifestyle (the top quintile of lifestyle score) regardless of genetic risk. In those at a high genetic risk, the risk of type 2 diabetes was 57% lower among participants with a healthy lifestyle than among those with an unhealthy lifestyle in the pooled cohorts. Among participants at high genetic risk, the standardized 10-y incidence of type 2 diabetes was 7.11% in those with an unhealthy lifestyle vs. 2.45% in those with a healthy lifestyle. Conclusions In 2 independent cohorts involving 558,302 Chinese participants, we did not observe an interaction between genetics and lifestyle with type 2 diabetes risk, but our findings provide replicable evidence to show lifestyle factors and genetic factors were independently associated with the risk of type 2 diabetes. Within any genetic risk category, a healthy lifestyle was associated with a significantly lower risk of type 2 diabetes among the Chinese population. [ABSTRACT FROM AUTHOR]

We aimed to test whether predefined dietary patterns that are inversely related to risk of type 2 diabetes (T2D) in Western populations were similarly associated with lower T2D risk in an Asian population. We included 45,411 middle-aged and older participants (ages 45–74 years) in the Singapore Chinese Health Study who were free of diabetes, cancer, and cardiovascular disease at baseline (1993–1998). Participants were followed up for T2D diagnosis through 2010. Dietary information was collected using a validated food frequency questionnaire. Dietary pattern scores were calculated for the alternate Mediterranean diet (aMED), Alternate Healthy Eating Index 2010 (AHEI-2010), the Dietary Approaches to Stop Hypertension (DASH) diet, an overall plant-based diet index, and a healthful plant-based diet index. During a median of 11.1 years of follow-up, 5,207 incident cases of T2D occurred. After adjustment for multiple potential confounders, the 5 dietary pattern scores were significantly associated with 16% (for aMED) to 29% (for DASH) lower risks of T2D when comparing the highest score quintiles with the lowest (all P -for-trend values < 0.001). These associations did not vary substantially by baseline age, sex, body mass index, or hypertension status but were limited to nonsmokers (aMED: P for interaction < 0.001; AHEI-2010: P for interaction = 0.03). Adherence to a high-quality diet, as reflected by several predefined diet quality indices derived in Western populations, was significantly associated with lower T2D risk in an Asian population. [ABSTRACT FROM AUTHOR]

: Wei Zheng and colleagues quantify the burden of tobacco-smoking-related deaths for adults in Asia. Please see later in the article for the Editors' Summary [ABSTRACT FROM AUTHOR]

We prospectively investigated whether coffee consumption was associated with decreased risk of colorectal cancer and whether cigarette smoking and stage of disease modify the association in the Singapore Chinese Health Study. During the first 12 years of follow-up, 961 colorectal cancer cases occurred in the cohort of over 60,000 middle-aged or older Chinese men and women living in Singapore. Baseline dietary exposures were assessed through in-person interviews using a validated food frequency questionnaire. The relation between coffee consumption and colorectal cancer risk was assessed by proportional hazards (Cox) regression. No overall association between coffee intake and colorectal cancer was observed. However, in analysis by subsite and stage restricted to ever smokers, the coffee-colon cancer association became statistically significant for advanced disease (P for trend = 0.01). The hazard ratio was 0.56 (95% confidence interval = 0.35-0.90) for advanced colon cancer in drinkers of 2 or more cups per day compared with those who drank no coffee or less than 1 cup per day. Although there is a null association between coffee intake and risk of colorectal cancer overall, coffee may protect against smoking related advanced colon cancer. [ABSTRACT FROM AUTHOR]

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. [Display omitted] In this large multiethnic epigenome-wide association study of total nicotine equivalents across three cohorts, we identified differential methylation at 408 CpG loci, of which 45 were novel and 51 were externally validated. Our findings highlight the generalizability of these internal smoking dose-related epigenetic modifications across multiple racial and ethnic populations. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To examine whether age at menarche was inversely associated with cardiovascular disease (CVD) mortality in Singaporean Chinese women. Methods: We followed prospectively 34,022 Chinese women aged 45 to 74 at enrollment (1993–1998), with complete data on study variables, through 2009 for primary cause of death from CVD, including coronary heart disease (CHD) and cerebrovascular disease (CERE). Hazard ratios (HRs) for CVD mortality were computed across menarcheal age categories and adjusted for potential confounders and body mass index. Results: Over 460,374 person-years of follow-up, 1852 women died from CVD, 998 from CHD and 557 from CERE. There was a significant interaction between age at menarche and smoking (P < .05). In nonsmokers, age at menarche was inversely associated with risk for CVD and CHD mortality. HRs (and 95% confidence interval) for CVD mortality across menarcheal age categories (≤12, 13–14, 15–16, ≥17) were 1.06 (0.87–1.29), 1 (referent), 0.89 (0.79–1.00), and 0.80 (0.69–0.93), respectively (P trend  < .001); HRs for CHD mortality were 1.06 (0.80–1.34), 1 (referent), 0.76 (0.65–0.90), and 0.72 (0.58–0.88), respectively (P trend  < .001). Among nonsmokers, there was no association between age at menarche and CERE mortality. Among smokers, menarcheal age was not associated with CVD, CHD or CERE mortality. Conclusions: Menarcheal age was inversely associated with risk of CVD mortality in nonsmoking Chinese women. [Copyright &y& Elsevier]