Association of Caucasian-identified variants with colorectal cancer risk in Singapore Chinese

Background: Genome-wide association studies (GWAS) in Caucasians have identified fourteen index single nucleotide polymorphisms (iSNPs) that influence colorectal cancer (CRC) risk. Methods: We investigated the role of eleven iSNPs or surrogate SNPs (sSNPs), in high linkage disequilibrium (LD, r2≥0.8) and within 100 kb vicinity of iSNPs, in 2,000 age- and gender-matched Singapore Chinese (SCH) cases and controls. Results: Only iSNP rs6983267 at 8q24.21 and sSNPs rs6695584, rs11986063, rs3087967, rs2059254, and rs7226855 at 1q41, 8q23.3, 11q23.1, 16q22.1 and 18q21.1 respectively showed evidence of association with CRC risk, with odds ratios (OR) ranging from 1.13 to 1.40. sSNP rs827401 at 10p14 was associated with rectal cancer risk (OR = 0.74, 95% CI 0.63-0.88) but not disease prognosis (OR = 0.91, 95% CI 0.69-1.20). Interestingly, sSNP rs3087967 at 11q23.1 was associated with CRC risk in men (OR = 1.34, 95% CI 1.14-1.58) but not women (OR = 1.07, 95% CI: 0.88-1.29), suggesting a gender-specific role. Half of the Caucasian-identified variants, including the recently fine-mapped BMP pathway loci, BMP4, GREM1, BMP2 and LAMA 5, did not show any evidence for association with CRC in SCH (OR ~1; p-value >0.1). Comparing the results of this study with that of the Northern and Hong Kong Chinese, only variants at chromosomes 8q24.21, 10p14, 11q23.1 and 18q21.1 were replicated in at least two out of the three Chinese studies. Conclusions: The contrasting results between Caucasians and Chinese could be due to different LD patterns and allelic frequencies or genetic heterogeneity. The results suggest that additional common variants contributing to CRC predisposition remained to be identified. © 2012 Thean et al

The effect of cyclin D1 (CCND1) G870A-polymorphism on breast cancer risk is modified by oxidative stress among Chinese women in Singapore

Cyclin D1 (CCND1), an intracellular cell-cycle regulatory protein with checkpoint function, can promote cell proliferation or induce growth arrest and apoptosis depending on the cellular context. We hypothesized that the direction of the association between the (CCND1) G870A-polymorphism and breast cancer risk may be modified by dietary and genetic factors influencing the oxidant-antioxidant balance, such as a dietary pattern with a high intake of n-6 fatty acids and a low intake of n-3 fatty acids, or a genetic profile that is deficient in glutathione S-transferases. We tested our hypothesis in a case-control study nested into the Singapore Chinese Health Study, a prospective investigation of diet and cancer in 63 000 Chinese men and women. Genomic DNA collected from 258 incident cases of breast cancer and 670 female cohort controls was examined for CCND1, GSTM1, GSTT1 and GSTP1 genes using fluorogenic 5′-nuclease assay. Unconditional logistic regression models were used to assess the effects with adjustment for potential confounders. All statistical tests were two-sided. The heterozygous CCND1 GA genotype significantly reduced the breast cancer risk in all subjects (OR = 0.67, 95% CI 0.45-0.99) when compared with the GG genotype. The association was restricted to women with a high (above median value) intake level of n-6 fatty acids (OR = 0.51, 95% CI 0.30-0.87), a low (below median value) intake level of the antagonistic marine n-3 fatty acids (OR = 0.54, 95% CI 0.32-0.93) or a total lack of the antioxidative GSTM1 (OR = 0.44, 95% CI 0.25-0.80) or GSTT1 genes (OR = 0.46, 95% CI 0.24-0.87). The effects were consistently stronger in cases with advanced disease. The AA genotype did not affect breast cancer risk. The results of this study are compatible with the hypothesis that the oxidant-antioxidant balance in cells is an important determinant of the direction of the cyclin D1 effect, leading either to cell proliferation or cell deat

The effect of the cyclin D1 (CCND1) A870G polymorphism on colorectal cancer risk is modified by glutathione-S-transferase polymorphisms and isothiocyanate intake in the Singapore Chinese Health Study

Cyclin D1 (CCND1) regulates cellular decision between proliferation and growth arrest. Despite the functional relevance of the CCND1 A870G single nucleotide polymorphism (SNP) published results on its association with colorectal cancer (CRC) were inconsistent. We examined the association between this CCND1 genotype and CRC in the Singapore Chinese Health Study, a prospective investigation of diet and cancer in 63 000 Chinese men and women. We explored the hypothesis that inconsistency regarding the CCND1/CRC association may be attributable to the modifying effect of additional CRC risk factors. Since GSTM1/GSTT1 genotype and dietary isothiocyanate (ITC) intake had previously been identified as CRC risk factors in this cohort, we now explored if they influenced the CCND1/CRC association. In a nested case-control study within the Singapore Cohort, genomic DNA collected from 300 incident CRC cases and 1169 controls was examined for CCND1, GSTM1, GSTT1 and GSTP1 polymorphisms. Unconditional logistic regression was used to assess genotype effects on cancer risk. No main effect of CCND1 was observed, yet the CCND1 effect was influenced by ITC intake and GST genotypes. The presence of at least one CCND1 A-allele was associated with increased risk among low dietary ITC consumers (intake below median value for the cohort) with a high-activity GST profile (≥2 of the 3 GST genotypes classified non-null or high-activity) [odds ratio (OR) = 2.05; 95% confidence interval (CI), 1.10-3.82]. In contrast, the presence of at least one A-allele was associated with a decreased risk among all remaining subjects (OR = 0.56; 0.36-0.86) (P for interaction = 0.01). Recent studies indicate that ITCs inhibit cell proliferation and cause apoptosis through pro-oxidant properties. The results of our current study on CRC and those of our previous breast cancer study are compatible with the notion of oxidative stress in target cells as important determinant of direction and magnitude of the CCND1 effec

Elevated levels of mercapturic acids of acrolein and crotonaldehyde in the urine of Chinese women in Singapore who regularly cook at home

10.1371/journal.pone.0120023PLoS ONE103e012002

BMI, All-Cause and Cause-Specific Mortality in Chinese Singaporean Men and Women: The Singapore Chinese Health Study

Background: The optimal range of relative weight for morbidity and mortality in Asian populations is an important question in need of more thorough investigation, especially as obesity rates increase. We aimed to examine the association between body mass index (BMI), all cause and cause-specific mortality to determine the optimal range of BMI in relation to mortality in Chinese men and women in Singapore. Methodology/Principal Findings: We analyzed data from a prospective cohort study of 51,251 middle-aged or older (45– 74) Chinese men and women in the Singapore Chinese Health Study. Participants were enrolled and data on body weight and covariates were collected in 1993–1998 and participants were followed through 2008. The analysis accounted for potential methodological issues through stratification on smoking and age, thorough adjustment of demographic and lifestyle confounders and exclusion of deaths early in the follow-up. Conclusions/Significance: Increased risk of mortality was apparent in underweight (,18.5) and obese BMI categories ($27.5) independent of age and smoking. Regardless of age or BMI, smoking considerably increased the rate of mortality and modified the association between BMI and mortality. The most favorable range of BMI for mortality rates and risk in non-smoking persons below age 65 was 18.5–21.4 kg/m 2, and for non-smoking persons aged 65 and above was 21.5

Plasma adiponectin levels and type 2 diabetes risk: a nested case-control study in a Chinese population and an updated meta-analysis.

Results from previous prospective studies assessing the relation between adiponectin and type 2 diabetes (T2D) were not entirely consistent, and evidence in Chinese population is scarce. Moreover, the last meta-analysis did not examine the impact of metabolic variables on the adiponectin-T2D association. Therefore, we prospectively evaluated the adiponectin-T2D association among 571 T2D cases and 571 age-sex-matched controls nested within the Singapore Chinese Health Study (SCHS). Furthermore, we conducted an updated meta-analysis by searching prospective studies on Pubmed till September 2016. In the SCHS, the odds ratio of T2D, comparing the highest versus lowest tertile of adiponectin levels, was 0.30 (95% confidence interval: 0.17, 0.55) in the fully-adjusted model. The relation was stronger among heavier participants (body mass index ≥23 kg/m2) compared to their leaner counterparts (P for interaction = 0.041). In a meta-analysis of 34 prospective studies, the pooled relative risk was 0.53 (95% confidence interval: 0.47, 0.61) comparing the extreme tertiles of adiponectin with moderate heterogeneity (I 2 = 48.7%, P = 0.001). The adiponectin-T2D association remained unchanged after adjusting for inflammation and dyslipidemia markers, but substantially attenuated with adjustment for insulin sensitivity and/or glycaemia markers. Overall evidence indicates that higher adiponectin levels are associated with decreased T2D risk in Chinese and other populations

Serum Amino Acids in Association with Prevalent and Incident Type 2 Diabetes in A Chinese Population

We aimed to simultaneously examine the associations of both essential and non-essential amino acids with both prevalent and incident type 2 diabetes in a Chinese population. A case-control study was nested within the Singapore Chinese Health Study. Participants included 144 cases with prevalent and 160 cases with incident type 2 diabetes and 304 controls. Cases and controls were individually matched on age, sex, and date of blood collection. Baseline serum levels of 9 essential and 10 non-essential amino acids were measured using liquid chromatography tandem mass spectrometry. We identified that five essential (isoleucine, leucine, lysine, phenylalanine, and valine) and five non-essential (alanine, glutamic acid, glutamine, glycine, and tyrosine) amino acids were associated with the prevalence of type 2 diabetes; four essential (isoleucine, leucine, tryptophan, and valine) and two non-essential (glutamine and tyrosine) amino acids were associated with the incidence of type 2 diabetes. Of these, valine and tyrosine independently led to a significant improvement in risk prediction of incident type 2 diabetes. This study demonstrates that both essential and non-essential amino acids were associated with the risk for prevalent and incident type 2 diabetes, and the findings could aid in diabetes risk assessment in this Chinese population

Adherence to a planetary health diet, environmental impacts, and mortality in Chinese adults

mportance Although the EAT-Lancet Commission has recently proposed a planetary health diet (PHD) to promote human and environmental health, little is known about how PHD affects environment and mortality risk among an Asian population. Objective To investigate whether a PHD score is associated with environmental impacts and mortality outcomes in a Chinese cohort living in Singapore. Design, Setting, and Participants This cohort study used data from the Singapore Chinese Health Study. Eligible participants were without known cardiovascular disease and cancer at baseline; they were recruited between 1993 and 1998 and followed up using record linkage data until 2020. Data were analyzed from September 2022 to April 2023. Exposures PHD score was calculated based on the reference consumption of 14 dietary components in PHD and individual energy intake assessed using a validated food frequency questionnaire in this cohort. Main Outcomes and Measures Diet-related environmental impacts were estimated using a food frequency questionnaire. Mortality outcomes (all-cause, cardiovascular disease, cancer, and respiratory disease) were identified via linkage with a nationwide registry. Results A total of 57 078 participants were included in this study (mean [SD] age, 56.1 (7.9) years; 31 958 women [56.0%]). During a median (IQR) follow-up of 23.4 (18.7-26.2) years, 22 599 deaths occurred. Comparing the highest and lowest quintiles, higher PHD scores were associated with lower greenhouse gas emissions (β = −0.13 kg CO2 equivalent; 95% CI, −0.14 to −0.12 kg CO2 equivalent), but with higher total water footprint (β = 0.12 m3; 95% CI, 0.11-0.13 m3) and land use (β = 0.29 m2; 95% CI, 0.28-0.31 m2). In the adjusted multivariable model, compared with the lowest quintile, participants in the highest quintile of PHD score had lower risk of all-cause mortality (hazard ratio [HR], 0.85; 95% CI, 0.81-0.89), cardiovascular disease mortality (HR, 0.79; 95% CI, 0.73-0.85), cancer mortality (HR, 0.93; 95% CI, 0.86-1.00), and respiratory disease mortality (HR, 0.81; 95% CI, 0.74-0.89). Conclusions and Relevance In this study of Singapore Chinese adults, higher adherence to PHD was associated with reduced risk of chronic disease mortality. However, environmental impacts were uncertain, as higher adherence was associated with lower greenhouse gas emissions but higher total water footprint and land use

Mitochondrial DNA Copy Number Is Associated with Breast Cancer Risk

Mitochondrial DNA (mtDNA) copy number in peripheral blood is associated with increased risk of several cancers. However, data from prospective studies on mtDNA copy number and breast cancer risk are lacking. We evaluated the association between mtDNA copy number in peripheral blood and breast cancer risk in a nested case-control study of 183 breast cancer cases with pre-diagnostic blood samples and 529 individually matched controls among participants of the Singapore Chinese Health Study. The mtDNA copy number was measured using real time PCR. Conditional logistic regression analyses showed that there was an overall positive association between mtDNA copy number and breast cancer risk (Ptrend = 0.01). The elevated risk for higher mtDNA copy numbers was primarily seen for women with <3 years between blood draw and cancer diagnosis; ORs (95% CIs) for 2nd, 3rd, 4th, and 5th quintile of mtDNA copy number were 1.52 (0.61, 3.82), 2.52 (1.03, 6.12), 3.12 (1.31, 7.43), and 3.06 (1.25, 7.47), respectively, compared with the 1st quintile (Ptrend = 0.004). There was no association between mtDNA copy number and breast cancer risk among women who donated a blood sample ≥3 years before breast cancer diagnosis (Ptrend = 0.41). This study supports a prospective association between increased mtDNA copy number and breast cancer risk that is dependent on the time interval between blood collection and breast cancer diagnosis. Future studies are warranted to confirm these findings and to elucidate the biological role of mtDNA copy number in breast cancer risk. © 2013 Thyagarajan et al

Burden of Total and Cause-Specific Mortality Related to Tobacco Smoking among Adults Aged ≥45 Years in Asia: A Pooled Analysis of 21 Cohorts

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