Association of interleukin 6 -174 G/C polymorphism with coronary artery disease and circulating IL-6 levels: a systematic review and meta-analysis

Abstract

Introduction Circulating IL-6 levels and at least one polymorphic form of IL6 gene (IL6 -174 G/C, rs1800795) have been shown to be independently associated with coronary artery disease (CAD) by several investigators. Despite more than 12 published meta-analyses on this subject, association of -174 G/C with CAD, especially amongst distinct ancestral population groups remain unclear. We, therefore, conducted a systematic review and an updated meta-analysis to comprehensively ascertain the association of IL6 -174 G/C with CAD and circulating IL-6 levels. Materials and methods Relevant case–control/cohort studies investigating association of -174 G/C with CAD and circulating IL-6 levels were identified following a comprehensive online search. Association status for CAD was determined for the pooled sample, as well as separately for major ancestral subgroups. Association status for circulating IL-6 levels was assessed for the pooled sample, as well as separately for CAD cases and CAD free controls. Study-level odds ratios (OR) and 95% confidence intervals (CI) were pooled using random/fixed-effects model. Results Quantitative synthesis for the CAD endpoint was performed using 55 separate qualifying studies with a collective sample size of 51,213 (19,160 cases/32,053 controls). Pooled association of -174 G/C with CAD was found to be statistically significant through dominant (OR 1.15; 95% CI 1.05–1.25, p = 0.002) as well as allelic genetic model comparisons (OR 1.13, 95% CI 1.06–1.21, p = 0.0003). This effect was largely driven by Asian and Asian Indian ancestral subgroups, which also showed significant association with CAD in both genetic model comparisons (OR range 1.29–1.53, p value range ≤ 0.02). Other ancestral subgroups failed to show any meaningful association. Circulating IL-6 levels were found to be significantly higher amongst the ‘C’ allele carriers in the pooled sample (Standard mean difference, SMD 0.11, 95% CI 0.01–0.22 pg/ml, p = 0.009) as well as in the CAD free control subgroup (SMD 0.10, 95% CI 0.02–0.17 pg/ml, p = 0.009), though not in the CAD case subgroup (SMD 0.17, 95% CI = − 0.02 to 0.37, p = 0.12). Conclusions The present systematic review and meta-analysis demonstrate an overall association between IL6 -174 G/C polymorphism and CAD, which seems to be mainly driven by Asian and Asian Indian ancestral subgroups. Upregulation of plasma IL-6 levels in the ‘C’ allele carriers seems to be at least partly responsible for this observed association. This warrants further investigations with large, structured case–control studies especially amongst Asian and Asian Indian ancestral groups.

IL-6 and HSPA1A Gene Polymorphisms May Influence the Levels of the Inflammatory and Oxidative Stress Parameters and Their Response to a Chronic Swimming Training

“…Recent systematic reviews with meta-analysis have shown that the CC homozygous genotype is an unfavorable genotype that increases susceptibility to coronary artery disease [5,6]. These findings are consistent with a previous prospective, population-based study (Rotterdam Study) that found greater arterial stiffness as a precursor to cardiovascular disease in individuals with the CC genotype compared to individuals with the wild-type GG genotype [7].…”

“…It is consistent with a previous study [33] in which the -174 CC genotype (compared to the GG genotype) was associated with higher susceptibility to upper respiratory tract infections among endurance athletes. In contrast, IL-6-174 GG homozygous carrier status has already been linked to reduced susceptibility to acute and chronic inflammatory diseases [5,6,34,35]. On the other hand, the decrease in circulating TNFα after 12-week swimming training in our study, which was observed in the whole ST group, but not in the CON group, was related to both GG and CC genotypes within IL-6-174G/C SNP.…”

IL6 gene polymorphism association with calcific aortic valve stenosis and influence on serum levels of interleukin-6

“…The rs1800795 polymorphism in the promoter region of IL6 gene is one of the most widely analyzed in cardiovascular diseases. A recent meta-analysis examined more than 40 studies related to rs1800795, with the firm conclusion that there is a clear association with coronary artery disease driven, at least in part, by upregulating plasma IL-6 levels ( 21 ). The hypothesis in that study is that carriers of the C allele, through various mechanisms not yet fully clarified, have upregulated transcription and translation of the gene.…”

“…To our knowledge, PALMD is not released to the circulation. 1 By contrast, we investigated whether the IL6 polymorphism could have an effect on the circulating levels of the cytokine in our patients, as it is described for coronary artery disease (21), by measuring IL-6 levels in 76 serum samples selected according to rs1800795 genotype. The CC genotype was associated with higher levels of serum IL-6 (23.5 pg/ml vs. 10.5 pg/ml for the other genotypes; P = 0.006) (Figure 3), even after adjustment for age, hypertension and coronary artery disease (estimate: 13.92, 95% CI 2.16-25.68, P = 0.021).…”

Association of IL-6 and TGF-β Gene Polymorphisms with the Risk of Thoracolumbar Osteoporotic Vertebral Compression Fractures

“…The current research on IL-6 gene polymorphism mainly focuses on SNPs in the promoter region, such as −597G/A (re1800797), −572G/C (rs1800796), −174G/C (rs1800795). They affect the expression level of IL-6 by regulating gene transcription and expression strength, and then make differences in the susceptibility of the population to diseases such as COVID-19, 7 coronary artery disease, 8 and type 2 diabetes. 9 IL-6 polymorphism has been reported to be involved in bone loss, 10 fracture, 11 and osteoarthritis.…”