Aizhen Jin

Diabetes mellitus and risk of hepatocellular carcinoma: findings from the Singapore Chinese Health Study

Background:The increasing prevalence of diabetes may contribute to the rising incidence of hepatocellular carcinoma (HCC) in the US and other developed countries where HCC incidence is relatively low. Data from prospective studies on diabetes and risk of HCC in at-risk populations due to high prevalence of viral hepatitis in southeast Asia are sparse.Methods:The Singapore Chinese Health Study is a prospective cohort of 63 257 middle-aged and older Chinese men and women enrolled in 1993–1998. Besides an in-person interview administered to all participants at baseline, testing of serologic markers of hepatitis B or C infections were performed on a subset of cohort subjects. After a mean follow-up of 14 years, 499 cohort participants developed HCC.Results:A history of diabetes at baseline was associated with a hazard ratio of 2.14 (95% confidence interval, 1.69–2.71). This statistically significant association was comparable in magnitude between men and women, and remained equally strong across strata of subjects defined by the number of years between their first clinical diagnosis of diabetes and time of enrolment in this cohort. Within a nested case-control set of cohort subjects tested for serological markers of hepatitis B or C infections, the diabetes–HCC association was found to be present mainly among those devoid of any markers.Conclusion:A history of diabetes at baseline is highly associated with non-viral HCC. Future studies are warranted to elucidate the biological mechanism underpinning the role of diabetes in nonviral-related hepatocarcinogenesis.

Glutathione S-transferase (GST) gene polymorphisms, cigarette smoking and colorectal cancer risk among Chinese in Singapore

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 smokers 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.

Coffee intake and gastric cancer risk: the Singapore Chinese health study.

Background: Despite experimental evidence showing chemopreventive effects of coffee-related compounds on gastric carcinogenesis, epidemiologic studies generally do not support coffee–gastric cancer associations. Observational data are lacking among high-risk populations with sufficient regular coffee consumption. Methods: We examined the association between caffeinated coffee intake and gastric cancer risk in a population-based cohort that enrolled 63,257 Chinese men and women ages 45 to 74 years between 1993 and 1998 in Singapore. Incident gastric cancer cases (n = 647) were identified after a mean follow-up of 14.7 years. Biomarkers of Helicobacter pylori (H. pylori) infection were measured in a subset of gastric cancer cases with blood collected before cancer diagnosis and their matched controls. Results: In the total cohort, daily versus nondaily coffee intake was associated with a statistically nonsignificant decrease in gastric cancer risk [HR = 0.85; 95% confidence interval (CI), 0.69–1.04]. In women, the inverse association strengthened and reached statistical significance (HR = 0.63; 95% CI, 0.46–0.87). In analyses restricted to never smokers and nondrinkers of alcohol, inverse associations strengthened in the total cohort (HR = 0.69; 95% CI, 0.52–0.91) and in women (HR = 0.52; 95% CI, 0.37–0.74). There was no coffee–gastric cancer risk association among men, regardless of smoking status or alcohol consumption. Similar results were observed in the nested case–control study after adjustment for H. pylori infection. Conclusion: Daily coffee consumption may reduce the risk of gastric cancer in high-risk populations, especially among women. Impact: Research aimed at identifying the compounds in coffee that may protect against gastric carcinogenesis is warranted. Cancer Epidemiol Biomarkers Prev; 23(4); 638–47. ©2014 AACR.

Dietary intake of one-carbon metabolism-related nutrients and pancreatic cancer risk: The Singapore Chinese Health Study

Background: Nutrients involved in one-carbon metabolism are hypothesized to protect against pancreatic cancer development. Methods: The Singapore Chinese Health Study database was used to prospectively examine the association between intake of one-carbon metabolism–related nutrients and pancreatic cancer risk. Between 1993 and 1998, 63,257 men and women ages 45 to 74 years were enrolled into the cohort. The daily intakes of the following one-carbon metabolism–related nutrients were assessed at enrollment using a 165-item food frequency questionnaire: betaine, choline, folate, and vitamins B2, B6, and B12. Multivariable HRs and 95% confidence intervals (CI) for pancreatic cancer risk associated with dietary intakes of one-carbon metabolism–related nutrients were calculated. Results: As of December 2013, 271 incident pancreatic cancer cases were identified during an average of 16.3 years of follow-up. Higher intakes of vitamin B6 and choline were associated with statistically significant decreases in the risk of developing pancreatic cancer. Compared with the lowest quartile, HRs (95% CIs) for the highest quartiles of vitamin B6 and choline were 0.52 (0.36–0.74; P trend = 0.001) and 0.67 (0.48–0.93; P trend = 0.04), respectively. There were no clear associations between the other one-carbon metabolism–related nutrients and pancreatic cancer risk. Conclusion: Our study suggests that higher intake of vitamin B6 and choline may lower the risk of pancreatic cancer. Impact: Our prospective findings are consistent with the in vivo evidence for protective roles of vitamin B6 and choline on pancreatic cancer development. Cancer Epidemiol Biomarkers Prev; 25(2); 417–24. ©2015 AACR.

Combined effects of MDM2 SNP309 and TP53 R72P polymorphisms, and soy isoflavones on breast cancer risk among Chinese women in Singapore.

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.

Dietary fatty acids and risk of hepatocellular carcinoma in the Singapore Chinese health study.

Lipidomic signature of lipid metabolism suggests that omega‐6 polyunsaturated fatty acids (PUFA) may play a role in oncogenesis of hepatocellular carcinoma (HCC). Hence, we examined the association between dietary fatty acids and risk of HCC.

Physical activity and risk of end‐stage kidney disease in the Singapore Chinese Health Study

To explore the relationship between physical activity and risk of end‐stage kidney disease (ESKD).

Mortality rates in major and subthreshold depression: 10-year follow-up of a Singaporean population cohort of older adults

ABSTRACT Objectives: To investigate the associations of major and subthreshold depression with all-cause, cardiovascular disease and stroke mortality, and the extent to which health behaviour, medical comorbidity and functional disability explained the associations. Methods: A cohort of 1070 persons aged ≥60 with Geriatric Mental State (GMS) diagnoses of major and subthreshold depression, and data on health behaviour (smoking, alcohol, physical activity) and physical comorbidity (hypertension, diabetes, cardiovascular disease, stroke, chronic pulmonary disease, multi-comorbidity and activity of daily living disability) at baseline (15 Feb 2003 - 30 Mar 2004) were followed up on mortality from 1 Jan 2005 to 31 Dec 2012. Results: Major and subthreshold depression was present in 5.1% and 9.9% of the participants at baseline. The all-cause mortality HR adjusted for age, sex, ethnicity and marital status was 1.73 (95% CI, 1.11-2.67) for major depression and 1.38 (95% CI, 0.96-1.97) for subthreshold depression. In hierarchical models, the addition of health behaviour and especially physical comorbidity substantially reduced the HR estimates for all-cause mortality associated with major depression (HR=1.39, 95% CI, 0.89-2.18) and subthreshold depression (HR=0.94, 95% CI, 0.64-1.37). Controlling for the effects of all variables, only major depression was significantly associated with increased cardiovascular disease and stroke mortality (HR=2.10, 95% CI, 1.07-4.11). Conclusions: Both major and subthreshold depression were associated with increased mortality, largely due to hazardous behaviours and physical comorbidity. Only major depression per se was independently associated with excess cardiovascular disease and stroke mortality.

Smoking and risk of kidney failure in the Singapore Chinese health study.

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 m2, 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.

Leukocyte telomere length in relation to risk of lung adenocarcinoma incidence: Findings from the Singapore Chinese Health Study: Telomere length and lung cancer

Telomeres are crucial in the maintenance of chromosome integrity and genomic stability. Critically short telomeres can trigger programed cell death while cells with longer telomeres may have increased likelihood of replicative errors, resulting in genetic mutations and chromosomal alterations, and ultimately promoting oncogenesis. Data on telomere length and lung cancer risk from large prospective cohort studies are spare. Relative telomere length in peripheral blood leukocytes was quantified using a validated monochrome multiplex quantitative polymerase chain reaction (qPCR) method in 26,540 participants of the Singapore Chinese Health Study. After a follow‐up of 12 years, 654 participants developed lung cancer including 288 adenocarcinoma, 113 squamous cell carcinoma and 253 other/unknown histological type. The Cox proportional hazard regression was used to estimate hazard ratio (HR) and 95% confidence interval (CI). HR of lung adenocarcinoma for individuals in the highest comparing the lowest 20 percentile of telomere length was 2.84 (95% CI 1.94–4.14, ptrend < 0.0001). This positive association was present in never smokers (ptrend < 0.0001), ever smokers (ptrend = 0.0010), men (ptrend = 0.0003), women (ptrend < 0.0001), and in shorter (ptrend = 0.0002) and longer (ptrend = 0.0001) duration of follow‐up. There was no association between telomere length and risk of squamous cell carcinoma or other histological type of lung cancer in all or subgroups of individuals. The agreement of results from this prospective cohort study with those of previous prospective studies and Mendelian randomization studies suggest a possible etiological role of telomere length in the development of lung adenocarcinoma.