ArticlesIdentification of IL6R and chromosome 11q13.5 as risk loci for asthma
Introduction
Eight loci were reported to associate with asthma risk with genome-wide significance, namely the locus containing GSDMB, ORMDL3, and GSDMA on chromosome 17q21,1 PDE4D,2 DENND1B,3 the locus containing IL1RL1 and IL18R1 on chromosome 2q12.1,4 HLA-DQ, IL33, IL2RB, and SMAD3.5 Notably, these findings point to a genetically-linked dysregulation of cytokine signalling in asthma, and provide various specific targets for the development of novel biological treatments. They also implicate previously unsuspected risk loci, such as the 17q21 region. As our understanding of the biological mechanisms underlying these associations improves, novel insights into the pathophysiology of asthma are likely to emerge.
The risk variants identified until now explain only a small fraction of the disease heritability (<1% each), indicating that many more loci remain to be identified. Because of the proven success of genome-wide association studies (GWAS) to identify common risk variants,6 further dissection of this uncharacterised component of disease risk through well powered genetic studies represents a unique opportunity to advance our knowledge of the mechanisms that trigger asthma.
In this Article, we describe a series of genetic association analyses done to identify novel risk loci for asthma, including (1) a GWAS of physician-diagnosed asthma with data for 7197 individuals of European descent from Australia; (2) a meta-analysis of these results with findings from 26 475 individuals studied by the GABRIEL consortium;5 and (3) testing of the most significant regions of association in a further 25 358 independent samples.
Section snippets
Participants
We first did a GWAS of 7197 individuals of European ancestry from Australia; throughout this paper, we refer to this analysis as the Australian GWAS. Participants were drawn from three cohorts (webappendix pp 2–6): the Australian Asthma Genetics Consortium (AAGC) cohort (n=1810), the Busselton Health Study cohort (n=1230), and the Queensland Institute of Medical Research (QIMR) GWAS cohort (n=4157). Patients were generally recruited between 1964, and 2010.
Of the 2669 asthmatic patients, 759
Results
To identify novel SNPs associated with asthma risk, we first did a GWAS in 2669 physician-diagnosed asthmatic patients and 4528 controls from Australia. We recognise that with this sample size, power was only adequate (≥80%) at the genome-wide level (α=5×10−8) to detect loci with strong effects (eg, an OR≥1·25 for an allele frequency of 0·40). The genomic inflation factor confirmed that population substructure or other potential technical artifacts did not have a systematic impact on the
Discussion
We identified two new loci with genome-wide significant association with asthma risk: rs4129267 in IL6R and rs7130588 on chromosome 11q13.5 (panel). Multiple lines of evidence suggest that IL6R is indeed the causal gene underlying our observed association with rs4129267. First, rs4129267 is strongly associated with variation in serum concentration of the soluble form of the IL-6 receptor (sIL-6R).18 Each copy of the rs4129267:T allele increases sIL-6R protein concentration by about 1·4-fold,18
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These authors contributed equally to this work