Ferreira, M and Matheson, M and Duffy, D and Marks, G and Hui, J and Le Souef, P and Danoy, P and Baltic, S and Nyholt, D and Jenkins, M and Hayden, C and Willemsen, G and Ang, W and Kuokkanen, M and Beilby, J and Cheah, F and De Geus, E and Ramasamy, A and Vedantam, S and Salomaa, V and Madden, P and Heath, A and Hopper, J and Visscher, P and Musk, B and Leeder, S and Jarvelin, M and Pennell, C and Boomsma, D and Hirschhorn, J and Walters, H and Martin, N and James, A and Jones, G and Abramson, M and Robertson, C and Dharmage, S and Brown, M and Montgomery, G and Thompson, P, Australian Asthma Genetics Consortium, Identification of IL6R and chromosome 11q13.5 as risk loci for asthma, The Lancet, 378, (9795) pp. 1006-1014. ISSN 0140-6736 (2011) [Refereed Article]
Copyright 2011 Elsevier Ltd.
Background: We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying asthma.
Methods: We performed a genome-wide association study (GWAS) in 2,669 physiciandiagnosed asthmatics and 4,528 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 multiSNP 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.
Findings: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 gene (IL6R) 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-SNP association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that may be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP and BACH2.
Interpretation: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.
|Item Type:||Refereed Article|
|Research Division:||Biomedical and Clinical Sciences|
|Research Group:||Cardiovascular medicine and haematology|
|Research Field:||Respiratory diseases|
|Objective Group:||Clinical health|
|Objective Field:||Clinical health not elsewhere classified|
|UTAS Author:||Walters, H (Professor Haydn Walters)|
|Web of Science® Times Cited:||247|
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