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

CHARGE Inflammation working group, 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 KempChen Lu, 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, Brenda Penninx, Meena Kumari, Harold Snieder, Behrooz Z Alizadeh*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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
Pages (from-to)393-409
Number of pages17
JournalHuman Molecular Genetics
Volume30
Issue number5
Early online date30-Jan-2021
DOIs
Publication statusPublished - 27-Apr-2021

Keywords

  • C-REACTIVE PROTEIN
  • SYSTEMIC-LUPUS-ERYTHEMATOSUS
  • RECEPTOR IL-6R GENE
  • SUSCEPTIBILITY LOCI
  • RHEUMATOID-ARTHRITIS
  • CHRONIC INFLAMMATION
  • PRODUCE IL-6
  • DISEASE
  • CELLS
  • ARCHITECTURE

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