Dual Effect of IL-6 -174 G/C Polymorphism and Promoter Methylation in the Risk of Coronary Artery Disease Among South Indians

Abstract

Inflammation plays an important role in the pathogenesis of atherosclerosis and coronary syndromes; moreover, various lines of evidence suggest that genetic factors do contribute to the risk of coronary artery disease (CAD). The proinflammatory cytokine IL-6 is a central mediator of inflammation associated with CAD. The present study is aimed to investigate the association of single nucleotide polymorphism in the promoter region of the IL-6 gene (-174 G [ C) and methylation with the susceptibility of CAD. Genotyping of IL-6 -174 G/C polymorphism was performed by PCR-RFLP. Methylation-specific PCR method was used to study the IL-6 gene promoter methylation. Analysis of 470 subjects (265 CAD patients and 205 controls) showed association of the -174 G/C variant with the CAD risk in dominant model (OR 1.58, 95% CI, 1.024-2.23, P = 0.04). Further, the analysis of the distribution of genotypes and alleles of -174 G [ C polymorphism according to clinical features of CAD, revealed significant association of genotype and allele (OR 1.86, 95% CI 1.18-2.84 P = 0.01, and OR 1.71, 95% CI 1.09-2.23 P = 0.02 respectively) with diabetes, and we found no association with hypertension (OR 0.95, 95% CI 0.57-1.59, P = 0.8). We also analyzed the methylation status of IL-6 promoter region between cases and controls showed significant hypo methylation in CAD subjects (OR 2.36, 95% CI 1.51-4.259, P = 0.006). Additionally, GC, CC genotypes and C allele carriers show hypomethylation in CAD cases compared to controls (54.58 vs. 76.85%, 29.83 vs. 40% respectively). In conclusion, the promoter polymorphism -174 G/C is associated with CAD risk and further carriers of 'C' allele at -174 locus showed significant hypo methylation which could contribute to increased risk of CAD. The present study highlights the association of allele and genotypes with differential DNA methylation of CpG islands in the IL-6 promoter region which may affect IL-6 gene regulation.

The effect of polymorphisms (174G> C and 572C> G) on the Interleukin-6 gene in coronary artery disease: a systematic review and meta-analysis

“… India 2014 65±5 64±6 200 200 12 Gao, Y. L. [ 38 ] China 2016 61.50±10.53 52.54±10.65 275 286 13 Ghazouani, Lakhdar [ 39 ] Tunisia 2010 58.1±12.0 56.7±14.1 418 406 14 Humphries, S. E [ 40 ]. England 2001 56·7±3·6 56·0±3·4 162 2589 15 Indumathi, B [ 41 ]. India 2019 56.00 ± 12.00 – 265 205 16 Jabir, N. R [ 42 ] Saudi Arabia 2017 60.6±8.85 47.7±5.06 90 89 17 Jia, X. W [ 43 ].…”

Identification of Potential Biomarkers for CAD Using Integrated Expression and Methylation Data

“…Numerous published studies took promoters as key differentially methylated regions in CAD, while other intragenic regions were less concerned (Heidari et al, 2019;Indumathi et al, 2019). Recently, a few studies have demonstrated methylation sites in the gene body or TSS1500 were also essential to the pathogenesis of CAD (Liu et al, 2017).…”

Identification of potential biomarkers for CAD using integration with expression and methylation data and validation by case-control study

“…Numerous published studies took promoters as key differentially methylated regions in CAD, while other intragenic regions were less concerned [26,27]. Recently, a few studies have demonstrated methylation sites in gene body or TSS1500 were also essential to the pathogenesis of CAD [28].…”