Interaction Between Peroxisome Proliferator Activated Receptor δ and Epithelial Membrane Protein 2 Polymorphisms Influences HDL-C Levels in the Chinese Population.

Peroxisome proliferator activated receptors (PPARs) are transcription factors involved in the regulation of key metabolic pathways. Numerous in vivo and in vitro studies have established their important roles in lipid metabolism. A few SNPs in PPAR genes have been reported to be associated with lipid levels. In this study, we aimed to investigate the interactive effects between single nucleotide polymorphisms (SNPs) in three PPAR isoforms α/δ/γ and other genetic variants across the genome on plasma high-density lipoprotein-cholesterol (HDL-C) levels. Study subjects (N = 2003) were genotyped using Illumina HumanOmniZhongHua-8 Beadchip. Fifty-three tag SNPs ± 100 kb of PPAR α, δ, and γ (r(2) < 0.2) were selected. The effect of interactions between PPAR SNPs and those across the genome on HDL-C was tested using linear regression models. One statistically significant interaction influencing HDL-C was detected between PPARδ SNP rs2267668 and epithelial membrane protein 2 (EMP2) downstream SNP rs7191411 (N = 1993, ß = 0.74, adjusted P = 0.022). This interaction was successfully replicated in the meta-analysis of two additional Chinese cohorts (N = 3948, P = 0.01). The present study showed a novel SNP × SNP interaction between rs2267668 in PPARδ and rs7191411 in EMP2 that has significant impact on circulating HDL-C levels in the Singaporean Chinese population.

A genome-wide association study of n-3 and n-6 plasma fatty acids in a Singaporean Chinese population.

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.

Interaction effects between Paraoxonase 1 variants and cigarette smoking on risk of coronary heart disease in a Singaporean Chinese population.

OBJECTIVE: Paraoxonase 1 (PON1) plays an important role in reducing the risk of coronary heart disease (CHD). Smoking is known to reduce PON1 activity. We aimed to investigate the effects of interactions between PON1 variants and smoking on CHD in the Singaporean Chinese population. METHODS: In a case-control study nested within Singapore Chinese Health Study (N=1914), subjects with and without CHD were classified into never-smokers and ever-smokers (ever smoked at least one cigarette a day for 1 year or longer). Associations at four independent SNPs at the PON1 locus (rs3735590, rs3917550, rs662, rs3917481) with CHD were evaluated using logistic regression, before/after stratification on smoking status. Interactions between smoking and PON1 variants were analyzed with likelihood ratio tests, by including the SNP*smoking interaction term in regression analyses. RESULTS: The T allele at the coding SNP, rs662, was associated with higher risk of CHD in ever-smokers only (OR=1.35, 95% CI 1.08-1.68; adjusted P=0.036). At the miR-SNP, rs3735590, carrying at least one copy of minor allele T was associated with increased risk of CHD in a dominant manner in never-smokers only (OR=1.53, 95% CI 1.11-2.11; adjusted P=0.036). Significant interactions between two PON1 SNPs and smoking in relation to CHD risk were identified (adjusted P=0.012 for rs662; adjusted P=0.044 for rs3735590). These associations remained significant after adjustment for known CHD risk factors and upon correction for multiple tests. CONCLUSIONS: Two PON1 SNPs, rs662 and rs3735590, were found to significantly interact with cigarette smoking to modulate the risk of CHD in the Singaporean Chinese population.

Association of single nucleotide polymorphism rs6903956 on chromosome 6p24.1 with coronary artery disease and lipid levels in different ethnic groups of the Singaporean population.

OBJECTIVE: A recent genome wide association study in the Chinese population has implicated rs6903956 within the ADTRP gene on chromosome 6p24.1 as a novel susceptibility locus for coronary artery disease (CAD). In this study, we evaluated the association of rs6903956 with CAD in the different ethnic groups of Singaporean population comprising Chinese, Malays and Asian Indians. DESIGN AND METHODS: The genotypes of the rs6903956 SNP were determined in 645 CAD patients and 755 control group Singaporean subjects by using the polymerase chain reaction restriction fragment length polymorphism method (PCR-RFLP). We then tested the association of this SNP with CAD and lipid profiles. RESULTS: The risk allele A of rs6903956 was associated significantly only in the Chinese with an odds ratio (OR) of 2.03 (95% CI 1.04-3.96, P=0.037) when analyzed by each ethnic group separately. In a meta-analysis with pooled subjects from all three ethnic groups, rs6903956 showed highly significant association with CAD both before (observed P=1.39e-04; OR=1.66; 95% CI 1.28-2.15) and after adjustment (P=4.63e-03; OR=1.86; 95% CI 1.21-2.87) for conventional risk factors of age, gender, BMI, smoking status and ethnicity. No significant association was observed between rs6903956 genotypes and lipid profiles in Chinese, Malays and Indians, suggesting that the association of this SNP with CAD is not mediated through plasma lipids. CONCLUSION: The SNP rs6903956 within the ADTRP gene on chromosome 6p24.1 is significantly associated with CAD in different ethnic groups of the Singaporean population.