Analysis of the Role of Interleukin 6 Receptor Haplotypes in the Regulation of Circulating Levels of Inflammatory Biomarkers and Risk of Coronary Heart Disease

Abstract

Variants at the interleukin 6 receptor (IL6R) gene regulate inflammation and are associated with risk of coronary heart disease (CHD). The aim of the present study was to investigate the effects of IL6R haplotypes on circulating levels of inflammatory biomarkers and risk of CHD. We performed a discovery analysis in SHEEP, a myocardial infarction (MI) case control study (n = 2,774) and replicated our results in two large, independent European populations, PROCARDIS, a CHD case control study (n = 7,998), and IMPROVE (n = 3,711) a prospective cardiovascular cohort study. Two major haplotype blocks (rs12083537A/G and rs4075015A/T—block 1; and rs8192282G/A, rs4553185T/C, rs8192284A/C, rs4240872T/C and rs7514452T/C—block 2) were identified in the IL6R gene. IL6R haplotype associations with C-reactive protein (CRP), fibrinogen, IL6, soluble IL6R (sIL6R), IL6, IL8 and TNF-α in SHEEP, CRP and fibrinogen in PROCARDIS and CRP in IMPROVE as well as association with risk of MI and CHD, were analyzed by THESIAS. Haplotypes in block 1 were associated neither with circulating inflammatory biomarkers nor with the MI/CHD risk. Haplotypes in block 2 were associated with circulating levels of CRP, in all three study populations, with fibrinogen in SHEEP and PROCARDIS, with IL8 and sIL6Rin SHEEP and with a modest, non significant, increase (7%) in MI/CHD risk in the three populations studied. Our results indicate that IL6R haplotypes regulate the circulating levels of inflammatory biomarkers. Lack of association with the risk of CHD may be explained by the combined effect of SNPs with opposite effect on the CHD risk, the sample size as well as by structural changes affecting sIL6R stability in the circulation.

Ectopic upregulation of membrane-bound IL6R drives vascular remodeling in pulmonary arterial hypertension

“…Of note, it has been demonstrated that SNPs in the IL6R gene (e.g., Asp358Ala [rs2228145]; ref. 33) can influence inflammation in the context of various inflammatory (34)(35)(36) and cardiac disorders (37)(38)(39). In summary, these findings offer insights into the role of the ectopic membrane-bound IL6R upregulation in PA-SMCs in PAH.…”

Molecular cross‐talk of IL‐6 in tumors and new progress in combined therapy

“…He contributed to the development of the first antibody against the IL‐6 receptor (tocilizumab) for the treatment of rheumatic arthritis. Subsequent research determined that IL‐6 is also closely related to diseases such as coronary heart disease, schizophrenia, and gestational diabetes mellitus . Recent studies have found that IL‐6 is closely linked to the biogenesis and growth of tumors, including those of breast cancer, myeloma, and lung cancer.…”

Lessons learned from twins in autoimmune and chronic inflammatory diseases

“…This is well represented by coronary heart disease and atherosclerosis in which the genetic predisposition is largely based on IL6 receptor polymorphisms [136,137] and severity correlates with the extent and duration of chronic inflammation [138]. In general terms, we continue to affirm that the predisposition to complex diseases such as those based on autoimmunity and chronic inflammation is secondary to the coexistence of a permissive genetic background and specific environmental factors and MZ twins are excellent intuitive models to estimate these factors.…”