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

Abstract

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.

Figure 1. Regional association plots for chromosomes 1q21.3 and 11q13.5

Association results (−log₁₀P-value, y-axis) from a meta-analysis of the Australian GWAS and the GABRIEL (5) studies for the 1q21.3 (A) and 11q13.5 (B) loci, focusing on a subset of SNPs genotyped in both studies. Results for rs4129267 (P = 2.0×10⁻⁶) and rs7130588 (P = 1.2×10⁻⁷) in this analysis are represented by the blue triangle in each plot. The orange triangle corresponds to results for rs4129267 (P = 2.3×10⁻⁸) and rs7130588 (P = 1.8×10⁻⁸) in the meta-analysis of our study, the GABRIEL study (5) and the follow-up panels (cf. Table 1), representing 15,797 asthmatic patients and 42,003 controls. The recombination rate (second y-axis) is plotted in light blue and is based on the CEU HapMap population. Exons for every gene are represented by vertical bars. Regional association plots for both loci in the Australian GWAS are presented in the webappendix (pp 18). GWAS=genome-wide association studies. SNP=single-nucleotide polymorphism. CEU=individuals from northern and western European ancestry from the Centre d’Etude du Polymorphisme Humain.

Figure 2. Multi-SNP prediction of asthma case-control status

Quantitative scores of genetic load were computed using information for seven non-overlapping groups of independent (r²<0.1, except rs2305480 and rs3894194 in group 1, r² 0.5) SNPs identified in the GABRIEL analysis (5) and tested for association with asthma case-control status in our study with logistic regression. The rightmost vertical bar represents the results obtained when including all seven quantitative scores as predictors in the logistic regression model. The horizontal black line represent a P = 0.05. The AUC, estimated from the logistic regression analysis, is shown above each bar. AUC=area under the receiver operator curve. GWAS=genome-wide association study.