Indumathi Bobbala, Katkam Shiva Krishna, Krishna L S R, Kutala Vijay Kumar
1Department of Clinical Pharmacology and Therapeutics, Nizam's Institute of Medical Sciences (NIMS), Punjagutta, Hyderabad, Telangana India.
2Department of Cardiology, Nizam's Institute of Medical Sciences (NIMS), Punjagutta, Hyderabad, Telangana India.
Indian J Clin Biochem. 2019 Apr;34(2):180-187. doi: 10.1007/s12291-018-0740-3. Epub 2018 Feb 21.
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, = 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 = 0.01, and OR 1.71, 95% CI 1.09-2.23 = 0.02 respectively) with diabetes, and we found no association with hypertension (OR 0.95, 95% CI 0.57-1.59, = 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, = 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.
炎症在动脉粥样硬化和冠状动脉综合征的发病机制中起重要作用；此外，各种证据表明遗传因素确实会增加冠状动脉疾病（CAD）的风险。促炎细胞因子白细胞介素-6（IL-6）是与CAD相关的炎症的核心介质。本研究旨在探讨IL-6基因启动子区域单核苷酸多态性（-174 G>C）及甲基化与CAD易感性的关系。采用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）方法对IL-6 -174 G/C多态性进行基因分型。采用甲基化特异性PCR方法研究IL-6基因启动子甲基化情况。对470名受试者（265例CAD患者和205名对照）的分析显示，在显性模型中，-174 G/C变异与CAD风险相关（比值比[OR]1.58，95%置信区间[CI]为1.024-2.23，P=0.04）。此外，根据CAD的临床特征对-174 G>C多态性的基因型和等位基因分布进行分析，发现基因型和等位基因（OR分别为1.86，95%CI为1.18-2.84，P=0.01；以及OR为1.71，95%CI为1.09-2.23，P=0.02）与糖尿病显著相关，而与高血压无关联（OR 0.95，95%CI 0.57-1.59，P=0.8）。我们还分析了病例组和对照组之间IL-6启动子区域的甲基化状态，结果显示CAD患者存在显著的低甲基化（OR 2.36，95%CI 1.51-4.259，P=0.006）。此外，与对照组相比，CAD病例中的GC、CC基因型和C等位基因携带者表现出低甲基化（分别为54.58%对76.85%，29.83%对40%）。总之，启动子多态性-174 G/C与CAD风险相关，并且-174位点的'C'等位基因携带者表现出显著的低甲基化，这可能导致CAD风险增加。本研究强调了等位基因和基因型与IL-6启动子区域CpG岛的差异性DNA甲基化之间的关联，这可能会影响IL-6基因的调控。
