Gene-Centric Analysis Identifies Variants Associated With Interleukin-6 Levels and Shared Pathways With Other Inflammation Markers

Shah, T; Zabaneh, D; Gaunt, T; Swerdlow, DI; Shah, S; Talmud, PJ; Day, IN; Whittaker, J; Holmes, MV; Sofat, R; Humphries, SE; Kivimaki, M; Kumari, M; Hingorani, AD; Casas, JP; (2013) Gene-Centric Analysis Identifies Variants Associated With Interleukin-6 Levels and Shared Pathways With Other Inflammation Markers. Circulation Cardiovascular genetics, 6 (2). 163-+. ISSN 1942-325X DOI:

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Background-Inflammatory cytokine interleukin-6 (IL-6), a possible risk factor for coronary heart disease, has an estimated heritability of >60%, but to date few genetic variants influencing IL-6 levels are known. Methods and Results-We used the ITMAT-Broad-Care (IBC) HumanCVD disease BeadChip in the Whitehall II study (N=4911) and British Women's Heart and Health Study (N=3445) to identify single-nucleotide polymorphisms associated with circulating IL-6 levels. Twenty-two single-nucleotide polymorphisms from 7 loci (IL6R/TDRD10, HLA-DRB1, BUD13, SEZ6L, IL1RN, TRIB3, and ABO) were associated with IL-6 (P<10(-5)), although none were associated with the IL6 gene itself. With the exception of TRIB3, all loci have been previously reported in genome-wide association studies for autoimmune and cardiovascular diseases. Fourteen single-nucleotide polymorphisms in the IL6R region in high-linkage disequilibrium (r(2)>0.9) with a nonsynonymous variant, rs2228145, were also associated with IL-6 and C-reactive protein concentration (P<10(-5)). An IL-6-specific weighted allele score explained 2% of the variance of log IL-6 levels (P=2.4410(-22)) in Whitehall II and 1% (P=1.910(-8)) in British Women's Heart and Health Studies. Conclusions-Multiple common genetic variants of modest effect influence IL-6 concentration. Several loci contain single-nucleotide polymorphisms, exhibiting overlapping associations with autoimmune and cardiovascular disorders and other circulating biomarkers. Genetic variants associated with IL-6 provide important tools for probing the causal relevance of IL-6 signaling in a range of cardiometabolic diseases. (Circ Cardiovasc Genet. 2013;6:163-170.)

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology
PubMed ID: 23505291
Web of Science ID: 317741400005


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