Elsevier

The Lancet

Volume 378, Issue 9795, 10–16 September 2011, Pages 1006-1014
The Lancet

Articles
Identification of IL6R and chromosome 11q13.5 as risk loci for asthma

https://doi.org/10.1016/S0140-6736(11)60874-XGet rights and content

Summary

Background

We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease.

Methods

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.

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 (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.

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.

Funding

National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix.

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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