Abstract
Interleukin-6 (IL-6) is a multifunctional cytokine with both pro and anti-inflammatory properties, synthesized by a wide range of tissues and cell types. Increased levels of circulating IL-6 in blood is associated with the pathophysiology of complex disorders like type 2 diabetes, cardiovascular and autoimmune diseases. Albeit, IL-6 levels are heritable with estimates up to 61%, only a few common genetic loci associated with circulating IL-6 levels have been identified. We therefore conducted a two stage (discovery and replication) meta genome-wide association study (GWAS) of circulating serum IL-6 concentrations comprising up to 67,428 individuals of european ancestry. About 2.5 million single nucleotide polymorphisms (SNPs) were available for testing after imputation to Hap Map 2 reference panel. We conducted an inverse variance based fixed effects meta-analysis. We identified three IL-6 associated, independent signals on chromosomes (chr) 2q14, 6p21 and 1q21, reaching genome-wide significance (p < 5.0 × 10−8) in the combined meta-analyses. Among the identified loci IL1F10/IL1RN (chr 2q14, p = 1.8 × 10−11), and HLA-DRB1/DRB5 (chr 6p21, p =1.5 × 10−10) were novel while IL6R (chr 1q21, p = 1.2 × 10−122) was a known locus. Our study identifies 2 novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.