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1.  Plasma S-adenosylmethionine, DNMT polymorphisms, and peripheral blood LINE-1 methylation among healthy Chinese adults in Singapore 
BMC Cancer  2013;13:389.
Background
Global hypomethylation of repetitive DNA sequences is believed to occur early in tumorigenesis. There is a great interest in identifying factors that contribute to global DNA hypomethylation and associated cancer risk. We tested the hypothesis that plasma S-adenosylmethionine (SAM) level alone or in combination with genetic variation in DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) was associated with global DNA methylation extent at long interspersed nucleotide element-1 (LINE-1) sequences.
Methods
Plasma SAM level and LINE-1 DNA methylation index were measured using stored blood samples collected from 440 healthy Singaporean Chinese adults during 1994-1999. Genetic polymorphisms of 13 loci in DNMT1, DNMT3A and DNMT3B were determined.
Results
LINE-1 methylation index was significantly higher in men than in women (p = 0.001). LINE-1 methylation index was positively associated with plasma SAM levels (p ≤ 0.01), with a plateau at approximately 78% of LINE-1 methylation index (55 nmol/L plasma SAM) in men and 77% methylation index (50 nmol/L plasma SAM) in women. In men only, the T allele of DNMT1 rs21124724 was associated with a statistically significantly higher LINE-1 methylation index (ptrend = 0.001). The DNMT1 rs2114724 genotype modified the association between plasma SAM and LINE-1 methylation index at low levels of plasma SAM in men.
Conclusions
Circulating SAM level was associated with LINE-1 methylation status among healthy Chinese adults. The DNMT1 genetic polymorphism may exert a modifying effect on the association between SAM and LINE-1 methylation status in men, especially when plasma SAM level is low. Our findings support a link between plasma SAM and global DNA methylation status at LINE-1 sequences.
doi:10.1186/1471-2407-13-389
PMCID: PMC3765398  PMID: 23957506
2.  Gender-specific Associations Between Soy and Risk of Hip Fracture in the Singapore Chinese Health Study 
American Journal of Epidemiology  2009;170(7):901-909.
Although there is some epidemiologic evidence that soy may reduce risk of osteoporotic fracture in women, it is not known whether this risk reduction also occurs for men. The authors examined gender-specific associations between soy intake and hip fracture risk in the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese living in Singapore. At recruitment between 1993 and 1998, each subject was administered a food frequency questionnaire and questions on medical history and lifestyle factors. As of December 31, 2006, 276 incident cases of hip fracture in men and 692 cases in women were identified via linkage with hospital discharge databases. For both genders, hip fracture risk was positively associated with cigarette smoking and was inversely associated with body mass index. There was a statistically significant association of tofu equivalents, soy protein, and isoflavones with hip fracture risk among women but not among men. Compared with women in the lowest quartile of intakes for tofu equivalents (<49.4 g/day), soy protein (<2.7 g/day), and isoflavones (<5.8 mg/1,000 kcal/day), those in the second–fourth quartiles exhibited 21%–36% reductions in risk (all P < 0.036). Risk levels were comparable across the second, third, and fourth quartiles of soy intake categories.
doi:10.1093/aje/kwp220
PMCID: PMC2765361  PMID: 19720865
Asian Continental Ancestry Group; hip fractures; isoflavones; osteoporosis; soy foods
3.  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
4.  Combined Lifestyle Factors and Risk of Incident Colorectal Cancer in a Chinese Population 
A body of research links dietary intake, alcohol consumption, smoking, physical activity, body mass index (BMI), and possibly sleep patterns with colorectal cancer risk. However, little research has examined the association of the combination of these lifestyle factors with incidence of colorectal cancer, especially in non-western populations. A protective lifestyle factor index of these 6 aforementioned factors was created and examined in relation to risk of developing colorectal cancer. This study is a prospective observational study of 50,466 Chinese men and women in Singapore aged 45–74 during enrollment in the Singapore Chinese Health Study in 1993–1998 and followed up through 2007. The main outcome measures were standardized rates and hazard ratios of incident colorectal cancer. The protective levels of each lifestyle factor were independently associated with reduced age- and sex-standardized incidence rates of colon cancer. When all the factors were combined into a single protective lifestyle factor index, there was a strong, monotonic decrease in incidence rate of colon cancer with an increasing score. Relative to participants with an index score of 0–3, the hazard ratios (95% confidence intervals) of colon cancer for an index score of 4, 5, 6, 7, 8, 9/10 were 0.58 (0.35–0.95), 0.56 (0.36–0.86), 0.50 (0.33–0.76), 0.43 (0.28–0.66), 0.39 (0.25–0.63), and 0.25 (0.12–0.54) (P for trend <0.0001). The results were consistent by sex. Conversely, there was no association with rectal cancer risk. An increasing protective lifestyle factor index score is associated with a marked decreased risk of developing colon cancer in Chinese men and women.
doi:10.1158/1940-6207.CAPR-12-0384
PMCID: PMC3618573  PMID: 23275007
Lifestyle; sleep; Colorectal Cancer; Asian
5.  Genetic variation in Transforming Growth Factor beta 1 and mammographic density in Singapore Chinese women 
Cancer research  2013;73(6):1876-1882.
Transforming growth factor-beta (TGF-β) plays a critical role in normal mammary development and morphogenesis. Decreased TGF-β signaling has been associated with increased mammographic density. Percent mammographic density (PMD) adjusted for age and body mass index (BMI) is a strong risk factor and predictor of breast cancer risk. PMD is highly heritable, but few genetic determinants have been identified. We investigated the association between genetic variation in TGFB1 and PMD using a cross-sectional study of 2,038 women who were members of the population-based Singapore Chinese Health Study cohort. We assessed PMD using a computer-assisted method. We used linear regression to examine the association between 9 tagging SNPs of TGFB1 and PMD and their interaction with parity, adjusting for age, BMI, and dialect group. We calculated ‘P-values adjusted for correlated tests’ (PACT) to account for multiple testing. The strongest association was observed for rs2241716. Adjusted PMD was higher by 1.5% per minor allele (PACT =0.04). When stratifying by parity, this association was limited to nulliparous women. For nulliparous women, adjusted PMD was higher by 8.6% per minor allele (PACT=0.003; P for interaction with parity=0.002). Three additional TGFB1 tagging SNPs, which were in linkage disequilibrium with rs2241716, were statistically significantly associated with adjusted PMD (PACT<0.05) for nulliparous women. However, none of these three SNPs showed statistically significant association after adjusting for rs2241716. Our data support that TGFB1 genetic variation may be an important genetic determinant of mammographic density measure that predicts breast cancer risk, particularly in nulliparous women.
doi:10.1158/0008-5472.CAN-12-1870
PMCID: PMC3740538  PMID: 23333936
TGFB1; polymorphism; mammographic density; Chinese
6.  Sleep duration, spot urinary 6-sulfatoxymelatonin levels and risk of breast cancer among Chinese women in Singapore 
We previously reported an inverse association between sleep duration and breast cancer risk in the prospective, population-based Singapore Chinese Health Study (SCHS) cohort (Wu et al., Carcinogenesis 2008;29:1244–8). Sleep duration was significantly positively associated with 6-sulfatoxymelatonin (aMT6s) levels determined in a spot urine, but aMT6s levels in breast cancer cases were lacking (Wu et al., Carcinogenesis 2008;29:1244–8). We updated the sleep duration–breast cancer association with 14 years of follow-up of 34,028 women in the SCHS. In a nested case–control study conducted within the SCHS, randomly timed, prediagnostic urinary aMT6s concentrations were compared between 248 incident breast cancer and 743 individually matched cohort controls. Three female controls were individually matched to each case on age at baseline interview (within 3 years), dialect group, menopausal status, date of baseline interview (within 2 years), date of urine sample collection (within 6 months) and timing of urine collection during the day (within 1 hr). Cox proportional hazards and conditional regression models with appropriate adjustment for confounders were used to examine the sleep– and aMT6s–breast cancer relationships. Breast cancer risk was not significantly associated with sleep duration; adjusted odds ratio (OR) for 9+ vs. ≤6 hr is 0.89 [95% confidence interval (95% CI) 5 0.64–1.22]. Prediagnostic aMT6s levels did not differ between breast cancer cases and matched controls; adjusted OR for highest versus lowest quartiles is 1.00 (95% CI 5 0.64-1.54). We conclude that sleep duration is not significantly associated with breast cancer risk reduction. Melatonin levels derived from randomly timed spot urine are unrelated to breast cancer. Randomly timed, spot urine-derived melatonin levels are noninformative as surrogates of nocturnal melatonin production.
doi:10.1002/ijc.27653
PMCID: PMC3477268  PMID: 22644618
sleep duration; spot urinary melatonin; breast cancer; prospective; Singaporean Chinese
7.  Asthma and the risk of type 2 diabetes in the Singapore Chinese Health Study 
Aim
Asthma is believed to increase the risk for several proinflammatory diseases, yet epidemiologic studies on asthma in relation to risk of developing type 2 diabetes are sparse and have reported inconsistent results. In the present study, we investigated the hypothesis that asthma is associated with an increased risk of incident type 2 diabetes in Chinese adults.
Methods
We used data from the Singapore Chinese Health Study, including Chinese men and women aged 45–74 years, free of cancer, heart disease, stroke, and diabetes at baseline (1993–1998) and followed through 2004 for incident physician-diagnosed diabetes. Cox regression models were used to examine the associations between self-reported history of physician-diagnosed asthma and risk of diabetes.
Results
During an average follow-up of 5.7 years per person, 2,234 of the 42,842 participants included in the current analyses reported diagnoses of type 2 diabetes. After adjustment for potential confounders, not including body mass index (BMI), asthma was associated with a 31% increased risk of incident diabetes (HR = 1.31; 95% CI: 1.00–1.72). The association was attenuated after adjustment for adult BMI (HR = 1.25 95% CI: 0.95–1.64). The asthma-diabetes association appeared stronger for adult- versus child-diagnosed asthma cases, and for participants who were obese compared to non-obese.
Conclusions
In Singaporean Chinese adults we observed a positive association between self-reported, physician-diagnosed asthma and risk of developing type 2 diabetes that was modestly attenuated upon adjustment for BMI.
doi:10.1016/j.diabres.2012.11.019
PMCID: PMC3615124  PMID: 23260853
Asthma; Type 2 diabetes; Obesity
8.  Body Mass Index and Risk of Pancreatic Cancer in a Chinese Population 
PLoS ONE  2014;9(1):e85149.
Few studies have examined the association between body mass index (BMI: kg/m2) and pancreatic cancer risk in Asian populations. We examined this relationship in 51,251 Chinese men and women aged 45–74 who enrolled between 1993 and 1998 in the population based, prospective Singapore Chinese Health Study. Data were collected through in-person interviews. By December 31, 2011, 194 cohort participants had developed pancreatic cancer. A Cox proportional hazards model was used to estimate hazard ratios (HR) and their 95% confidence intervals (95% CI). We hypothesized the association between BMI and pancreatic cancer risk may vary by smoking status (ever v. never) and there was evidence for this as the interaction between BMI and smoking status was significant (p = 0.018). Among ever smokers, being classified as underweight (BMI <18.5 kg/m2), was associated with a significantly elevated risk of pancreatic cancer relative to smokers with a BMI of 21.5–24.4 kg/m2 (HR = 1.99, 95% CI  =  1.03–3.84). This association was strengthened after exclusion of the first three years of follow-up time. Among never smokers, there was no association between BMI and pancreatic cancer risk. However, after excluding pancreatic cancer cases and person-years in the first three years of follow-up, never smokers with a BMI ≥ 27.5 kg/m2 showed a suggestive increased risk of pancreatic cancer relative to never smokers with a BMI of 21.5–24.4 kg/m2 (HR  =  1.75, 95% CI  =  0.93–3.3). In conclusion, Singaporean Chinese who were underweight with a history of smoking had an increased risk of developing pancreatic cancer, whereas there was no significant association between BMI and pancreatic cancer in never smokers.
doi:10.1371/journal.pone.0085149
PMCID: PMC3893175  PMID: 24454807
9.  Genetic and environmental predictors of serum 25(OH)D concentrations among middle-aged and elderly Chinese in Singapore 
The British journal of nutrition  2012;109(3):493-502.
Vitamin D is known for maintaining calcium homeostasis and bone structure, and may also decrease susceptibility to chronic and infectious diseases. However, data on vitamin D status and its predictors among Southeast Asian populations is limited. We evaluated the distribution and determinants (genetic and environmental) of serum 25-hydroxyvitamin D (25(OH)D) concentrations among 504 middle-aged and elderly participants (aged 45–74 years) in the Singapore Chinese Health Study. Data on dietary and other lifestyle factors were collected by trained interviewers. Serum 25(OH)D concentrations and genetic polymorphisms in vitamin D metabolism pathway enzymes [cytochrome P450 (CYP) 2R1, 3A4, 27B1, 24A1; vitamin D binding protein (GC); and vitamin D receptor (VDR)] were measured using stored biospecimens. Mean 25(OH)D concentration was 68.8 nmol/L. Serum 25(OH)D concentrations were positively associated with dietary vitamin D intake, and inversely associated with hours sitting at work. BMI was not associated with 25(OH)D concentrations. CYP2R1 rs10741657, rs12794714, rs1993116; CYP3A4 rs2242480; and GC rs4588, rs7041, rs16847015, rs2298849 were statistically significantly associated with 25(OH)D concentrations. Individuals with the Gc2-2 haplotype (rs4588AA/rs7041TT) had statistically significantly lower 25(OH)D concentrations compared to all other Gc haplotypes (p-trend<0.001). The majority of participants (86%) had 25(OH)D concentrations ≥50 nmol/L, which is consistent with the 2011 Institute of Medicine (United States) recommendation for bone health, and 32% had concentrations of ≥75 nmol/L that are thought to be required for broader health effects. Dietary vitamin D intake, hours spent indoors at work, and genetic variation in CYP2R1, CYP3A4 and GC are significant predictors of 25(OH)D concentrations among Singapore Chinese.
doi:10.1017/S0007114512001675
PMCID: PMC3442149  PMID: 22583563
25-hydroxyvitamin D; CYP2R1; CYP3A4; GC
10.  Genome-wide association studies of gastric adenocarcinoma and esophageal squamous cell carcinoma identify a shared susceptibility locus in PLCE1 at 10q23 
Nature genetics  2012;44(10):1090-1097.
We conducted a genome-wide association study of gastric cancer (GC) and esophageal squamous cell carcinoma (ESCC) in ethnic Chinese subjects in which we genotyped 551,152 single nucleotide polymorphisms (SNPs). We report a combined analysis of 2,240 GC cases, 2,115 ESCC cases, and 3,302 controls drawn from five studies. In logistic regression models adjusted for age, sex, and study, multiple variants at 10q23 had genome-wide significance for GC and ESCC independently. A notable signal was rs2274223, a nonsynonymous SNP located in PLCE1, for GC (P=8.40×1010; per allele odds ratio (OR) = 1.31) and ESCC (P=3.85×10−9; OR = 1.34). The association with GC differed by anatomic subsite. For tumors located in the cardia the association was stronger (P=4.19 × 10−15; OR= 1.57) and for those located in the noncardia stomach it was absent (P=0.44; OR=1.05). Our findings at 10q23 could provide insight into the high incidence rates of both cancers in China.
doi:10.1038/ng.2411
PMCID: PMC3513832  PMID: 22960999
11.  MITOCHONDRIAL COPY NUMBER IS ASSOCIATED WITH COLORECTAL CANCER RISK 
Background
Mitochondria are eukaryotic organelles responsible for energy production. Quantitative changes in human mitochondrial DNA (mtDNA) copy number have been implicated in various cancer types. Data from prospective cohort studies on mtDNA copy number and colorectal cancer risk have been lacking.
Methods
We evaluated the association between mtDNA copy number in peripheral blood and colorectal cancer risk in a nested case-control study of 422 colorectal cancer cases (168 cases with pre-diagnostic blood and 254 cases with post-diagnostic blood) and 874 controls who were free of colorectal cancer among participants of the Singapore Chinese Health Study. The relative mtDNA copy number was measured using real time PCR. Unconditional logistic regression methods were employed to examine the association between mtDNA copy number and colorectal cancer risk.
Results
There was a U-shaped relationship between the relative mtDNA copy number and colorectal cancer risk. Compared with the 2nd quartile, the odds ratios (95% confidence intervals) for subjects in the lowest and highest quartiles of relative mtDNA copy numbers were 1.81 (1.13–2.89) and 3.40 (2.15–5.36), respectively (Pcurvilinearity <0.0001). This U-shaped relationship was present in both men and women, similar for colon cancer and rectal cancer, and independent of the timing of blood draw with regards to cancer diagnosis.
Conclusions
This is the first prospectively designed study to show a U-shaped association between the relative mtDNA copy number and risk of colorectal cancer.
Impact
The findings of the present study support that mtDNA may play a critical role in the colorectal carcinogenesis in humans.
doi:10.1158/1055-9965.EPI-12-0138-T
PMCID: PMC3437007  PMID: 22787200
Mitochondria; colorectal cancer; prospective; cohort; mitochondrial DNA copy number
12.  Serum free estradiol and estrogen receptor-α mediated activity are related to decreased incident hip fractures in older women 
Bone  2012;50(6):1311-1316.
There is paucity of data from Asian women on the association between serum estrogens and osteoporotic hip fracture risk. We conducted a case-control study nested within a population-based prospective cohort, The Singapore Chinese Health Study, to evaluate serum estrogens levels, ERα-mediated estrogenic activity and hip fracture risk in postmenopausal Asian women. Among 35,298 women who were recruited between 1993 and 1998, 15,410 women donated blood for research between 1999 and 2004. From this subcohort, we identified 140 cases who subsequently suffered hip fracture after blood donation, and 278 age-matched controls. Serum levels of total estrone, estradiol and sex hormone binding globulin levels were measured in a blinded fashion among cases and controls. ERα-mediated estrogenic activity of serum samples was quantified using a sensitive ERα-driven cell bioassay. Women with hip fracture had lower serum estrogens than control women. Compared to the lowest quintile, women in the highest quintile of free estradiol exhibited a statistically significant 57% reduction in risk of hip fracture (95% confidence interval (CI), 6%–80%), with a dose-dependent relationship (p for trend = 0.021). High levels of ERα-mediated estrogenic activity was also associated with decreased risk of hip fracture (p for trend=0.048). Overall, women with relatively high levels of both free estradiol and ERα-mediated estrogenic activity had a 55% reduction in hip fracture risk (95% CI, 17%–76%) compared to women with low levels of both. High levels of free estradiol and ERα-mediated estrogen activity in sera were associated with reduced hip fracture risk in Chinese postmenopausal women.
doi:10.1016/j.bone.2012.03.006
PMCID: PMC3353105  PMID: 22445734
Estrogens; Hip Fracture; ERα-mediated estrogenic activity; Population-based; Asian women
13.  Genetic variation in peroxisome proliferator-activated receptor gamma, soy, and mammographic density in Singapore Chinese women 
Background
Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor important for adipogenesis and adipocyte differentiation. Data from animal studies suggest that PPARγ may be involved in breast tumorigenesis, but results from epidemiologic studies on the association between PPARγ variation and breast cancer risk have been mixed. Recent data suggest that soy isoflavones can activate PPARγ. We investigated the inter-relations of soy, PPARγ, and mammographic density (MD), a biomarker of breast cancer risk in a cross-sectional study of 2,038 women who were members of the population-based Singapore Chinese Health Study Cohort.
Methods
We assessed MD using a computer-assisted method. We used linear regression to examine the association between 26 tagging SNPs of PPARγ and their interaction with soy intake and MD. To correct for multiple testing, we calculated P-values adjusted for multiple correlated tests (PACT).
Results
Out of the 26 tested SNPs in the PPARγ, 6 SNPs were individually shown to be statistically significantly associated with MD (PACT=0.004∼0.049). A stepwise regression procedure identified that only rs880663 was independently associated with MD which decreased by 1.89% per minor allele (PACT=0.008).This association was significantly stronger in high soy consumers as MD decreased by 3.97% per minor allele of rs880663 in high soy consumers (PACT=0.006; P for interaction with lower soy intake=0.017).
Conclusions
Our data support that PPARγ genetic variation may be important in determining MD, particularly in high soy consumers.
Impact
Our findings may help to identify molecular targets and lifestyle intervention for future prevention research.
doi:10.1158/1055-9965.EPI-11-1042
PMCID: PMC3408217  PMID: 22301832
PPARγ; PPARG; polymorphism; soy; mammographic density; Chinese
14.  Genetic variation in folylpolyglutamate synthase and gamma-glutamyl hydrolase and plasma homocysteine levels in the Singapore Chinese Health Study 
The enzymes folylpolyglutamate synthase (FPGS) and gamma-glutamyl hydrolase (GGH) are essential for determining intracellular folate availability for one-carbon metabolism (OCM) pathways. FPGS adds glutamyl groups to the folate molecule, thereby converting folate into the preferred substrate for several enzymes in OCM pathways. GGH removes glutamyl groups, allowing folate metabolites to leave the cell. The purpose of this study was to evaluate whether single nucleotide polymorphisms (SNPs) in the FPGS and GGH genes influence measured plasma homocysteine levels. Study participants were a sub-cohort (n = 482) from the Singapore Chinese Health Study. SNPs were selected using HapMap tagSNPs and SNPs previously reported in the scientific literature. Multiple linear regression was used to evaluate the association between individual SNPs and plasma homocysteine levels. Two FPGS (rs10106, rs1098774) and 9 GGH (rs719235, rs1031552, rs1800909, rs3758149, rs3780126, rs3824333, rs4617146, rs11545076, rs11545078) SNPs were included in the final analysis. Neither of the FPGS SNPs, but three GGH SNPs were associated with plasma homocysteine levels: rs11545076 (p=0.001), rs1800909 (p=0.02), and rs3758149 (p = 0.006). Only one (rs11545076) remained statistically significant after adjusting for multiple comparisons. This study suggests that GGH SNPs, rs11545076, rs1800909, and rs3758149, may have functional relevance and result in alterations in plasma homocysteine levels. Since this is one of the first studies to assess FPGS and GGH genetic variants in relation to plasma homocysteine, further research is needed to confirm these findings and characterize the functional effects of these variants.
doi:10.1016/j.ymgme.2011.09.035
PMCID: PMC3253895  PMID: 22018726
FPGS; GGH; Folate; Homocysteine; SNP
15.  Glutathione S-transferase (GST) gene polymorphisms, cigarette smoking and colorectal cancer risk among Chinese in Singapore 
Carcinogenesis  2011;32(10):1507-1511.
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.
doi:10.1093/carcin/bgr175
PMCID: PMC3179426  PMID: 21803734
16.  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
17.  Body Mass Index and risk of colorectal cancer in Chinese Singaporeans: the Singapore Chinese Health Study 
Cancer  2011;117(16):3841-3849.
OBJECTIVES
To examine the association between body mass index (BMI) and incident colorectal cancer across the spectrum of BMI, including underweight, because detailed prospective cohort data on this topic in Asians is scarce, as is data on underweight (BMI < 18.5 kg/m2) in any population
RESEARCH DESIGN AND METHODS
Analysis of the Singapore Chinese Health Study included 51,251 men and women ages 45–74 years enrolled in 1993–1998 and followed up through 2007. Incident cancer cases and deaths among cohort members were identified through record linkage and 980 cases were identified. Cox regression models were used to investigate the association of baseline BMI with risk of incident colorectal cancer during mean 11.5 years of follow-up.
RESULTS
A significant U-shaped, quadratic association was observed between BMI and colon cancer risk, with increased risk in BMI’s ≥27.5 and < 18.5 kg/m2. The association was more pronounced in never-smokers; and most prominent when further limiting the sample to those free of diabetes and cases with greater than five years of follow up. Localized cases had a more pronounced association in BMI’s ≥27.5, whereas advanced cases had a more pronounced association in BMI’s < 18.5 kg/m2. No association was found in relation to rectal cancer risk. The association was also stronger among subjects aged 65 years and above.
CONCLUSIONS
BMI displays a U-shaped, quadratic association with colon cancer risk in this Chinese population in Southeast Asia.
doi:10.1002/cncr.25936
PMCID: PMC3151024  PMID: 21815135
Body mass index; obesity; underweight; Asians; colorectal cancer
18.  Aromatase (CYP19) promoter gene polymorphism and risk of non-viral hepatitis-related hepatocellular carcinoma 
Cancer  2011;117(15):3383-3392.
Background
Experimental studies suggest that sex hormones may induce or promote the development of hepatocellular carcinoma (HCC). Androgens are converted to estrogens by the CYP19 gene product, aromatase. Hepatic aromatase level and activity have been shown to be markedly elevated in HCC. Aromatase expression in liver tumors is driven by a promoter upstream of CYP19 exon I.6.
Method
We first identified an A/C polymorphism in the exon I.6 promoter of the CYP19 gene. To determine whether allelic variants in the CYP19 I.6 promoter differ in their ability to drive gene expression, we carried out an in-vitro reporter gene assay. We then studied the association between this polymorphism and HCC risk in two complementary case-control studies: one in high-risk southern Guangxi, China, and another in low-risk US non-Asians of Los Angeles County.
Results
Transcriptional activity was 60% higher for promoter vectors carrying the rs10459592 C allele compared to those carrying an A allele (p=0.007). In both study populations, among subjects negative for at-risk serologic markers of hepatitis B or C, there was a dose-dependent association between number of high activity C allele and risk of HCC (p for trend=0.014). Risk of HCC was significantly higher [odds ratio (OR) = 2.25, 95% confidence interval (CI) = 1.18–4.31] in subjects homozygous for the C allele compared to those homozygous for the A allele.
Conclusion
Our study provides epidemiologic evidence for the role of hepatic aromatization of androgen into estrogen in the development of non-viral hepatitis-related HCC.
doi:10.1002/cncr.25939
PMCID: PMC3138892  PMID: 21319151
Aromatase enzyme; hepatocellular carcinoma; gene polymorphism; viral hepatitis; sex hormones
19.  Coffee Intake and Risk of Colorectal Cancer Among Chinese in Singapore: The Singapore Chinese Health Study 
Nutrition and Cancer  2010;62(1):21-29.
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.
doi:10.1080/01635580903191528
PMCID: PMC3404428  PMID: 20043256
20.  Combined effects of MDM2 SNP309 and TP53 R72P polymorphisms, and soy isoflavones on breast cancer risk among Chinese women in Singapore 
Breast Cancer Research and Treatment  2011;130(3):1011-1019.
The MDM2 oncoprotein regulates the p53 pathway and, while functional polymorphisms of the MDM2 and p53 genes have been investigated for association with breast cancer risk, results are largely null or non-conclusive. We have earlier reported that the increased intake of soy isoflavones reduces risk of postmenopausal breast cancer, and experimental studies suggest that dietary isoflavones can down-regulate the expression of the MDM2 oncoprotein. In this study, we investigated the association between the MDM2 SNP309 and TP53 R72P polymorphisms and breast cancer risk using a case–control study of 403 cases and 662 controls nested among 35,303 women in The Singapore Chinese Health Study, a population-based, prospective cohort of middle-aged and elderly men and women who have been continuously followed since 1993. The G allele of the TP53 R72P polymorphism and T allele of the MDM2 SNP309 polymorphism were putative high-risk alleles and exhibited a combined gene–dose-dependent joint effect on breast cancer risk that was more clearly observed in postmenopausal women. Among postmenopausal women, the simultaneous presence of G allele in TP53 and T allele in MDM2 polymorphisms was associated with an odds ratio (OR) of 2.42 [95% confidence interval (CI) 1.06–5.50]. Furthermore, the protective effect of dietary soy isoflavones on postmenopausal breast cancer was mainly confined to women homozygous for the high activity MDM2 allele (GG genotype). In this genetic subgroup, women consuming levels of soy isoflavones above the median level exhibited risk that was half of those with below median intake (OR 0.52; 95% CI 0.28–0.99). Our findings support experimental data implicating combined effects of MDM2 protein and the p53-mediated pathway in breast carcinogenesis, and suggest that soy isoflavones may exert protective effect via down-regulation of the MDM2 protein.
doi:10.1007/s10549-011-1680-2
PMCID: PMC3404431  PMID: 21833626
MDM2; p53; Soy isoflavones; Breast cancer; Chinese
21.  Soft Drink and Juice Consumption and Risk of Pancreatic Cancer: The Singapore Chinese Health Study 
Background
Sugar-sweetened carbonated beverages (called soft drinks) and juices, which have a high glycemic load relative to other foods and beverages, have been hypothesized as pancreatic cancer risk factors. However, data thus far are scarce, especially from non-European descent populations. We investigated whether higher consumption of soft drinks and juice increases the risk of pancreatic cancer in Chinese men and women.
Methods
A prospective cohort analysis was done to examine the association between soft drink and juice consumption and the risk of pancreatic cancer in 60,524 participants of the Singapore Chinese Health Study with up to 14 years of follow-up. Information on consumption of soft drinks, juice, and other dietary items, as well as lifestyle and environmental exposures, was collected through in-person interviews at recruitment. Pancreatic cancer cases and deaths were ascertained by record linkage of the cohort database with records of population-based Singapore Cancer Registry and the Singapore Registry of Births and Deaths.
Results
The first 14 years for the cohort resulted in cumulative 648,387 person-years and 140 incident pancreatic cancer cases. Individuals consuming ≥2 soft drinks/wk experienced a statistically significant increased risk of pancreatic cancer (hazard ratio, 1.87; 95% confidence interval, 1.10–3.15) compared with individuals who did not consume soft drinks after adjustment for potential confounders. There was no statistically significant association between juice consumption and risk of pancreatic cancer.
Conclusion
Regular consumption of soft drinks may play an independent role in the development of pancreatic cancer.
doi:10.1158/1055-9965.EPI-09-0862
PMCID: PMC3404432  PMID: 20142243
22.  Combined Lifestyle Factors and Cardiovascular Disease Mortality in Chinese Men and Women 
Circulation  2011;124(25):2847-2854.
Background
Lifestyle factors directly influence cardiovascular disease (CVD) risk, yet little research has examined the association of combined lifestyle factors with CVD mortality, especially in Asian populations.
Methods and Results
We examined the association of 6 combined lifestyle factors (dietary pattern, physical activity, alcohol intake, usual sleep, smoking status, and body mass index) with CVD mortality in 50 466 (44 056 without a history of diabetes mellitus, CVD, or cancer and 6410 with diabetes mellitus or history of clinical CVD) Chinese men and women in Singapore who were 45 to 74 years of age during enrollment in the Singapore Chinese Health Study in 1993 to 1998 and followed up through 2009. Each lifestyle factor was independently associated with CVD mortality. When combined, there was a strong, monotonic decrease in age- and sex-standardized CVD mortality rates with an increasing number of protective lifestyle factors. Relative to participants with no protective lifestyle factors, the hazard ratios of CVD mortality for 1, 2, 3, 4, and 5 to 6 protective lifestyle factors were 0.60 (95% confidence interval, 0.45-0.84), 0.50 (95% confidence interval, 0.38-0.67), 0.40 (95% confidence interval, 0.30-0.53), 0.32 (95% confidence interval, 0.24-0.43), and 0.24 (95% confidence interval, 0.17-0.34), respectively, among those without a history of diabetes mellitus, CVD, or cancer (P for trend <0.0001). A parallel graded inverse association was observed in participants with a history of CVD or diabetes mellitus at baseline. Results were consistent for coronary heart disease and cerebrovascular disease mortality.
Conclusion
An increasing number of protective lifestyle factors is associated with a marked decreased risk of coronary heart disease, cerebrovascular disease, and overall CVD mortality in Chinese men and women.
doi:10.1161/CIRCULATIONAHA.111.048843
PMCID: PMC3400937  PMID: 22104554
Asian continental ancestry group; cardiovascular disease; life style; mortality; risk factors
23.  Mortality due to coronary heart disease and kidney disease among middle-aged and elderly men and women with gout in the Singapore Chinese Health Study 
Annals of the Rheumatic Diseases  2011;71(6):924-928.
Objectives
Whether the link between gout and mortality is causal or confounded by lifestyle factors or comorbidities remains unclear. Studies in Asia are warranted due to the rapid modernisation of the locale and ageing of the population.
Methods
The association between gout and mortality was examined in a prospective cohort, the Singapore Chinese Health Study, comprising 63 257 Singapore Chinese individuals, aged 45–74 years during the enrolment period of 1993–8. All enrollees were interviewed in person on lifestyle factors, current diet and medical histories. All surviving cohort members were contacted by telephone during 1999–2004 to update selected exposure and medical histories (follow-up I interview), including the history of physician-diagnosed gout. Cause-specific mortality in the cohort was identified via record linkage with the nationwide death registry, up to 31 December 2009.
Results
Out of 52 322 participants in the follow-up I interview, 2117 (4.1%) self-reported a history of physician-diagnosed gout, with a mean age at diagnosis of 54.7 years. After a mean follow-up period of 8.1 years, there were 6660 deaths. Relative to non-gout subjects, subjects with gout had a higher risk of death (HR 1.18; 95% CI 1.06 to 1.32), and specifi cally from death due to coronary heart disease (CHD) (HR 1.38, 95% CI 1.10 to 1.73) and kidney disease (HR 5.81, 95% CI 3.61 to 9.37). All gout–mortality risk associations were present in both genders but the risk estimates appeared higher for women.
Conclusion
Gout is an independent risk factor for mortality, and specifically for death due to CHD and kidney disease.
doi:10.1136/ard.2011.200523
PMCID: PMC3400339  PMID: 22172492
24.  Coffee consumption and reduced risk of hepatocellular carcinoma: findings from the Singapore Chinese Health Study 
Cancer causes & control : CCC  2011;22(3):503-510.
Background
Coffee consumption has been associated with reduced markers of hepatic cell damage, reduced risk of chronic liver disease, and cirrhosis across a variety of populations. Data on the association between coffee consumption and risk of hepatocellular carcinoma (HCC), especially in high-risk populations, are sparse.
Methods
This study examines the relationship between coffee and caffeine consumption, and the risk of developing HCC within the Singapore Chinese Health Study, a prospective cohort of 63,257 middle-aged and older Chinese men and women, a relatively high-risk population for HCC. Baseline data on coffee consumption and other dietary and lifestyle factors were collected through inperson interviews at enrollment between 1993 and 1998.
Results
As of 31 December 2006, 362 cohort participants had developed HCC. High levels of coffee or caffeine consumption were associated with reduced risk of HCC (p for trend < 0.05). Compared with non-drinkers of coffee, individuals who consumed three or more cups of coffee per day experienced a statistically significant 44% reduction in risk of HCC (hazard ratio 0.56, 95% confidence interval, 0.31–1.00, p = .049) after adjustment for potential confounders and tea consumption.
Conclusion
These data suggest that coffee consumption may reduce the risk of developing HCC in Chinese in Singapore.
doi:10.1007/s10552-010-9725-0
PMCID: PMC3400401  PMID: 21258859
Coffee; Caffeine; HCC; Hepatocellular; Liver cancer; GGT
25.  Nutrigenetics and Nutrigenomics: Viewpoints on the Current Status and Applications in Nutrition Research and Practice 
Nutrigenetics and nutrigenomics hold much promise for providing better nutritional advice to the public generally, genetic subgroups and individuals. Because nutrigenetics and nutrigenomics require a deep understanding of nutrition, genetics and biochemistry and ever new ‘omic’ technologies, it is often difficult, even for educated professionals, to appreciate their relevance to the practice of preventive approaches for optimising health, delaying onset of disease and diminishing its severity. This review discusses (i) the basic concepts, technical terms and technology involved in nutrigenetics and nutrigenomics; (ii) how this emerging knowledge can be applied to optimise health, prevent and treat diseases; (iii) how to read, understand and interpret nutrigenetic and nutrigenomic research results, and (iv) how this knowledge may potentially transform nutrition and dietetic practice, and the implications of such a transformation. This is in effect an up-to-date overview of the various aspects of nutrigenetics and nutrigenomics relevant to health practitioners who are seeking a better understanding of this new frontier in nutrition research and its potential application to dietetic practice.
doi:10.1159/000327772
PMCID: PMC3121546  PMID: 21625170
Dietetics; Nutrigenetics; Nutrigenomics; Nutrition Research; Personalised nutrition

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