1. Genome wide association study of circulating interleukin 6 levels identifies novel loci
- Author
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Ahluwalia, T.S., Armstrong, N.J., Aslibekyan, S., Beekman, M., Cheng, Y., deGeus, E., Delgado, G.E., Marek, D., Kanoni, S., Nolte, I.M., Porcu, E., Seppälä, I., Standl, M., Teumer, A., Thalamuthu, A., Trompet, S., Benjamin, E.J., Feitosa, M.F., Homuth, G., Lahti, J., Liu, Y., Timpson, N.J., Visvikis-Siest, S., Völker, U., Baune, B.T., Boomsma, D., Deary, I.J., Evans, D.M., Ferreira, M.A., Gaunt, T., Gudnason, V., Hamsten, A., Humphries, S.E., Koeing, W., Kumari, M., Lawlor, D.A., Nauck, M., Price, J.F., Sørensen, T.I.A., Stacey, D., Stathopoulou, M.G., Tanaka, T., Wannamethee, S.G., Rotter, J.I., Dehghan, A., Boerwinkle, E., Sneider, H., Psaty, B.M., Prins, B.P., Alizadeh, B.Z., Ahluwalia, T.S., Armstrong, N.J., Aslibekyan, S., Beekman, M., Cheng, Y., deGeus, E., Delgado, G.E., Marek, D., Kanoni, S., Nolte, I.M., Porcu, E., Seppälä, I., Standl, M., Teumer, A., Thalamuthu, A., Trompet, S., Benjamin, E.J., Feitosa, M.F., Homuth, G., Lahti, J., Liu, Y., Timpson, N.J., Visvikis-Siest, S., Völker, U., Baune, B.T., Boomsma, D., Deary, I.J., Evans, D.M., Ferreira, M.A., Gaunt, T., Gudnason, V., Hamsten, A., Humphries, S.E., Koeing, W., Kumari, M., Lawlor, D.A., Nauck, M., Price, J.F., Sørensen, T.I.A., Stacey, D., Stathopoulou, M.G., Tanaka, T., Wannamethee, S.G., Rotter, J.I., Dehghan, A., Boerwinkle, E., Sneider, H., Psaty, B.M., Prins, B.P., and Alizadeh, B.Z.
- 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.
- Published
- 2020