Identification of IL6R and chromosome 11q13.5 as risk loci for asthma
Ferreira, M. A. R., Matheson, M. C., Duffy, D. L., Marks, G. B., Hui, J., Le Souëf, P., Danoy, P., Baltic, S., Nyholt, D.R., Jenkins, M., Hayden, C., Willemsen, G., Ang, W., Kuokkanen, M., Beilby, J., Cheah, F., De Geus, E. J. C., Ramasamy, A., Vedantam, S., Salomaa, V., Madden, P. A., Heath, A. C., Hopper, J. L., Visscher, P. M., Musk, B., Leeder, S. R., Jarvelin, M. R., Pennell, C., Boomsma, D. I., Hirschhorn, J. N., Walters, H., Martin, N. G., James, A., Jones, G., Abramson, M. J., Robertson, C. F., Dharmage, S. C., Brown, M.A., Montgomery, G. W., & Thompson, P. J. (2011) Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. The Lancet, 378(9795), pp. 1006-1014.
We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease. We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26 475), and these were tested in an additional 25 358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset. Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57 800): rs4129267 (OR 1·09, combined p= 2·4×10-8) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1·09, p=1·8×10-8) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1·33, p=7×10-4), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2. The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma. National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix. © 2011 Elsevier Ltd.
Impact and interest:
Citation counts are sourced monthly from and citation databases.
These databases contain citations from different subsets of available publications and different time periods and thus the citation count from each is usually different. Some works are not in either database and no count is displayed. Scopus includes citations from articles published in 1996 onwards, and Web of Science® generally from 1980 onwards.
Citations counts from theindexing service can be viewed at the linked Google Scholar™ search.
|Item Type:||Journal Article|
|Keywords:||interleukin 6 receptor, leucine, adolescent, adult, aged, allergic asthma, article, asthma, atopy, Australia, child, chromosome 11q, controlled study, female, gene replication, genetic association, genetic load, genetic risk, human, major clinical study, male, preschool child, priority journal, school child, Aged, 80 and over, Child, Preschool, Chromosomes, Human, Pair 11, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hypersensitivity, Immediate, Linkage Disequilibrium, Membrane Proteins, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Interleukin-6, Young Adult|
|Divisions:||Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
|Copyright Owner:||Copyright © 2011 Elsevier Ltd|
|Deposited On:||22 Oct 2015 02:52|
|Last Modified:||26 Feb 2016 02:59|
Repository Staff Only: item control page