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1.  Elevated 4-Aminobiphenyl and 2, 6-Dimethylaniline Hemoglobin Adducts and Increased Risk of Bladder Cancer among Lifelong Nonsmokers - The Shanghai Bladder Cancer Study 
Background
4-Aminobiphenyl (ABP) is an established human bladder carcinogen, with tobacco smoke being a major source of human exposure. Other arylamine compounds, including 2,6-dimethylaniline (2,6-DMA), have been implicated as possible human bladder carcinogens. Hemoglobin adducts of 4-ABP and 2,6-DMA are validated biomarkers of exposure to those compounds in humans.
Methods
The Shanghai Bladder Cancer Study enrolled 581 incident bladder cancer cases and 604 population controls. Each participant was solicited for his/her history of tobacco use and other lifestyle factors, and donation of blood and urine specimens. Red blood cell lysates were used to quantify both hemoglobin adducts of 4-ABP and 2,6-DMA. Urine samples were used to quantify total cotinine. Odds ratios (ORs) and 95% confidence intervals (CIs) for bladder cancer were estimated using unconditional logistic regression methods.
Results
Among lifelong nonsmokers, ORs (95% CIs) of bladder cancer for low (below median of positive values) and high versus undetectable levels of 2,6-DMA hemoglobin adducts were 3.87 (1.39-10.75) and 6.90 (3.17-15.02), respectively (Ptrend<0.001). Similarly, among lifelong nonsmokers, ORs (95% CIs) of bladder cancer for 3rd and 4th versus 1st/2nd quartiles of 4-ABP hemoglobin adducts was 1.30 (0.76-2.22) and 2.29 (1.23-4.24), respectively (Ptrend=0.00). The two associations were independent of each other.
Conclusion
Hemoglobin adducts of 4-ABP and 2,6-DMA were significantly and independently associated with increased bladder cancer risk among lifelong nonsmokers in Shanghai, China.
Impact
The findings of the present study in China with previous data in Los Angeles, California strongly implicate arylamines as potential causal agents of human bladder cancer.
doi:10.1158/1055-9965.EPI-12-1447
PMCID: PMC4065796  PMID: 23539508
2.  Cytochrome P4501A2 Phenotype and Bladder Cancer Risk: The Shanghai Bladder Cancer Study 
Cytochrome P450 1A2 (CYP1A2) is hypothesized to catalyze the activation of arylamines, known human bladder carcinogens present in cigarette smoke. The relationship between CYP1A2 phenotype and bladder cancer risk was examined in a case-control study involving 519 patients and 514 controls in Shanghai, China. Both CYP1A2 and N-acetyltransferase 2 (NAT2) phenotypic status were determined by a caffeine-based urinary assay. The present study showed that among smokers at urine collection, bladder cancer patients had statistically significantly higher CYP1A2 phenotype scores compared with control subjects (P = 0.001). The odds ratios (95% confidence intervals) of bladder cancer for the 2nd, 3rd, and 4th quartiles of the CYP1A2 score were 1.31 (0.53–3.28), 2.04 (0.90–4.60) and 2.82 (1.32–6.05), respectively, relative to the lowest quartile (P for trend = 0.003). NAT2 slow acetylation phenotype was associated with a statistically significant 40% increased risk of bladder cancer, and the relationship was independent of subjects’ smoking status. Subjects possessing the NAT2 slow acetylation phenotype and the highest tertile of CYP1A2 scores showed the highest risk for bladder cancer. Their odds ratios (95% confidence intervals) was 2.13 (1.24–3.68) relative to their counterparts possessing the NAT2 rapid acetylation phenotype and the lowest tertile of CYP1A2 scores. The findings of the present study demonstrate that CYP1A2 phenotype may be an important contributing factor in the development of smoking-related bladder cancer in humans.
doi:10.1002/ijc.26121
PMCID: PMC3167995  PMID: 21480221
3.  Plasma carotenoids and risk of acute myocardial infarction in The Singapore Chinese Health Study 
Background
Modification of low density lipoprotein due to oxidative stress is essential in the development of coronary atherosclerosis. Data of specific carotenoids except β-carotene on cardioprotective effects in humans are limited.
Objective and methods
This study examined the associations between plasma concentrations of specific carotenoids and incidence of acute myocardial infarction. The study included 280 incident cases of acute myocardial infarction and 560 matched controls nested within the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese men and women aged 45 to 74 years old enrolled in 1993-1998 in Singapore. Retinol and carotenoids in prediagnostic plasma were quantified using high-performance liquid chromatography.
Results
High levels of plasma β-cryptoxanthin and lutein were associated with decreased risk of acute myocardial infarction after adjustment for multiple risk factors for coronary heart disease. For β-cryptoxanthin, the odds ratio (95% confidence interval) for the highest (Q5) versus the lowest (Q1) quintile was 0.67 (0.37-1.21) (P for trend = 0.03). For lutein, the odds ratios (95% confidence intervals) for Q2-Q3 and Q4-Q5 versus Q1 were 0.71 (0.45-1.12) and 0.58 (0.35-0.94) respectively (P for trend = 0.03). There was no statistically significant association between other carotenoids or retinol and risk of acute myocardial infarction.
Conclusions
High plasma levels of β-cryptoxanthin and lutein were associated with decreased risk of acute myocardial infarction. The findings of this study support a cardioprotective role of these two carotenoids in humans.
doi:10.1016/j.numecd.2009.12.005
PMCID: PMC2891412  PMID: 20227258
antioxidants; carotenoids; coronary disease; nested case-control study; Chinese
4.  Green tea and prevention of esophageal and lung cancers 
Green tea contains high concentrations of tea polyphenols that have shown inhibitory effects against the development, progress, and growth of carcinogen-induced tumors in animal models at different organ sites, including the esophagus and lung. Green tea polyphenols also have shown to suppress cell proliferation and induce apoptosis. Besides antioxidative property, green tea polyphenols have pro-oxidative activities under certain conditions and modulate phase II metabolic enzymes that can enhance the detoxification pathway of environmental toxicants and carcinogens. Although epidemiological studies have provided inconclusive results on the effect of green tea consumption against the development of esophageal and lung cancers in humans overall, the inverse association between green tea intake and risk of esophageal cancer risk is more consistently observed in studies with adequate control for potential confounders. Epidemiological studies also have demonstrated an inverse, albeit moderate, association between green tea consumption and lung cancer, especially in non-smokers. This article reviews data on the cancer-preventive activities of green tea extract and green tea polyphenols and possible mechanisms against the esophageal and lung carcinogenesis in experimental animals, and summarizes the current knowledge from epidemiological studies on the relationship between green tea consumption and esophageal and lung cancer risk in humans.
doi:10.1002/mnfr.201000637
PMCID: PMC3400335  PMID: 21538848
Esophageal cancer; Green tea; Lung cancer; Polyphenol
5.  Urinary Levels of Cigarette Smoke Constituent Metabolites Are Prospectively Associated with Lung Cancer Development in Smokers 
Cancer Research  2011;71(21):6749-6757.
Polycyclic aromatic hydrocarbons (PAH) are believed to be among the principal causative agents for lung cancer in smokers, but no epidemiologic studies have evaluated the relationship of PAH uptake and metabolism to lung cancer. In this study, we quantified prediagnostic urinary levels of r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydro-phenanthrene (PheT), a validated biomarker of PAH uptake and metabolism, as well as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), and cotinine and its glucuronides (total cotinine), validated biomarkers of uptake of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and nicotine, respectively, in relation to lung cancer risk among current smokers in a nested case–control study within a cohort of 18,244 Chinese men in Shanghai, China. Urinary levels of PheT, total NNAL, and total cotinine were significantly higher in cases than controls (N = 476 matched pairs). ORs (95% confidence intervals) for lung cancer in the second, third, fourth, and fifth quintiles of PheT were 1.70 (1.00–2.88), 1.07 (0.62–1.84), 1.48 (0.86–2.53), and 2.34 (1.33–4.11), respectively, relative to the lowest quartile (Ptrend = 0.023) after adjustment for self-reported smoking intensity and duration and urinary total NNAL and total cotinine. This study also confirmed that urinary total NNAL and total cotinine are independently related to lung cancer risk.
doi:10.1158/0008-5472.CAN-11-0209
PMCID: PMC3392910  PMID: 22028322
6.  Environmental Tobacco Smoke in Relation to Bladder Cancer Risk – The Shanghai Bladder Cancer Study 
Background
Environmental tobacco smoke (ETS) contains tobacco carcinogens. Hepatic cytochrome P450 (CYP) 1A2 and N-acetyltransferase (NAT2) are important isoenzymes in activation and detoxification, respectively, of tobacco carcinogens. Data on ETS and bladder cancer risk are sparse.
Methods
We examined the effects of ETS alone and combined with NAT2/CYP1A2 on bladder cancer risk among lifelong-nonsmokers in a case-control study involving 195 patients and 261 controls in Shanghai, China. A comprehensive history of ETS exposure was determined through in-person interviews while CYP1A2 and NAT2 phenotypes by a caffeine-based urinary assay.
Results
ETS exposure was related to an overall statistically non-significant 38% increased bladder cancer risk. The risk increased with increasing number of cigarettes smoked by household members or number of hours per day at workplace where coworkers smoked. Compared with no ETS exposure, subjects living with smoking parents during childhood had an OR of 2.43 (95% CI=0.99–5.96) for bladder cancer. When all ETS sources were combined, the risk increased with increasing total ETS score (Ptrend = 0.03). The OR for high versus nil ETS exposure was 3.00 (95% CI =1.24–7.26). The increased risk with ETS was mainly seen among individuals possessing a CYP1A2 high efficiency and/or a NAT2 slow acetylation phenotype (Ptrend = 0.04).
Conclusions
ETS was associated with an increased bladder cancer risk for lifelong-nonsmokers. The association was stronger for people possessing the at-risk phenotypes of CYP1A2 and/or NAT2.
Impact
Reducing exposure to ETS for children and genetically more susceptible individuals could be more effective for bladder cancer prevention.
doi:10.1158/1055-9965.EPI-10-0823
PMCID: PMC3003610  PMID: 21056942
7.  Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms and gastric cancer risk: a prospective study of men in Shanghai, China 
Isothiocyanates (ITC) in cruciferous vegetables may be chemopreventive against gastric cancer development. Glutathione S-transferases (GSTs) may modify the chemopreventive effect of ITC. The relationship between urinary total ITC and risk of gastric cancer was prospectively examined. Between 1986 and 1989, 18,244 middle-aged men in Shanghai, China were enrolled in a prospective study of diet and cancer and donated baseline urine and blood samples. Urinary ITC was quantified for 307 incident cases of gastric cancer that occurred during the first 16 years of follow-up, and 911 matched control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression methods. Seropositivity for antibodies to Helicobacter pylori and homozygous deletions of GSTM1 and GSTT1 were determined. Compared with the first tertile, ORs (95% CIs) of gastric cancer for the second and third tertiles of urinary total ITC were 0.83 (0.61–1.15) and 0.66 (0.47–0.94) (Ptrend=0.02). A stronger protective effect of ITC against gastric cancer development was seen among men with homozygous deletion of GSTM1 (third tertile versus first tertile, OR = 0.50, 95% CI = 0.27–0.93) or GSTT1 (third tertile versus first tertile, OR = 0.47, 95% CI = 0.25–0.88), and particularly with deletions of both GSTM1 and GSTT1 (second and third tertiles versus first tertile, OR = 0.44, 95% CI = 0.21–0.93). In this cohort of Chinese men at high risk for gastric cancer, isothiocyanates may protect against the development of gastric cancer. The protection may be stronger for individuals genetically deficient in enzymes that metabolize these chemopreventive compounds.
doi:10.1002/ijc.24583
PMCID: PMC2757456  PMID: 19610060
cruciferous vegetables; ITC; GST polymorphisms; urinary biomarkers; gastric cancer
8.  Urinary levels of tobacco-specific nitrosamine metabolites in relation to lung cancer development in two prospective cohorts of cigarette smokers 
Cancer research  2009;69(7):2990-2995.
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 pre-diagnostic 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 2nd and 3rd tertiles of total NNAL were 1.43 (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.
doi:10.1158/0008-5472.CAN-08-4330
PMCID: PMC2664854  PMID: 19318550
tobacco; NNK; NNAL; cotinine; lung cancer
9.  Urinary total isothiocyanates and colorectal cancer: a prospective study of men in Shanghai, China 
Laboratory and epidemiological evidence suggest that dietary isothiocyanates (ITCs) may have a chemopreventive effect on cancer. Humans are exposed to ITCs primarily through ingestion of cruciferous vegetables which contain glucosinolates, the precursors to ITCs. The association between urinary total ITC level and colorectal cancer risk was examined in a cohort of 18,244 men in Shanghai, China, with 16 years of follow-up. Urinary total ITCs were quantified on 225 incident cases of colorectal cancer and 1119 matched controls. Odds ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated using logistic regression models. High levels of urinary total ITCs were associated with a reduced risk of colorectal cancer five years after baseline measurements of ITCs whereas a statistically nonsignificant increase in the risk of colorectal cancer was observed for cases within five years of post-enrollment (OR=1.93; 95% CI =0.85, 4.39 for the upper three quartiles of urinary ITCs versus the lowest quartile). The inverse ITC-colorectal cancer association became stronger with a longer duration of follow-up. Compared with the first quartile, ORs (95% CIs) for the second, third, and fourth quartiles of total ITCs in urine collected 10 or more years before cancer diagnosis were 0.61 (0.35, 1.05), 0.51 (0.29, 0.92), and 0.46 (0.25, 0.83), respectively, for risk of colorectal cancer (P for trend = 0.006). The present study suggests that dietary ITCs may exert tumor inhibitory effects, especially during earlier stages of the multistage process of carcinogenesis.
doi:10.1158/1055-9965.EPI-07-2841
PMCID: PMC2474764  PMID: 18559550
cruciferous vegetables; ITCs; GST polymorphisms; urinary biomarkers; colon cancer; rectal cancer
10.  Sleep Duration and Coronary Heart Disease Mortality Among Chinese Adults in Singapore 
American journal of epidemiology  2008;168(12):1367-1373.
While some studies have found a positive association between both short and long sleep durations and cardiovascular disease (CVD), others have found an association only with a long or short sleep duration. In addition, there are limited data from non-Western populations on this topic. The authors examined the association between sleep duration and coronary heart disease (CHD) mortality among Chinese adults in Singapore (1993-2006), performing a prospective cohort study among 58,044 participants aged ≥45 years (55.9% women) without preexisting CVD. The main outcome of interest was CHD mortality (n = 1,416). The authors found both short and long sleep durations to be positively associated with CHD mortality, independent of smoking, alcohol intake, and body mass index. Compared with persons with a sleep duration of 7 hours (referent), the multivariable relative risk of CHD mortality for a sleep duration of ≤5 hours was 1.57 (95% confidence interval: 1.32, 1.88); for a sleep duration of ≥9 hours, it was 1.79 (95% confidence interval: 1.48, 2.17). This association persisted in subgroup analyses by sex sleep and body mass index. In a population-based cohort of Chinese adults from Singapore, sleep durations of ≤5 hours and ≥9 hours (versus 7 hours) were modestly associated with CHD mortality. These results suggest that duration may be an important marker for CVD.
doi:10.1093/aje/kwn281
PMCID: PMC2643470  PMID: 18952563
Asian continental ancestry group; cardiovascular diseases; coronary disease; mortality; Singapore; sleep
11.  Genetic Polymorphisms in the Methylenetetrahydrofolate Reductase and Thymidylate Synthase Genes and Risk of Hepatocellular Carcinoma 
Hepatology (Baltimore, Md.)  2007;46(3):749-758.
Methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TYMS) are known to play a role in DNA methylation, synthesis, and repair. The genetic mutations in MTHFR and TYMS genes may have influences on their respective enzyme activities. Data on the association studies of the MTHFR and TYMS genetic polymorphisms and risk of hepatocellular carcinoma (HCC) are sparse. MTHFR and TYMS genotypes were determined on 365 HCC cases and 457 healthy control subjects among Hispanic and non-Hispanic whites and African-Americans in Los Angeles County, California, and among Chinese in the city of Nanning, Guangxi, China. Relative to the high-activity genotype, each low-activity genotype of MTHFR was associated with a statistically nonsignificant 30% to 50% reduction in risk of HCC. Relative to the TYMS3′UTR +6/+6 genotype, individuals with 1 or 2 copies of the deletion allele had a statistically significant 50% reduction in risk of HCC. When we examined HCC risk by the total number of mutant alleles in the 3 polymorphic loci of MTHFR/TYMS (range, 0-4), there was a monotonic decrease in risk with increasing number of mutant alleles (P for trend = 0.003). Individuals possessing the maximum number of mutant alleles (i.e., 4) had an odds ratio of 0.46 (95% confidence interval = 0.23-0.93) for HCC compared with those with no or only 1 mutant allele.
Conclusion
This study supports the hypothesis that reduced MTHFR activity and enhanced TYMS activity, both of which are essential elements in minimizing uracil misincorporation into DNA, may protect against the development of HCC.
doi:10.1002/hep.21735
PMCID: PMC2391240  PMID: 17659576
12.  Urinary Levels of N-Nitroso Compounds in Relation to Risk of Gastric Cancer: Findings from the Shanghai Cohort Study 
PLoS ONE  2015;10(2):e0117326.
Background
N-Nitroso compounds are thought to play a significant role in the development of gastric cancer. Epidemiological data, however, are sparse in examining the associations between biomarkers of exposure to N-nitroso compounds and the risk of gastric cancer.
Methods
A nested case-control study within a prospective cohort of 18,244 middle-aged and older men in Shanghai, China, was conducted to examine the association between urinary level of N-nitroso compounds and risk of gastric cancer. Information on demographics, usual dietary intake, and use of alcohol and tobacco was collected through in-person interviews at enrollment. Urinary levels of nitrate, nitrite, N-nitroso-2-methylthiazolidine-4-carboxylic acid (NMTCA), N-nitrosoproline (NPRO), N-nitrososarcosine (NSAR), N-nitrosothiazolidine-4-carboxylic acid (NTCA), as well as serum H. pylori antibodies were quantified in 191 gastric cancer cases and 569 individually matched controls. Logistic regression method was used to assess the association between urinary levels of N-nitroso compounds and risk of gastric cancer.
Results
Compared with controls, gastric cancer patients had overall comparable levels of urinary nitrate, nitrite, and N-nitroso compounds. Among individuals seronegative for antibodies to H. pylori, elevated levels of urinary nitrate were associated with increased risk of gastric cancer. The multivariate-adjusted odds ratios for the second and third tertiles of nitrate were 3.27 (95% confidence interval = 0.76–14.04) and 4.82 (95% confidence interval = 1.05–22.17), respectively, compared with the lowest tertile (P for trend = 0.042). There was no statistically significant association between urinary levels of nitrite or N-nitroso compounds and risk of gastric cancer. Urinary NMTCA level was significantly associated with consumption of alcohol and preserved meat and fish food items.
Conclusion
The present study demonstrates that exposure to nitrate, a precursor of N-nitroso compounds, may increase the risk of gastric cancer among individuals without a history of H. pylori infection.
doi:10.1371/journal.pone.0117326
PMCID: PMC4319940  PMID: 25658333
13.  Urinary Tobacco Smoke Constituent Biomarkers for Assessing Risk of Lung Cancer 
Cancer research  2014;74(2):401-411.
Tobacco constituent biomarkers are metabolites of specific compounds present in tobacco or tobacco smoke. Highly reliable analytical methods, based mainly on mass spectrometry, have been developed for quantitation of these biomarkers in both urine and blood specimens. There is substantial inter-individual variation in smoking-related lung cancer risk that is determined in part by individual variability in the uptake and metabolism of tobacco smoke carcinogens. Thus, by incorporating these biomarkers in epidemiological studies we can potentially obtain a more valid and precise measure of in vivo carcinogen dose than by using self-reported smoking history, ultimately improving the estimation of smoking-related lung cancer risk. Indeed, we have demonstrated this by using a prospective study design comparing biomarker levels in urine samples collected from smokers many years prior to their development of cancer, versus those in their smoking counterparts without a cancer diagnosis. The following urinary metabolites were associated with lung cancer risk, independent of smoking intensity and duration: cotinine plus its glucuronide, a biomarker of nicotine uptake; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), a biomarker of the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK); and r-1-,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT), a biomarker of polycyclic aromatic hydrocarbons (PAH). These results provide several possible new directions for using tobacco smoke constituent biomarkers in lung cancer prevention, including improved lung cancer risk assessment, intermediate outcome determination in prevention trials and regulation of tobacco products.
doi:10.1158/0008-5472.CAN-13-3178
PMCID: PMC4066207  PMID: 24408916
14.  Impact of Post-Diagnosis Smoking on Long-Term Survival of Cancer Patients: The Shanghai Cohort Study 
Background
Cancer is the number one cause of death among men in China. Cigarette smoking is the most preventable cause of cancer. Data on the impact of continued smoking after cancer diagnosis on survival of cancer patients are sparse.
Methods
We studied the association between post-diagnosis smoking and risk of all-cause death among 1,632 incident cancer patients in the Shanghai Cohort Study, a population-based prospective cohort of 18,244 men in Shanghai. The change of smoking status after baseline interview was ascertained through annual in-person interviews. Cox proportional hazards regression models were used to estimate hazard ratio (HR) and 95% confidence interval (CI) for all-cause mortality associated with change in smoking status.
Results
Patients who continued smoking after cancer diagnosis experienced a statistically significant 59% (95% CI = 36–86%) increase in risk of death compared with cancer patients who did not smoke after cancer diagnosis. Among current smokers at cancer diagnosis, HRs (95% CIs) were 1.79 (1.49–2.16) in all cancer patients, 2.36 (1.63–3.42) in lung cancer patients, 1.63 (0.98–2.73) in stomach cancer patients, 2.31 (1.40–3.81) in colorectal cancer patients, and 2.95 (1.09–7.95) in bladder cancer patients who continued smoking compared with their counterparts who stopped smoking after cancer diagnosis.
Conclusion
Post-diagnosis cigarettes smoking significantly increased the risk of death for male cancer patients.
Impact
These data provide new information regarding smoking and cancer survival, which should inform future research into the contextual and individual-level barriers that may result in inadequate attention of smoking among cancer patients in the post-diagnosis setting.
doi:10.1158/1055-9965.EPI-13-0805-T
PMCID: PMC3919701  PMID: 24319070
15.  Incense Use and Cardiovascular Mortality among Chinese in Singapore: The Singapore Chinese Health Study 
Environmental Health Perspectives  2014;122(12):1279-1284.
Background: Incense burning is common in many parts of the world. Although it is perceived that particulate matter from incense smoke is deleterious to health, there is no epidemiologic evidence linking domestic exposure to cardiovascular mortality.
Objective: We examined the association between exposure to incense burning and cardiovascular mortality in the Singapore Chinese Health Study.
Methods: We enrolled a total of 63,257 Singapore Chinese 45–74 years of age during 1993–1998. All participants were interviewed in person to collect information about lifestyle behaviors, including the practice of burning incense at home. We identified cardiovascular deaths via record linkage with the nationwide death registry through 31 December 2011.
Results: In this cohort, 76.9% were current incense users, and most of the current users (89.9%) had burned incense daily for ≥ 20 years. Relative to noncurrent users, current users had a 12% higher risk of cardiovascular mortality [multivariable adjusted hazard ratio (HR) = 1.12; 95% CI: 1.04, 1.20]. The HR was 1.19 (95% CI: 1.03, 1.37) for mortality due to stroke and 1.10 (95% CI: 1.00, 1.21) for mortality due to coronary heart disease. The association between current incense use and cardiovascular mortality appeared to be limited to participants without a history of cardiovascular disease at baseline (HR = 1.16; 95% CI: 1.07, 1.26) but not linked to those with a history (HR = 1.00; 95% CI: 0.86, 1.17). In addition, the association was stronger in never-smokers (HR = 1.12; 95% CI: 1.02, 1.23) and former smokers (HR = 1.19; 95% CI: 1.00, 1.42) than in current smokers (HR = 1.05; 95% CI: 0.91, 1.22).
Conclusions: Long-term exposure to incense burning in the home environment was associated with an increased risk of cardiovascular mortality in the study population.
Citation: Pan A, Clark ML, Ang LW, Yu MC, Yuan JM, Koh WP. 2014. Incense use and cardiovascular mortality among Chinese in Singapore: The Singapore Chinese Health Study. Environ Health Perspect 122:1279–1284; http://dx.doi.org/10.1289/ehp.1307662
doi:10.1289/ehp.1307662
PMCID: PMC4256695  PMID: 25127437
16.  Calcium intake increases risk of prostate cancer among Singapore Chinese 
Cancer research  2010;70(12):4941-4948.
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, non-dairy 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 of 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 (BMI). 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/day) versus 1st (median=211 mg/day) 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 below median (22.9 kg/m2) BMI. Dietary calcium may be a risk factor for prostate cancer even at relatively low intake.
doi:10.1158/0008-5472.CAN-09-4544
PMCID: PMC4219618  PMID: 20516117
calcium; body mass index; insulin-like growth factor; prostate cancer; Singapore Chinese
17.  Hormone metabolism genes and mammographic density in Singapore Chinese women 
Background
Female steroid hormone levels and exogenous hormone use influence breast cancer risk. We investigated the association between genetic variation in the hormone metabolism and signaling pathway and mammographic density (MD), a strong predictor of breast cancer risk.
Methods
We genotyped 161 SNPs in 15 hormone metabolism pathway gene regions and evaluated MD in 2,038 Singapore Chinese women. Linear regression analysis was used to investigate SNP-MD association. An overall pathway summary was obtained using the adaptive ranked truncated product test.
Results
We did not find any of the individually tested SNPs to be associated with MD after a multiple testing correction. There was no evidence of an overall effect on MD of genetic variation in the hormone metabolism pathway.
Conclusions
In this cross-sectional study, genetic variation in hormone metabolism pathway was not associated with MD in Singapore Chinese women.
Impact
Consistent with existing data from Caucasian populations, polymorphisms in hormone pathway genes are not likely to be strong predictors of MD in Asian women.
doi:10.1158/1055-9965.EPI-13-0157
PMCID: PMC4197055  PMID: 23429186
Hormone metabolism; polymorphism; mammographic density; Chinese
18.  Reduced Aflatoxin Exposure Presages Decline in Liver Cancer Mortality in an Endemic Region of China 
Primary liver cancer (PLC) is the third leading cause of cancer mortality globally. In endemic areas of sub-Saharan Africa and Asia PLC largely arises from chronic infection with hepatitis B virus (HBV) and ingestion of aflatoxins. While synergistic interactions between these two risk factors have been observed in cohort studies in China, here we determined the impact of agricultural reforms in the 1980s leading to diminished maize consumption and implementation of subsidized universal vaccination against HBV in the 2000s on PLC primary prevention. A population-based cancer registry was used to track PLC mortality in Qidong, China and was compared to the timeline of HBV immunization. Randomly selected serum samples from archived cohort collections from the 1980s to present were analyzed for aflatoxin biomarkers. Greater than 50% reductions in PLC mortality rates occurred across birth cohorts from the 1960s to the 1980s for Qidongese less than 35 years of age although all were born before universal vaccination of newborns. Median levels of the aflatoxin biomarker decreased from 19.3 pg/mg albumin in 1989 to undetectable (<0.5 pg/mg) by 2009. A population attributable benefit of 65% for reduced PLC mortality was estimated from a government facilitated switch of dietary staple from maize to rice; 83% of this benefit was in those infected with HBV. Food policy reforms in China resulted in a dramatic decrease in aflatoxin exposure, which, independent of HBV vaccination, reduced liver cancer risk. The extensive HBV vaccine coverage now in place augurs even greater risk reductions in the future.
doi:10.1158/1940-6207.CAPR-13-0168
PMCID: PMC3800239  PMID: 23963804
aflatoxin; primary prevention; liver cancer
19.  Prediagnostic levels of serum one-carbon metabolites and risk of hepatocellular carcinoma 
Background
Rats fed diets deficient in choline develop hepatocellular carcinoma (HCC). Tumor DNA from these animals is characteristically hypomethylated, suggesting that disruption of the one-carbon metabolism pathway is an underlying mechanism for hepatocarcinogenesis. Prospective studies in humans on circulating choline and other one-carbon metabolites and HCC risk have been lacking.
Methods
We prospectively examined the association between prediagnostic serum concentrations of one-carbon metabolites including betaine, choline, cystathionine, homocysteine, methionine, 5-methyltetrahydrofolate (5-MTHF), pyridoxal-5-phosphate (PLP, the bioactive form of vitamin B6) and S-adenosylmethionine (SAM), and risk of developing HCC based on a nested case-control study of 297 incident cases and 631 matched controls from a cohort of 18,244 men in Shanghai, China. Logistic regression methods were used to calculate odds ratios (OR) and 95% confidence intervals (CI) adjusted for established risk factors for HCC.
Results
Serum choline and PLP were associated with statistically significant reduced risk of HCC, while serum cystathionine, methionine and SAM were associated with increased HCC risk (all Ptrend<0.05). The inverse associations for HCC risk with choline and PLP remained statistically significant after adjusting for all potential confounders. The multivariate-adjusted ORs (95% CIs) for the highest versus lowest quintiles of serum choline and PLP were 0.35 (0.16, 0.78) (P=0.010) and 0.44 (0.25, 0.78) (P=0.005), respectively. There were no associations for HCC risk with 5-MTHF, betaine, or homocysteine.
Conclusion
The inverse associations between choline and vitamin B6 and the risk of HCC development are novel and warrant further investigation.
Impact
Identifying new modifiable factors for HCC prevention are warranted.
doi:10.1158/1055-9965.EPI-13-0497
PMCID: PMC3928816  PMID: 23897582
choline; hepatocellular carcinoma; one-carbon metabolism; vitamin B6
20.  Serum urate levels and consumption of common beverages and alcohol among Chinese in Singapore 
Arthritis care & research  2013;65(9):1432-1440.
Objective
Western studies suggest that beverages may affect serum urate (SU) levels but data from Asian populations are scarce. We evaluated the associations between beverages and SU levels in Singapore Chinese.
Methods
The study population consisted of 483 subjects from the Singapore Chinese Health Study cohort, aged 45-74 years, recruited between 1993 and 1998. Lifestyle factors, medical histories and diet were collected through in-person interviews. SU and other biomarkers were measured from blood collected between 1994 and 1996.
Results
Mean age was 57.6 years and 44% were men. The geometric mean of SU was 321 μmol/L (range 157-719 μmol/L). Mean SU levels increased with alcohol consumption (P for trend = 0.024). The mean SU level of daily alcohol drinkers was 42.6 μmol/L higher than that of non-drinkers. Similarly, increasing frequency of green tea intake was associated with rising SU levels. The highest mean SU level was observed in daily green tea drinkers (difference of 25.0 μmol/L) relative to non-drinkers (P for trend = 0.009). Compared to non-drinkers, daily alcohol drinkers had an almost 5-fold increase in association with hyperuricaemia [odds ratio (OR) = 4.83; 95% confidence interval (CI) = 1.10-21.23) while daily green tea drinkers had a 2-fold increase in association with hyperuricaemia (OR=2.12, 95% CI=1.03-4.36). The present study did not show elevated levels of SU in individuals who consumed black tea, coffee, fruit juice or soda.
Conclusions
Alcohol consumption increases SU levels. The finding that daily drinking of green tea is associated with hyperuricaemia needs validation in future studies.
doi:10.1002/acr.21999
PMCID: PMC3710722  PMID: 23463601
serum urate; coffee; tea; soft drinks; fruit juice; alcohol; Chinese
21.  Serum estrogen receptor bioactivity and breast cancer risk among postmenopausal women 
Endocrine-related cancer  2014;21(2):263-273.
The estrogen levels of Asian women are different from those of Western women, and this could affect estrogen receptor (ER) bioactivity and breast cancer risk. We conducted a case-control study of 169 postmenopausal breast cancer cases and 426 matched controls nested within a population-based prospective cohort, The Singapore Chinese Health Study, to evaluate serum levels of estrogens and their receptor (ERα and ERβ)-mediated estrogenic activities in relation to breast cancer risk. Breast cancer cases had higher levels of estrogens and estrogen receptor mediated bioactivities in baseline serum than controls. Compared to the lowest quartile, women in the highest quartile for estrone or ERα-mediated bioactivity had increased breast cancer risk. After additional adjustment for ERβ bioactivity, free E2 and estrone; serum ERα-mediated estrogenic activity remained associated with increased breast cancer risk. Compared to the lowest quartile, women in the highest quartile for ERα-mediated bioactivity had an odds ratio of 2.39 (95% confidence interval=1.17–4.88, p for trend=0.016). Conversely, the positive association between estrone and cancer risk became null after adjustment for ERα-mediated estrogenic activity, suggesting that the effect of estrone could be mediated through ERα. Identification of the factor(s) contributing to increased ERα-mediated estrogenic bioactivity in sera, and its role as a predictor for breast cancer risk needs to be validated in future studies.
doi:10.1530/ERC-13-0233
PMCID: PMC3962747  PMID: 24322303
breast cancer; estrogen; estrogen receptor; estrogen receptor bioassay
22.  Knowledge and Behaviors toward Hepatitis B and the Hepatitis B Vaccine in the Laotian Community in Minnesota 
Minnesota is home to a large population of immigrants from Laos as well as one of the largest disparities in hepatitis B (HBV) infection; in Minnesota, Asians are 80 times more likely to be infected than Whites. In response to community concern, a community-based participatory research project was conducted involving a cross-sectional study of 167 adult Laotian immigrants in the Minneapolis/St. Paul metropolitan area assessing knowledge and behaviors related to HBV and its vaccine. Fifty-eight percent of the participants reported not knowing about HBV and just under half incorrectly reported on person-to-person transmission. As expected, vaccination and screening for HBV was more common among those who knew of HBV (p=0.02 for both). Fourteen (8.4%) of the participants had been vaccinated, however, only 2 (14.8%) of those individuals received all three doses. This study outlines gaps in knowledge and resources that could address the staggering HBV disparity in this community.
doi:10.1007/s10903-012-9768-2
PMCID: PMC3951138  PMID: 23307096
hepatitis B; vaccination; screening; Laotian; immigrant; community based participatory research
23.  Fried meat intake is a risk factor for lung adenocarcinoma in a prospective cohort of Chinese men and women in Singapore 
Carcinogenesis  2013;34(8):1794-1799.
Probable human carcinogens are generated during Chinese-style high-temperature cooking of meat and have been detected in the ambient air and on the meat surface. Although the inhalation of these compounds is an established risk factor for lung cancer, exposure via fried meat consumption has not yet been prospectively evaluated as a risk factor. The relationship between fried meat intake and lung cancer risk was investigated using data from a prospective cohort study among Chinese in Singapore. Lung cancer cases (n = 1130) were identified from 61 321 men and women, 70% of whom were lifetime never smokers. Proportional hazards regression methods were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Overall, there was no association between fried meat intake and risk of all lung cancers combined. For lung adenocarcinoma, fried meat intake had a statistically significant association with increased risk. The association between fried meat intake and risk of lung adenocarcinoma became stronger when analyses were restricted to lifetime never smokers. Compared with the lowest tertile of fried meat intake, the HRs (95% CIs) for the second and third tertiles were 1.43 (0.98, 2.08) and 1.51 (1.03, 2.22), respectively (P for trend = 0.04). The positive association was present among both men and women. There was no association between fried meat intake and risk of non-adenocarcinomas of the lung. Our prospective results for fried meat intake support consumption as an important route of exposure to compounds from Chinese-style high-temperature cooking for the development of lung adenocarcinoma.
doi:10.1093/carcin/bgt113
PMCID: PMC3731803  PMID: 23568952
24.  Calcium intake is not related to breast cancer risk among Singapore Chinese women 
There is experimental evidence that calcium protects against breast cancer development. Prospective epidemiologic studies supporting a protective effect of calcium on breast cancer risk have mainly been limited to Western populations. We examined the association between calcium intake and breast cancer risk in the Singapore Chinese Health Study, a large population-based prospective cohort. Calcium intake and supplement use was assessed by in-person interviewer using a validated food frequency questionnaire. After a mean follow-up of 14.2±3.5 years, 823 cohort participants developed invasive breast cancer. Multivariate proportional hazards regression models were fitted to examine the associations between calcium intake and breast cancer risk. Vegetables were the primary food source of calcium in this study population, followed by dairy products, grains and soy foods. Calcium intake was not associated with breast cancer risk, comparing highest quartile (>345.6 mg/1000 kcal/day) to lowest quartile (<204.5mg/1000 kcal/day) of intake. There was no evidence of effect modification by menopausal status, body mass index, dietary vitamin D or stage of disease at diagnosis. Our findings do not support a hypothesis for calcium in breast cancer chemoprevention, contrary to findings from previous studies among Western populations with higher calcium intake primarily from dairy products and supplements.
doi:10.1002/ijc.28027
PMCID: PMC3727233  PMID: 23319293
calcium intake; breast cancer; Asian; Chinese; cohort studies
25.  Breast cancer risk assessment using genetic variants and risk factors in a Singapore Chinese population 
Introduction
Genetic variants for breast cancer risk identified in genome-wide association studies (GWAS) in Western populations require further testing in Asian populations. A risk assessment model incorporating both validated genetic variants and established risk factors may improve its performance in risk prediction of Asian women.
Methods
A nested case-control study of female breast cancer (411 cases and 1,212 controls) within the Singapore Chinese Health Study was conducted to investigate the effects of 51 genetic variants identified in previous GWAS on breast cancer risk. The independent effect of these genetic variants was assessed by creating a summed genetic risk score (GRS) after adjustment for body mass index and the Gail model risk factors for breast cancer.
Results
The GRS was an independent predictor of breast cancer risk in Chinese women. The multivariate-adjusted odds ratios (95% confidence intervals) of breast cancer for the second, third, and fourth quartiles of the GRS were 1.26 (0.90 to 1.76), 1.47 (1.06 to 2.04) and 1.75 (1.27 to 2.41) respectively (P for trend <0.001). In addition to established risk factors, the GRS improved the classification of 6.2% of women for their absolute risk of breast cancer in the next five years.
Conclusions
Genetic variants on top of conventional risk factors can improve the risk prediction of breast cancer in Chinese women.
doi:10.1186/bcr3678
PMCID: PMC4095592  PMID: 24941967

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