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Background: Although red meat consumption has been associated with risk of atherosclerotic coronary artery disease and stroke, no prospective study has examined this with the risk of chronic limb-threatening ischemia (CLTI)., Methods: In a prospective study of 63,257 Chinese in Singapore, who were aged 45-74 years old at recruitment, diet was assessed via a validated semi-quantitative food frequency questionnaire. Incident CLTI cases were ascertained via linkage with nationwide hospital records for lower extremity amputation or angioplasty for peripheral arterial disease. Multivariable Cox models were used to examine associations between quartiles of meat intake and CLTI risk., Results: After a mean follow-up of 18.8 years, there were 1069 cases of CLTI. Higher intake of red meat intake was associated with increased risk of CLTI in a stepwise manner. Comparing extreme quartiles of red meat intake, the hazard ratio (HR) for the association with CLTI risk was 1.24 [95% confidence interval (CI) = 1.03-1.49; P-trend = 0.02]. In stratified analysis, red meat intake had a stronger association with CLTI risk among those without diabetes [HR (95% CI) comparing extreme quartiles = 1.41 (1.10-1.80); P-trend = 0.03] than among those with diabetes at baseline [HR (95% CI) comparing extreme quartiles = 1.04 (0.79-1.38); P-trend = 0.05] (P-interaction = 0.03). Otherwise, the associations were not different by sex, BMI, smoking status, hypertension, alcohol consumption, or history of cardiovascular diseases. Using a theoretical model in substitution analysis that substituted three servings per week of red meat with poultry or fish/shellfish, the relative risk of CLTI was reduced by 13-14%., Conclusions: Consumption of red meat was associated with higher CLTI risk in this Asian cohort. Substituting red meat with poultry or fish/shellfish may reduce this risk., (© 2024. The Author(s).)

Background: It is unclear if improving diet quality after midlife could reduce the risk of physical frailty at late life. We aimed to associate changes in diet quality after midlife with physical frailty at late life., Methods: Diet quality in 12,580 participants from the Singapore Chinese Health Study was assessed with the Dietary Approaches to Stop Hypertension (DASH) scores at baseline (1993-1998; mean age 53 years) and follow-up 3 (2014-2016; mean age 73 years). Physical frailty was assessed using the modified Cardiovascular Health Study phenotype at follow-up 3. Multivariable logistic regressions examined associations between DASH scores and physical frailty., Results: Comparing participants in extreme quartiles of DASH scores, the odds ratios (OR) [95% confidence interval (CI)] for physical frailty were 0.85 (0.73,0.99) at baseline and 0.49 (0.41, 0.58) at follow-up 3. Compared to participants with consistently low DASH scores, participants with consistently high scores (OR 0.74, 95% CI: 0.59, 0.94) and those with > 10% increase in scores (OR 0.78, 95% CI: 0.64, 0.95) had lower odds of frailty. Compared to those in the lowest DASH tertiles at both time-points, significantly lower odds of physical frailty were observed in those who were in the highest DASH tertiles at both time points [0.59 (0.48, 0.73)], and in those who improved their scores from the lowest [0.68 (0.51, 0.91)] or second tertile at baseline [0.61 (0.48, 0.76)] to the highest tertile at follow-up 3., Conclusions: Maintaining a high diet quality or a substantial improvement in diet quality after midlife could lower the risk of physical frailty at late life., (© 2024. The Author(s).)

Background: Family history, and genetic and non-genetic risk factors can stratify women according to their individual risk of developing breast cancer. The extent of overlap between these risk predictors is not clear., Methods: In this case-only analysis involving 7600 Asian breast cancer patients diagnosed between age 30 and 75 years, we examined identification of high-risk patients based on positive family history, the Gail model 5-year absolute risk [5yAR] above 1.3%, breast cancer predisposition genes (protein-truncating variants [PTV] in ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, or TP53), and polygenic risk score (PRS) 5yAR above 1.3%., Results: Correlation between 5yAR (at age of diagnosis) predicted by PRS and the Gail model was low (r=0.27). Fifty-three percent of breast cancer patients (n=4041) were considered high risk by one or more classification criteria. Positive family history, PTV carriership, PRS, or the Gail model identified 1247 (16%), 385 (5%), 2774 (36%), and 1592 (21%) patients who were considered at high risk, respectively. In a subset of 3227 women aged below 50 years, the four models studied identified 470 (15%), 213 (7%), 769 (24%), and 325 (10%) unique patients who were considered at high risk, respectively. For younger women, PRS and PTVs together identified 745 (59% of 1276) high-risk individuals who were not identified by the Gail model or family history., Conclusions: Family history and genetic and non-genetic risk stratification tools have the potential to complement one another to identify women at high risk., (© 2022. The Author(s).)

Background: Patients with diabetes are at increased risk of developing chronic limb-threatening ischemia (CLTI) due to peripheral arterial disease, and this often results in lower extremity amputation (LEA). Little is known of the interaction between diabetes and other vascular risk factors in affecting the risk of CLTI., Methods: We investigated the association of diabetes, and its interaction with hypertension, body mass index (BMI) and smoking, with the risk of LEA due to CLTI in the population-based Singapore Chinese Health Study. Participants were interviewed at recruitment (1993-1998) and 656 incident LEA cases were identified via linkage with nationwide hospital database through 2017. Multivariate-adjusted Cox proportional hazards models were used to compute hazard ratios (HRs) and 95% CIs for the associations., Results: The HR (95% CI) for LEA risk was 13.41 (11.38-15.79) in participants with diabetes compared to their counterparts without diabetes, and the risk increased in a stepwise manner with duration of diabetes (P for trend < 0.0001). Hypertension and increased BMI independently increased LEA risk in those without diabetes but did not increase the risk in those with diabetes (P for interaction with diabetes ≤ 0.0006). Conversely, current smoking conferred a risk increment of about 40% regardless of diabetes status., Conclusions: Although diabetes conferred more than tenfold increase in risk of LEA, hypertension and increased BMI did not further increase LEA risk among those with diabetes, suggesting a common mechanistic pathway for these risk factors. In contrast, smoking may act via an alternative pathway and thus confer additional risk regardless of diabetes status., (© 2022. The Author(s).)

Background: Among older adults, living alone is often associated with higher risk of Emergency Department (ED) admissions. However, older adults living alone are very heterogeneous in terms of health. As more older adults choose to live independently, it remains unclear if the association between living alone and ED admissions is moderated by health status. We studied the association between living alone and ED admission outcomes (number of admissions, inpatient days and inpatient costs) among older adults with and without multimorbidity., Methods: We used data from 16,785 individuals of the third follow-up of the Singapore Chinese Health Study, a population-based cohort of older Singapore Chinese (mean age: 73(61-96) years). Participants were interviewed face-to-face from 2014 to 2016 for sociodemographic/health factors and followed-up for one year on ED admission outcomes using Singapore Ministry of Health's Mediclaim Database. We first applied multivariable logistic regression and two-part models to test if living alone is a risk factor for ED admission outcomes. We then ran stratified and joint effect analysis to examine if the associations between living alone and ED admission outcomes were moderated by multimorbidity., Results: Compared to living with others, living alone was associated with higher odds of ED admission [Odds Ratio (OR) 1.28, 95 % Confidence Interval(CI) 1.08-1.51)], longer inpatient days (+0.61, 95 %CI 0.25-0.97) and higher inpatient costs (+322 USD, 95 %CI 54-591). The interaction effects of living arrangement and multimorbidity on ED admissions and inpatient costs were not statistically different, whereas the interaction between living arrangements and multimorbidity on inpatient days was borderline significant (p-value for interaction=0.050). Compared to those living with others and without multimorbidity, the relative mean increase was 1.13 inpatient days (95 %CI 0.39-1.86) for those living alone without multimorbidity, and 0.73 inpatient days ( 95 %CI 0.29-1.17) for those living alone with multimorbidity., Conclusions: Older adults living alone were at higher risk of ED admission and higher inpatient costs regardless of multimorbidity, while those living alone without multimorbidity had the longest average inpatient days. To enable aging in place while avoiding ED admissions, interventions could provide instrumental support and regular health monitoring to older adults living alone, regardless of their health status., (© 2021. The Author(s).)

Background: Blood type has been associated with the risk of gastric cancer, but few studies have examined the association with esophageal squamous cell carcinoma (ESCC)., Methods: We conducted a case-control study using genotyping data of Chinese individuals, including cases of 2022 ESCC, 1189 gastric cardia adenocarcinoma, 1161 gastric noncardia adenocarcinoma, and 2696 controls. Genetic blood type was imputed using three single nucleotide polymorphisms. We used logistic regression to examine the association between blood type and the risk of each cancer., Results: Compared to blood type O, the risk of ESCC was significantly elevated for blood type B and AB, with the highest risk for type AB (OR, 95%CI: 1.34, 1.07-1.67). Analysis of genotype suggested that the association of ESCC was from carrying the B allele. Similarly, blood type was significantly associated with gastric noncardia adenocarcinoma (P < 0.001) with risk significantly elevated in type A (1.37, 1.14-1.65) and AB (1.44, 1.10-1.89) compared to type O. Blood type was not associated with gastric cardia adenocarcinoma (P = 0.13)., Conclusions: This study provides novel insights into the association between blood type and the risk of ESCC and restricted previously observed association to only gastric noncardia cancer, providing important evidence to clarify the pattern of association and suggesting mechanisms of action.

Background: Although obesity can be clinically defined by body mass index (BMI), waist circumference, percent body fat, or visceral fat area, it is unclear which specific measure is best associated with mobility disability in oldest-old adults., Methods: Among 589 Chinese participants aged 85 years and older in a population-based cohort in Singapore, we measured waist circumference, computed BMI, estimated appendicular skeletal muscle mass, percent body fat, and visceral fat area using bioelectrical impedance analysis, and evaluated mobility disability using the Loco-Check questionnaire. We computed areas under the receiver operating characteristic curves (AUC ROC ) to compare how well these measures discriminated between those with and without mobility disability. Logistic regression models were used to estimate the odds ratios (OR) and 95% confidence intervals (CI) for the associations between obesity defined by these measures and mobility disability., Results: Compared to BMI, which had an AUC ROC (95% CI) of 0.68 (0.64-0.72) for the discrimination of mobility disability, only visceral fat area had a significantly higher discriminative performance [AUC ROC (95% CI) of 0.71 (0.67-0.75) (P adjusted  = 0.002)]. The optimal cut-offs of visceral fat area for the discrimination of mobility disability were ≥ 104 cm 2 in men and ≥ 137 cm 2 in women. In fully adjusted models, only obesity defined by visceral fat area was significantly associated with mobility disability [OR (95% CI) of 2.04 (1.10-3.77)]; obesity defined by the other measures were not associated with mobility disability after adjusting for visceral fat., Conclusion: In oldest-old adults, visceral fat area was the best discriminator for obesity associated with mobility disability.

Background: Shorter telomere length (TL) has been associated with poor health behaviors, increased risks of chronic diseases and early mortality. Excessive shortening of telomere is a marker of accelerated aging and can be influenced by oxidative stress and nutritional deficiency. Plasma n6:n3 polyunsaturated fatty acid (PUFA) ratio may impact cell aging. Increased dietary intake of marine n-3 PUFA is associated with reduced telomere attrition. However, the effect of plasma PUFA on leukocyte telomere length (LTL) and its interaction with genetic variants are not well established., Methods: A nested coronary artery disease (CAD) case-control study comprising 711 cases and 638 controls was conducted within the Singapore Chinese Health Study (SCHS). Samples genotyped with the Illumina ZhongHua-8 array. Plasma n-3 and n-6 PUFA were quantified using mass spectrometry (MS). LTL was measured with quantitative PCR method. Linear regression was used to test the association between PUFA and LTL. The interaction between plasma PUFAs and genetic variants was assessed by introducing an additional term (PUFA×genetic variant) in the regression model. Analysis was carried out in cases and controls separately and subsequently meta-analyzed using the inverse-variance weighted method. We further assessed the association of PUFA and LTL with CAD risk by Cox Proportional-Hazards model and whether the effect of PUFA on CAD was mediated through LTL by using structural equation modeling., Results: Higher n6:n3 ratio was significantly associated with shorter LTL (p = 0.018) and increased CAD risk (p = 0.005). These associations were mainly driven by elevated plasma total n-3 PUFAs, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (p < 0.05). There was a statistically significant interaction for an intergenic single nucleotide polymorphism (SNP) rs529143 with plasma total n-3 PUFA and DHA on LTL beyond the genome-wide threshold (p < 5 ×  10 - 8 ). Mediation analysis showed that PUFA and LTL affected CAD risk independently., Conclusions: Higher plasma n6:n3 PUFA ratio, and lower EPA and DHA n-3 PUFAs were associated with shorter LTL and increased CAD risk in this Chinese population. Furthermore, genetic variants may modify the effect of PUFAs on LTL. PUFA and LTL had independent effect on CAD risk in our study population.

Background: Although retinol binding protein 4 (RBP4) has been implicated in insulin resistance in experimental studies, the association between RBP4 and risk of type 2 diabetes remains unclear. We assessed this association in a Chinese population, and pooled our results with those from two prior studies., Methods: Plasma RBP4 levels were measured among 571 incident type 2 diabetes cases and 571 controls nested within the Singapore Chinese Health Study. All participants were free of diabetes, cancer and cardiovascular disease at blood collection (1999-2004). Incident cases of physician-diagnosed diabetes were self-reported at subsequent interviews (2006-2010)., Results: Plasma RBP4 levels were significantly higher in men than women, and the respective median values were 30 (interquartile range: 24-35) μg/mL and 25 (interquartile range: 21-31) μg/mL, respectively. With adjustment for diabetes risk factors, compared to the lowest quartile, the odds ratio (OR) and confidence interval (CI) for risk of type 2 diabetes associated with the highest quartile of RBP4 levels were 1.23 (0.73-2.07; P -trend = 0.14) in all subjects, 0.63 (0.27-1.45; P -trend = 0.65) in men, and 2.29 (1.05-5.00; P -trend = 0.018) in women. The difference in the risk estimates between men and women was statistically significant ( P -interaction = 0.032). When we pooled our results with two prior studies, ORs (95% CIs) comparing high versus low category of RBP4 was 1.01 (0.70-1.46; I 2  = 8.2%; P -heterogeneity = 0.34) in men, and 1.73 (1.28-2.33; I 2  = 0%; P -heterogeneity = 0.80) in women., Conclusions: Increased plasma RBP4 levels were associated with higher risk of type 2 diabetes in women but not in men., Competing Interests: The study protocol was approved by the Institutional Review Boards at the National University of Singapore and the University of Pittsburgh. Informed consent was provided and completed by participants at the baseline interview.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Experimental studies have shown that exposure to incense burning may have deleterious effects on kidney function and architecture. However, the association between chronic exposure to incense smoke and risk of end-stage renal disease (ESRD) has not been reported in epidemiologic studies., Methods: We investigated this association in the Singapore Chinese Health Study, a prospective population-based cohort of 63,257 Chinese men and women of 45-74 years of age in Singapore during recruitment from 1993 to 1998. Information on the practice of incense burning at home, diet, lifestyle and medical history was collected at baseline interviews. ESRD cases were identified through linkage with the nationwide Singapore Renal Registry through 2015. We used Cox proportional hazards regression analysis to estimate hazard ratio (HR) and 95% confidence interval (CI) of ESRD associated with domestic incense burning., Results: Among cohort participants, 76.9% were current incense users. After an average 17.5 years of follow-up, there were 1217 incident ESRD cases. Compared to never users, the multivariable-adjusted HR for ESRD risk was 1.05 (95% CI, 0.80 to 1.38) for former users and 1.26 (95% CI, 1.02 to1.57) for current users of incense. In analysis by daily or non-daily use and duration, the increased ESRD risk was observed in daily users who had used incense for > 20 years; HR was 1.25 (95% CI, 1.07 to 1.46). Conversely, the risk was not increased in those who did not use incense daily or who had used daily but for ≤20 years., Conclusions: Our findings demonstrate that long-term daily exposure to domestic incense burning could be associated with a higher risk of ESRD in the general population.

Background: Evidence from basic research links exposure to endocrine disrupting chemicals (EDCs) with a higher risk for breast cancer. However, there is less evidence from observational epidemiological research and the results are equivocal. Therefore, we examined the association between occupational exposure to substances where exposure to EDCs is likely and the risk of breast cancer., Methods: A prospective study consisting of a population-based cohort of 33,458 Singaporean Chinese women aged 45-74 years enrolled in the Singapore Chinese Health Study (SCHS) from 1993 to 98 and followed through 2014. Subjects' self-reported occupational exposure and duration to industries, job titles, and substance types were garnered at baseline, and cases of incident breast cancer (N = 988) were determined by linkage with the Singapore Cancer Registry. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated for exposure to substances, job titles, and industries., Results: There was no association between cumulative exposure to substances via occupation where EDC exposure is likely and risk of breast cancer. These results were consistent for hypothesized high (HR 0.94, 95% CI: 0.66-1.35), medium (HR 1.03 95% CI: 0.77-1.38) and low (HR 0.74, 95% CI 0.48-1.13) combined substance exposure groups when compared with those who were not exposed via occupation. Similar null associations were observed when examining job titles and industry categories., Conclusions: There was no association between EDC related occupational exposures and breast cancer risk in working women of the Singaporean Chinese Health Study. Future studies that employ rigorous methods with regard to exposure assessment of EDCs are needed.

Background: Recent genome-wide association studies (GWAS) have identified 97 body-mass index (BMI) associated loci. We aimed to evaluate if dietary intake modifies BMI associations at these loci in the Singapore Chinese population., Methods: We utilized GWAS information from six data subsets from two adult Chinese population (N = 7817). Seventy-eight genotyped or imputed index BMI single nucleotide polymorphisms (SNPs) that passed quality control procedures were available in all datasets. Alternative Healthy Eating Index (AHEI)-2010 score and ten nutrient variables were evaluated. Linear regression analyses between z score transformed BMI (Z-BMI) and dietary factors were performed. Interaction analyses were performed by introducing the interaction term (diet x SNP) in the same regression model. Analysis was carried out in each cohort individually and subsequently meta-analyzed using the inverse-variance weighted method. Analyses were also evaluated with a weighted gene-risk score (wGRS) contructed by BMI index SNPs from recent large-scale GWAS studies., Results: Nominal associations between Z-BMI and AHEI-2010 and some dietary factors were identified (P = 0.047-0.010). The BMI wGRS was robustly associated with Z-BMI (P = 1.55 × 10 - 15 ) but not with any dietary variables. Dietary variables did not significantly interact with the wGRS to modify BMI associations. When interaction analyses were repeated using individual SNPs, a significant association between cholesterol intake and rs4740619 (CCDC171) was identified (β = 0.077, adjP interaction  = 0.043)., Conclusions: The CCDC171 gene locus may interact with cholesterol intake to increase BMI in the Singaporean Chinese population, however most known obesity risk loci were not associated with dietary intake and did not interact with diet to modify BMI levels.

Background: Obesity has been proposed as a potential protective factor against lung cancer. We examined the association between BMI and lung cancer risk in a pooled analysis based on nested case-control studies from four cohort studies., Methods: A case-control study was nested within four cohorts in USA, Europe, China and Singapore that included 4172 cases and 8471 control subjects. BMI at baseline was calculated as weight in kilograms divided by height in meters squared (kg/m 2 ), and classified into 4 categories: underweight (BMI < 18.5), normal weight (18.5 ≤ BMI < 25), overweight (25 ≤ BMI < 30) and obese (≥30). Odds ratios (ORs) and 95% confidence intervals (CIs) for BMI-lung cancer associations were estimated using unconditional logistic regression, adjusting for potential confounders., Results: Considering all participants, and using normal weight as the reference group, a decreased risk of lung cancer was observed for those who were overweight (OR 0.77, 95% CI: 0.68-0.86) and obese (OR 0.69, 95% CI: 0.59-0.82). In the stratified analysis by smoking status, the decreased risk for lung cancer was observed among current, former and never smokers (P for interaction 0.002). The adjusted ORs for overweight and obese groups were 0.79 (95% CI: 0.68-0.92) and 0.75 (95% CI: 0.60-0.93) for current smokers, 0.70 (95% CI: 0.53-0.93) and 0.55 (95% CI: 0.37-0.80) for former smokers, 0.77 (95% CI: 0.59-0.99), and 0.71 (95% CI: 0.44-1.14) for never smokers, respectively. While no statistically significant association was observed for underweight subjects who were current smokers (OR 1.24, 95% CI: 0.98-1.58), former smokers (OR 0.27, 95% CI: 0.12-0.61) and never smokers (OR 0.83, 95% CI: 0.5.-1.28)., Conclusion: The results of this study provide additional evidence that obesity is associated with a decreased risk of lung cancer. Further biological studies are needed to address this association.

Background: SuPAR is a biomarker that reflects the level of immune activation. As inflammation plays an important role in the ageing process of the cardiovascular system, we hypothesized that suPAR might be a useful predictive biomarker of the ageing heart., Methods: We performed conventional and tissue Doppler echocardiography and measured plasma suPAR levels., Results: We studied community adults (n=120, 37.5% female) (mean age: 70.3±9.3 years) without known cardiovascular disease (CVD). Participants with impaired myocardial relaxation were older (84% vs 59% were aged ≥71 years, p=0.002), with more diabetes mellitus (27% vs 11%, p=0.034). SuPAR levels were higher among participants with impaired myocardial relaxation (3.9 ng/ml vs 3.0 ng/ml, p=0.015). At the univariate level, older age (OR 3.6; 95%CI 1.6, 8.5; p=0.003), diabetes mellitus (OR 3.04; 95%CI 1.1, 8.8; p=0.04), systolic blood pressure (OR 1.03; 95%CI 1.001, 1.1; p=0.041) and suPAR levels ≥3.00ng/ml (OR 3.4; 95%CI 1.16, 7.4; p=0.002) were associated with impaired myocardial relaxation. In multivariable regression analysis, only older age (OR 2.8; 95%CI 1.1, 6.7; p=0.026) and suPAR (OR 2.7; 95%CI 1.2, 6.1; p=0.018) remained independently associated with impaired myocardial relaxation. Receiver operating characteristics (ROC) curve analysis revealed an area under the curve (AUC) value of 0.63 (95% CI 0.54, 0.71) for model that included age alone. Addition of suPAR significantly increased AUC value to 0.70 (95%CI 0.60, 0.79), which was significantly larger than the model with age alone (p=0.016)., Conclusion: We demonstrate additional ability of suPAR, over age, to predict impaired myocardial relaxation., Trial Registration: ClinicalTrials.gov Identifier: NCT02791139 (Registered May 31, 2016).

Background: Fibroblast growth factor 21 (FGF-21) is mainly secreted by liver and has been reported to be involved in the pathogenesis of type 2 diabetes. Some prospective studies have shown a positive association between FGF-21 and diabetes risk. However, no study has examined whether the association differed by sex, which has been reported between FGF-21 and atherosclerosis. Therefore, we prospectively evaluated the sex-specific association between FGF-21 and diabetes in a Chinese population., Methods: Serum FGF-21 concentration was measured in a case-control study comprising of 251 incident diabetes cases and 251 age-sex-matched controls nested within a prospective population-based cohort, the Singapore Chinese Health Study. At blood collection between 1999 and 2004, participants were free of diagnosed diabetes, cardiovascular disease, and cancer. Incident self-reported diabetes cases were identified at follow-up II interview (2006-2010). Odds ratio (OR) and 95% confidence interval (CI) were calculated using multivariable logistic regression models., Results: After adjustment for risk biomarkers of diabetes including lipids, liver enzymes and inflammatory marker, the OR of type 2 diabetes with per one unit increment in log FGF-21 concentration was 1.16 (95% CI 0.90-1.50). Significant interaction was found with sex ( P -interaction = 0.029): the OR (95% CI) was 1.50 (1.00-2.25) in women and 0.89 (0.52-1.53) in men., Conclusions: Higher serum FGF-21 level was associated with an increased risk of diabetes in Chinese women but not in men. The sex difference in the association between FGF-21 and diabetes risk deserves further investigation and replication in other populations.

Background: The liver-derived C-reactive protein (CRP) is a sensitive and systemic biomarker of inflammation, and has been associated with increased risk of developing type 2 diabetes in populations other than Chinese. Therefore, we prospectively examined the relation between plasma levels of CRP and risk of type 2 diabetes (T2D) among a Chinese population., Methods: Plasma high-sensitive CRP (hs-CRP) concentrations were assayed among 571 T2D cases and 571 controls nested in the prospective cohort of the Singapore Chinese Health Study. Both cases and controls were free of physician-diagnosed diabetes, cardiovascular disease and cancer at blood collections (1999-2004). Incident physician-diagnosed T2D cases were self-reported during the follow-up visits (2006-2010), and controls were matched for age (±3 years) and date (±6 months) of blood collection and gender. Multivariable logistic regression models were used to compute the odds ratio (OR) and the corresponding 95% confidence intervals (CIs)., Results: The mean (SD) concentrations of hs-CRP were 2.79 (2.65) and 1.86 (2.03) mg/L, respectively, in cases and controls (P < 0.001). After multivariate adjustment for T2D risk factors such as lifestyle, body mass index, plasma triglycerides and HDL cholesterol, the OR comparing the extreme quartiles of hs-CRP was 1.74 [95% CI 1.12-2.70; P for trend = 0.016]. When the analysis was limited to 279 cases who had HbA1c ≥6.5% at the time of blood collection and their controls, the OR comparing the extreme quartiles of hs-CRP was 2.43 (95% CI 1.25-4.71; P for trend = 0.003). When confined to the other 292 subjects with HbA1c <6.5% and their controls, the corresponding OR was 1.24 (95% CI 0.64-2.39; P for trend = 0.93)., Conclusions: We found that CRP was not associated with increased risk of incident diabetes in this cohort of Chinese in Singapore. Previous positive findings from prospective studies might be partly due to undiagnosed T2D among the cases during blood collection.

Polyunsaturated fatty acids (PUFAs) have a major impact on human health. Recent genome-wide association studies (GWAS) have identified several genetic loci that are associated with plasma levels of n-3 and n-6 PUFAs in primarily subjects of European ancestry. However, the relevance of these findings has not been evaluated extensively in other ethnic groups. The primary aim of this study was to evaluate for genetic loci associated with n-3 and n-6 PUFAs and to validate the role of recently identified index loci using data from a Singaporean Chinese population. Using a GWAS approach, we evaluated associations with plasma concentrations of three n-3 PUFAs [alphalinolenic acid (ALA), eicosapentaenoic acid and docosahexaenoic acid], four n-6 PUFAs [linoleic acid (LA), gammalinolenic acid, dihomogammalinolenic acid (DGLA) and arachidonic acid], and estimates of delta-5 desaturase and delta-6 desaturase activities among the participants (N = 1361) of the Singaporean Chinese Health Study. Our results reveal robust genome-wide associations (p value <5 × 10(-8)) with ALA, all four n-6 PUFAs, and delta-6 desaturase activity at the FADS1/FADS2 locus. We further replicated the associations between common index variants at the NTAN1/PDXDC1 locus and n-6 PUFAs LA and DGLA, and between the JMJD1C locus and n-6 PUFA LA (p value between 0.0490 and 9.88 × 10(-4)). These associations were independent of dietary intake of PUFAs. In aggregate, we show that genetic loci that influence plasma concentrations of n-3 and n-6 PUFAs are shared across different ethnic groups.

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.