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

Revez, J. A., Bain, L., Chapman, B., Powell, J. E., Jansen, R., Duffy, D. L., Tung, J. Y., Collaborators, A. A. G. C., Matheson, M. C., Marks, G. B., Hui, J., Le Souëf, P., Danoy, P., Baltic, S., Nyholt, D. R., Jenkins, M., Hayden, C., Beilby, J., Cheah, F., Madden, P. A., Heath, A. C., Hopper, J. L., Musk, B., Leeder, S. R., Walters, E. H., James, A., Jones, G., Abramson, M. J., Robertson, C.F., Dharmage, S.C., Brown, M.A., Thompson, P. J., Penninx, B. W., Visscher, P. M., De Geus, E. J. C., Boomsma, D. I., Hinds, D. A., Martin, N. G., Montgomery, G. W., & Ferreira, M. A. R. (2013) A new regulatory variant in the interleukin-6 receptor gene associates with asthma risk. Genes and Immunity, 14(7), pp. 441-446.

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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.

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ID Code: 89279
Item Type: Journal Article
Refereed: Yes
Keywords: alanine, interleukin 6 receptor, messenger RNA, tocilizumab, adult, allele, article, asthma, blood level, controlled study, correlation analysis, female, gene, genetic association, genetic risk, genetic variability, human, IL6R gene, intron, major clinical study, male, priority journal, single nucleotide polymorphism, Adolescent, Aged, Case-Control Studies, Child, Genetic Predisposition to Disease, Humans, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Interleukin-6, RNA, Messenger
DOI: 10.1038/gene.2013.38
ISSN: 1466-4879
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Deposited On: 21 Oct 2015 01:59
Last Modified: 22 Feb 2016 04:05

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