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 Räikkönen, 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 Koeing, Meena Kumari, Zoltan Kutalik, Deborah A Lawlor, Terho Lehtimäki, Winfried März, Karen Mather, Silvia Naitza, Mathias 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

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Article numberddab023
JournalHuman Molecular Genetics
Early online date30 Jan 2021
DOIs
Publication statusE-pub ahead of print - 30 Jan 2021

Keywords

  • anti-inflammatory agents
  • cytokine
  • chromosomes
  • interleukin-6
  • genome-wide association study
  • hla-drb1 gene

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