Gene-centric analysis identifies variants associated with interleukin-6 levels and shared pathways with other inflammation markers

Tina Shah*, Delilah Zabaneh, Tom Gaunt, Daniel I. Swerdlow, Sonia Shah, Philippa J. Talmud, Ian N. Day, John Whittaker, Michael V. Holmes, Reecha Sofat, Steve E. Humphries, Mika Kivimaki, Meena Kumari, Aroon D. Hingorani, Juan P. Casas

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

28 Citations (Scopus)


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 (r2>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.

Original languageEnglish
Pages (from-to)163-170
Number of pages8
JournalCirculation: Cardiovascular Genetics
Issue number2
Publication statusPublished - 1 Apr 2013


  • C-reactive protein
  • Genetic association study
  • Genetics
  • Interleukins

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