Genome-wide association study of circulating interleukin 6 levels identifies novel loci
Tarunveer S. Ahluwalia, Bram P. Prins, Mohammadreza Abdollahi, Nicola J. Armstrong, Stella Aslibekyan, Lisa Bain, Barbara J. Jefferis, Jens Baumert, Marian Beekman, Yoav Ben‐Shlomo, Joshua C Bis, Braxton D. Mitchell, Eco J. C. de Geus, Graciela E. Delgado, Diana Marek, Joel Eriksson, Eero Kajantie, Stavroula Kanoni, John P. Kemp, Lu Chen, Riccardo E. Marioni, Stela McLachlan, Yuri Milaneschi, Ilja M. Nolte, Alexandros M Petrelis, Eleonora Porcu, Maria Sabater‐Lleal, Elnaz Naderi, Ilkka Seppälä, Tina Shah, Gaurav Singhal, Marie Standl, Alexander Teumer, Anbupalam Thalamuthu, Elisabeth Thiering, Stella Trompet, Christie M. Ballantyne, Emelia J. Benjamin, Juan P. Casas, Catherine Toben, George Dedoussis, Joris Deelen, Peter Durda, Jorgen Engmann, Mary F. Feitosa, Harald Grallert, Ann Hammarstedt, Sarah E. Harris, Georg Homuth, Jouke‐Jan Hottenga, Sirpa Jalkanen, Yalda Jamshidi, Magdalene C. Jawahar, Tine Jess, Mika Kivimäki, Marcus E. Kleber, Jari Lahti, Ching‐Ti Liu, Pedro Marques‐Vidal, Dan Mellström, Simon P. Mooijaart, Martina Müller‐Nurasyid, Brenda W.J.H. Penninx, Joana Revez, Peter Rossing, Katri Räikkönen, Naveed Sattar, Hubert Scharnagl, Bengt Sennblad, Angela Silveira, Beaté St Pourcain, Nicholas J. Timpson, Julian N. Trollor, CHARGE Inflammation Working Group, Jenny van Dongen, Diana Van Heemst, Sophie Visvikis‐Siest, Péter Vollenweider, Uwe Völker, Mélanie Waldenberger, Gonneke Willemsen, Delilah Zabaneh, Richard Morris, Donna K. Arnett, Bernhard T. Baune, Dorret I Boomsma, Yen-Pei C. Chang, Ian J. Deary, Panos Deloukas, Johan G. Eriksson, David M. Evans, Manuel A. R. Ferreira, Tom R. Gaunt, Vilmundur Guðnason, Anders Hamsten, Joachim Heinrich, Aroon D. Hingorani, Steve E. Humphries, J. Wouter Jukema, Wolfgang Köenig
Abstract
Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and 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.