A new regulatory variant in the interleukin-6 receptor gene associates with asthma risk

J. A. Revez, L. Bain, B. Chapman, J. E. Powell, R. Jansen, D. L. Duffy, J. Y. Tung, A. A.G.C. Collaborators, Melanie C. Matheson, Guy B. Marks, Jennie Hui, Peter Le Souëf, Patrick Danoy, Svetlana Baltic, Dale R. Nyholt, Mark Jenkins, Catherine Hayden, John Beilby, Faang Cheah, Pamela A. MaddenAndrew C. Heath, John L. Hopper, Bill Musk, Stephen R. Leeder, Eugene H. Walters, Alan James, Graham Jones, Michael J. Abramson, Colin F. Robertson, Shyamali C. Dharmage, Matthew A. Brown, Philip J. Thompson, B. W. Penninx, P. M. Visscher, E. J.C. De Geus, D. I. Boomsma, D. A. Hinds, N. G. Martin, G. W. Montgomery, M. A.R. Ferreira

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

The main genetic determinant of soluble interleukin 6 receptor (sIL-6R) levels is the missense variant rs2228145 that maps to the cleavage site of IL-6R. For each Ala allele, sIL-6R serum levels increase by ∼20 ng ml -1 and asthma risk by 1.09-fold. However, this variant does not explain the total heritability for sIL-6R levels. Additional independent variants in IL6R may therefore contribute to variation in sIL-6R levels and influence asthma risk. We imputed 471 variants in IL6R and tested these for association with sIL-6R serum levels in 360 individuals. An intronic variant (rs12083537) was associated with sIL-6R levels independently of rs4129267 (P=0.0005), a proxy single-nucleotide polymorphism for rs2228145. A significant and consistent association for rs12083537 was observed in a replication panel of 354 individuals (P=0.033). Each rs12083537:A allele increased sIL-6R serum levels by 2.4 ng ml -1. Analysis of mRNA levels in two cohorts did not identify significant associations between rs12083537 and IL6R transcription levels. On the other hand, results from 16 705 asthmatics and 30 809 controls showed that the rs12083537:A allele increased asthma risk by 1.04-fold (P=0.0419). Genetic risk scores based on IL6R regulatory variants may prove useful in explaining variation in clinical response to tocilizumab, an anti-IL-6R monoclonal antibody.

Original languageEnglish
Pages (from-to)441-446
Number of pages6
JournalGenes and Immunity
Volume14
Issue number7
DOIs
StatePublished - 2013

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