Genome-wide association study of circulating interleukin 6 levels identifies novel loci

Ahluwalia, T. S.; Prins, B. P.; Abdollahi, M.; Armstrong, N. J.; Aslibekyan, S.; Bain, L.; Jefferis, B.; Baumert, J.; Beekman, M.; Ben-Shlomo, Y.; Bis, J. C.; Mitchell, B. D.; De Geus, E.; Delgado, G. E.; Marek, D.; Eriksson, J.; Kajantie, E.; Kanoni, S.; Kemp, J. P.; Lu, C.; Marioni, R. E.; Mclachlan, S.; Milaneschi, Y.; Nolte, I. M.; Petrelis, A. M.; Porcu, E.; Sabater-Lleal, M.; Naderi, E.; Seppala, I.; Shah, T.; Singhal, G.; Standl, M.; Teumer, A.; Thalamuthu, A.; Thiering, E.; Trompet, S.; Ballantyne, C. M.; Benjamin, E. J.; Casas, J. P.; Toben, C.; Dedoussis, G.; Deelen, J.; Durda, P.; Engmann, J.; Feitosa, M. F.; Grallert, H.; Hammarstedt, A.; Harris, S. E.; Homuth, G.; Hottenga, J. -J.; Jalkanen, S.; Jamshidi, Y.; Jawahar, M. C.; Jess, T.; Kivimaki, M.; Kleber, M. E.; Lahti, J.; Liu, Y.; Marques-Vidal, P.; Mellstrom, D.; Mooijaart, S. P.; Muller-Nurasyid, M.; Penninx, B.; Revez, J. A.; Rossing, P.; Raikkonen, K.; Sattar, N.; Scharnagl, H.; Sennblad, B.; Silveira, A.; Pourcain, B. S.; Timpson, N. J.; Trollor, J.; Van Dongen, J.; Van Heemst, D.; Visvikis-Siest, S.; Vollenweider, P.; Volker, U.; Waldenberger, M.; Willemsen, G.; Zabaneh, D.; Morris, R. W.; Arnett, D. K.; Baune, B. T.; Boomsma, D. I.; Chang, Y. -P. C.; Deary, I. J.; Deloukas, P.; Eriksson, J. G.; Evans, D. M.; Ferreira, M. A.; Gaunt, T.; Gudnason, V.; Hamsten, A.; Heinrich, J.; Hingorani, A.; Humphries, S. E.; Jukema, J. W.; Koenig, W.; Kumari, M.; Kutalik, Z.; Lawlor, D. A.; Lehtimaki, T.; Marz, W.; Mather, K. A.; Naitza, S.; Nauck, M.; Ohlsson, C.; Price, J. F.; Raitakari, O.; Rice, K.; Sachdev, P. S.; Slagboom, E.; Sorensen, T. I. A.; Spector, T.; Stacey, D.; Stathopoulou, M. G.; Tanaka, T.; Wannamethee, S. G.; Whincup, P.; Rotter, J. I.; Dehghan, A.; Boerwinkle, E.; Psaty, B. M.; Snieder, H.; Alizadeh, B. Z.

doi:10.1093/hmg/ddab023

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro-A nd anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.