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 Jefferis, Jens Baumert, Marian Beekman, Yoav Ben-Shlomo, Joshua C. Bis, Braxton D. Mitchell, Eco De Geus, Graciela E. Delgado, Diana Marek, Joel Eriksson, Eero Kajantie, Stavroula Kanoni, John P. Kemp, Chen LuRiccardo 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 Kivimaki, Marcus E. Kleber, Jari Lahti, Yongmei Liu, Pedro Marques-Vidal, Dan Mellström, Simon P. Mooijaart, Martina Müller-Nurasyid, Brenda Penninx, Joana A. Revez, Peter Rossing, Katri Raïkkönen, Naveed Sattar, Hubert Scharnagl, Bengt Sennblad, Angela Silveira, Beate St Pourcain, Nicholas J. Timpson, Julian Trollor, Jenny Van Dongen, Diana Van Heemst, Sophie Visvikis-Siest, Peter Vollenweider, Uwe Völker, Melanie Waldenberger, Gonneke Willemsen, Delilah Zabaneh, Richard W. 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. Ferreira, Tom Gaunt, Vilmundur Gudnason, Anders Hamsten, Joachim Heinrich, Aroon Hingorani, Steve E. Humphries, J. Wouter Jukema, Wolfgang Koenig, Meena Kumari, Zoltan Kutalik, Deborah A. Lawlor, Terho Lehtimäki, Winfried März, Karen A. Mather, Silvia Naitza, Matthias Nauck, Claes Ohlsson, Jackie F. Price, Olli Raitakari, Ken Rice, Perminder S. Sachdev, Eline Slagboom, Thorkild I.A. Sørensen, Tim Spector, David Stacey, Maria G. Stathopoulou, Toshiko Tanaka, S. Goya Wannamethee, Peter Whincup, Jerome I. Rotter, Abbas Dehghan, Eric Boerwinkle, Bruce M. Psaty, Harold Snieder, Behrooz Z. Alizadeh

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

24 Citations (Scopus)
18 Downloads (Pure)

Abstract

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.

Original languageEnglish
Pages (from-to)393-409
Number of pages17
JournalHuman Molecular Genetics
Volume30
Issue number5
DOIs
Publication statusPublished - 1 Mar 2021

Bibliographical note

Funding:
Novo Nordisk Foundation (NNF18OC0052457 to T.S.A.). Detailed Funding statements from participating study cohorts can be found in Supplementary Material, Table S12.

Publisher Copyright: © The Author(s) 2021. Published by Oxford University Press.

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