Association of serum lipids and coronary artery disease with polymorphisms in the Apolipoprotein AI-CIII-AIV gene cluster

Genetic variants are considered as one of the main determinants of the concentration of serum lipids and coronary artery disease (CAD). Polymorphisms in the Apolipoprotein (Apo) AI-CIII-AIV gene cluster has been known to affect the concentrations of various lipid sub-fractions and the risk of CAD. The present study assessed associations between polymorphisms of the Apo AI-CIII-AIV gene cluster, [ApoA-I,-75G > A, (rs1799837); ApoC-III 3238C > G, (SstI), (rs5128) and ApoA-IV, Thr347Ser(347A > T), (rs675)] with serum lipids and their contributions to CAD in North Indian population. We recruited age, sex matched, 200 CAD patients and 200 healthy controls and tested them for fasting levels of serum lipids. We genotyped selected polymorphisms using polymerase chain reaction-restriction fragment length polymorphism. There were no statistically significant association of selected polymorphisms (or their combinations) with CAD even after employing additive, dominant and recessive models. However there was significant association of selected polymorphisms with various lipid traits amongst the control cohort (p < 0.05). Mean levels of high density lipoprotein cholesterol and triglycerides were found to be significantly higher among controls carrying at least one mutant allele at ApoA1- 75G > A (p = 0.019) and ApoCIII SstI (p < 0.001) polymorphism respectively. Our study observed that the selected polymorphisms in the ApoAI-CIII-AIV gene cluster although significantly affect various lipid traits but this affect does not seem to translate into association with CAD, at least among North Indian population

Association of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms with coronary artery disease (CAD) in a North Indian population

There is significant variation in reported associations of the MTHFR C677T (rs1801133) and A1298C (rs1801131) polymorphisms and coronary artery disease (CAD) in different global populations. This study aims to identify any individual or combined associations between the 1298 and 677 loci of MTHFR and CAD in a North Indian population. A total of 159 patients and 166 controls were genotyped using validated TaqMan assays. Odds ratio analysis identified associations at crude level and multiple logistic regression controlled for confounding variables. Linkage disequilibrium between the loci was assessed along with haplotype association analysis. At the C677T locus, homozygosity of the T allele identified a significantly protective association (OR = 0.38, CI: 0.24–0.60). For the A1298C locus the AC genotype had a protective effect in codominant model (OR = 0.53, CI: 0.32–0.85) and CC genotype showed a susceptible association in recessive model when controlled for age, sex and lipids (OR = 2.70, CI: 1.27–5.77). This study identified that, independently, both heterozygous genotypes show a protective association with CAD. In addition the CC genotype of A1298C in recessive model was a susceptible genotype. The combined associations of MTHFR are protective (primarily due to the effects of C677T locus) suggesting an interaction between the loci and their associations with CAD within this sample

Paraoxonase 1 GENE polymorphisms contribute to coronary artery disease risk

Polymorphisms in paraoxonase 1 (PON1) coding for PON1 enzyme have been studied as genetic markers of coronary artery disease (CAD). PON1 Q192R and PON1 L55M polymorphisms have been analyzed extensively, but data on association and role of these polymorphisms in the etiology of CAD are conflicting. In this study, we tested the genetic association between PON1 Q192R and PON1 L55M polymorphisms and CAD among north Indians. MATERIALS AND METHODS: Two hundred eighty-five angiographically proven patients with coronary artery disease and 200 sex-matched and ethnically matched controls were genotyped for 2 PON1 polymorphisms by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Genotype/ allele frequencies were compared in patients and controls using the chi-square test. RESULTS: At PON1-192 locus, there were significant differences between patients and controls (P< 0.05), leading to significant odds ratios for RR genotype (OR= 1.92, CI: 1.19-3.10) and *R allele (OR= 1.30, CI: 1.00-1.70). These odds ratios were higher in the sub-sample of smokers (2.84 and 1.45, respectively). Binary logistic regression analysis also confirmed that *R allele carriers (QR and RR) have a higher risk of CAD (OR= 3.54, CI: 1.67-5.53). PON1-55 locus did not show significant differences between patients and controls, but LL genotype and *L allele were significant risk factors in the nonsmoker group. RL haplotype was also significantly associated with CAD risk (OR= 1.44, CI: 1.08-1.93). CONCLUSIONS: PON1-192R allele and RR genotype are significantly associated with CAD patients from the north Indian population (Uttar Pradesh). This association was stronger in smokers, supporting the conclusion that an interaction between PON1 activity and smoking augments CAD risk. Further studies with larger sample size are warranted to confirm these associations in different Indian populations

Genetic association of pro-inflammatory cytokine gene polymorphisms with coronary artery disease (CAD) in a North Indian population

Background: Cytokines regulate the expression of inflammatory molecules which destabilize the atheromatic plaques. This study focuses on studying the association of inflammatory cytokine polymorphisms like TNF-α -308 (G/A), TNF-β +252 (A/G), IL-6 -174 (G/C) and IL-6 -597 (G/A), and IFN-ɣ +874 (T/A) with coronary artery disease (CAD) among north Indian patients. Materials and methods: 143 CAD and 137 normal healthy controls were recruited in this study. DNA extraction was carried out by high salting out method. TNF-α -308 (G/A) (rs1800797), TNF-β +252 (A/G) (rs909253), IL-6 -174 (G/C) (rs1800795), IL6 -597 (G/A) (rs1800797), and IFN-ɣ +874 (T/A) (rs2430561) SNPs were genotyped by TaqMan®SNP genotyping assays. Different statistical analyses were performed using SPSS v 22.0 and SNPStats. p≤0.05 was considered significant. Results: Significant risk association with CAD was found for TNF-α -308 (G/A) “A” allele (OR =5.6, CI 1.8-17.4, p=0.001) and TNF-β +252 (A/G) “G” allele (OR=3.4, CI=1.9-6.0, p<0.001). However, no statistical significance was found for IL-6 -174 (G/C) or IL6 -597 (G/A), with CAD. TNF-α -308 (G/A), and TNF-β +252 (A/G) haplotype “GG” “AG” increased CAD risk significantly (GG haplotype, adjusted OR = 2.6, CI 1.4-5.0, p=0.003 and AG haplotype OR =8.5, CI 2.2-33.35, p=0.002) after adjustments for age, sex, TC, TG, HDL, APOB, smoking and diet. Discussion: The present study found significant risk association for TNF-α -308 (G/A), and TNF-β +252 (A/G) genotypes, alleles and haplotypes, with CAD in a North Indian Population

Forest plot depicting results after analyses for the allelic model <i>(Allele T vs. G)</i> of <i>NOS3</i> Glu298Asp polymorphism.

<p>Effect size estimates for all ancestral groups in this plot were obtained using random effects for analysis. Effect size using fixed effects was recalculated for Asian-Indian group which showed homogenous distribution among its included studies. Recalculated effect size estimate for Asian-Indians was, OR, 95%CI = 1.23, 1.05–1.44; Z = 2.59; P = 0.01.</p

Meta-analysis results for <i>NOS3</i> gene polymorphisms.

<p>Abbreviations: OR, 95% CI: Odds Ratio with its 95% Confidence Interval; <b>^F</b>: Results derived using Fixed effects for analysis. Random effects were used for all other calculations.</p><p>*Dominant genetic model for Glu298Asp: <i>TT+GT vs. GG;</i> for T786-C: <i>CC+CT vs. TT;</i> for 4b/a: <i>4a4a+4a4b vs. 4b4b.</i></p><p>**Recessive genetic model for Glu298Asp: <i>TT vs. GG+GT;</i> for T786-C: <i>CC vs. TT+CT;</i> for 4b/a: <i>4a4a vs. 4a4b+4b4b.</i></p><p>***Allelic genetic model for Glu298Asp: <i>Allele T vs. G;</i> for T786-C: <i>Allele C vs. T;</i> for 4b/a: <i>Allele 4a vs. 4b.</i></p><p>Meta-analysis results for <i>NOS3</i> gene polymorphisms.</p

Association of Endothelial Nitric Oxide Synthase Gene Polymorphisms with Coronary Artery Disease: An Updated Meta-Analysis and Systematic Review

<div><p>Several association studies of endothelial nitric oxide synthase (<i>NOS3</i>) gene polymorphisms with respect to coronary artery disease (CAD) have been published in the past two decades. However, their association with the disease, especially among different ethnic subgroups, still remains controversial. This prompted us to conduct a systematic review and an updated structured meta-analysis, which is the largest so far (89 articles, 132 separate studies, and a sample size of 69,235), examining association of three polymorphic forms of the <i>NOS3</i> gene (i.e. Glu298Asp, T786-C and 27bp VNTR b/a) with CAD. In a subgroup analysis, we tested their association separately among published studies originating predominantly from European, Middle Eastern, Asian, Asian-Indian and African ancestries. The pooled analysis confirmed the association of all the three selected SNP with CAD in three different genetic models transcending all ancestries worldwide. The Glu298Asp polymorphism showed strongest association (OR range = 1.28–1.52, and P<0.00001 for all comparisons), followed by T786-C (OR range = 1.34–1.42, and P<0.00001 for all comparisons) and 4b/a, (OR range = 1.19–1.41, and P≤0.002 for all comparisons) in our pooled analysis. Subgroup analysis revealed that Glu298Asp (OR range = 1.54–1.87, and P<0.004 for all comparisons) and 4b/a (OR range = 1.71–3.02, and P<0.00001 for all comparisons) have highest degree of association amongst the Middle Easterners. On the other hand, T786-C and its minor allele seem to carry a highest risk for CAD among subjects of Asian ancestry (OR range = 1.61–1.90, and P≤0.01 for all comparisons).</p></div

Forest plots depicting meta-analysis results for <i>IL1A</i> +4845 G>T (rs17561) polymorphism.

<p>Panel A: Effect size estimation using dominant genetic model (<i>TT+GT vs</i>. <i>GG</i>); Panel B: Effect size estimation using recessive genetic model (<i>TT vs</i>. <i>CT+GG</i>); Panel C: Effect size estimation using allelic genetic model (<i>Allele T vs</i>. <i>Allele G</i>). Pooled effect size estimates for dominant genetic model in Panel A was obtained using random effects for analysis, while fixed effects were used for effect size estimation for all ancestral groups. Revised effect size estimates for all ancestral groups analyzed in dominant genetic model are given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153480#pone.0153480.t002" target="_blank">Table 2</a>. Fixed effects were used for effect size estimation in recessive and allelic genetic models for pooled as well as all ancestral groups.</p

Interleukin-1 Gene Cluster Polymorphisms and Their Association with Coronary Artery Disease: Separate Evidences from the Largest Case-Control Study amongst North Indians and an Updated Meta-Analysis

<div><p>Several researchers have reported significant association of numerous single nucleotide polymorphisms (SNPs) residing in the interleukin-1 (IL-1) gene cluster with coronary artery disease (CAD). However, their association status amongst North Indian ancestry (NIA) have never been systematically assessed. Despite a published meta-analysis on this subject, their association status worldwide as well as amongst different major ancestral subgroups still remains unclear. We therefore decided to prospectively test the association of 11 IL-1 gene cluster SNPs with CAD, vide a case-control study amongst a cohort of NIA and attempted to validate our results with the help of an updated meta-analysis of all relevant published association studies. Included studies were segregated into ancestral subgroups and association statuses for each subgroup were determined. A total of 323 cases and 400 healthy, age and sex matched controls belonging to NIA were prospectively enrolled and subsequently genotyped for 11 selected IL-1 gene cluster SNPs. Although results for none of the evaluated IL-1 gene cluster SNPs reached the adjusted level of significance (p<0.0045), clear trends of association were seen for <i>IL1B</i> -511 C>T and <i>IL1RN</i> 86bp VNTR in several of the constructed genetic models (p range = 0.01–0.044 and 0.005–0.034 respectively). The presence of >1, ‘T’ (minor) allele of <i>IL1B</i> -511 C>T in a genotype seemed to provide protection against CAD (OR = 0.62, p = 0.044), while the presence of >1, ‘C’ (major) allele seemed to increase the risk of CAD (OR = 1.36, p = 0.041). The minor allele (allele 2) of <i>IL1RN</i> 86bp VNTR and its homozygous genotype (2/2 genotype) also seemed to carry an increased risk for CAD (OR = 1.62, p = 0.005 and OR = 2.25, p = 0.031 respectively). On the other hand, several haplotype combinations constructed out of <i>IL1B</i> and <i>IL1RN</i> gene variants clearly showed statistically significant associations with CAD (p<0.0045). Our meta-analysis was conducted for 8 previously assessed IL-1 SNPs. We included 53 different studies which involved a total sample of 26,210 (13,982 cases and 12,228 controls). Our pooled results concurred with the findings of our case-control study and was not able to deduce any statistically significant associations for any of the 8 studied SNPs (p>0.05). Subgroup analysis, however, yielded interesting results, where significant differences in association statuses were seen for <i>IL1A</i> +4845 G>T, <i>IL1B</i> -511 C>T, <i>IL1RN</i> 86bp VNTR and <i>IL1RN</i> +8006 T>C for select ancestral subgroups. The hints of associations deduced for subjects belonging to NIA in our case-control study for both <i>IL1B</i> -511 C>T and <i>IL1RN</i> 86bp VNTR were duly validated vide significant p values seen for NIA in all three genetic models (OR range = 0.62–0.76, p range = 0.01–0.04 and OR range = 1.51–2.25, p range = 0.004–0.04 respectively). On the other hand, Mixed Ancestry (MA) subgroup carrying <i>IL1B</i> -511 C>T, <i>IL1RN</i> 86bp VNTR or <i>IL1RN</i> +8006 T>C polymorphisms seemed to enjoy significant protection against CAD. A few other ancestral subgroups also demonstrated significant associations for a few of the studied SNPs vide one of the three genetic models. Clinical interpretation of derived results is however recommended.</p></div

Forest plots depicting meta-analysis results for <i>IL1RN</i> 86bp VNTR (PMID 14563376) polymorphism.

<p>Panel A: Effect size estimation using dominant genetic model (<i>2/2+X/2 vs</i>. <i>X/X</i>); Panel B: Effect size estimation using recessive genetic model (<i>2/2 vs</i>. <i>X/2+X/X</i>); Panel C: Effect size estimation using allelic genetic model (<i>Allele 2 vs</i>. <i>Allele X</i>). Pooled effect size estimates for dominant, recessive and allelic genetic models were obtained using random effects for analysis. Random effects were also used to calculate effect size estimates for European Ancestry group in allelic genetic model. Fixed effects were used for dominant and recessive genetic model in the European Ancestry group, as well as all ancestral groups in all three genetic models. Revised effect size estimates using fixed effects are given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0153480#pone.0153480.t002" target="_blank">Table 2</a>. Comparisons were performed according to “allele 2” and “allele X” nomenclature where allele X is defined here as any other allele, than allele 2.</p