Genome-wide association study of asthma identifies RAD50-IL13 and HLA-DR/DQ regions

Abstract

Background: Asthma is a heterogeneous disease that is caused by the interaction of genetic susceptibility with environmental influences. Genome-wide association studies (GWASs) represent a powerful approach to investigate the association of DNA variants with disease susceptibility. To date, few GWASs for asthma have been reported.

Objectives: A GWAS was performed on a population of patients with severe or difficult-to-treat asthma to identify genes that are involved in the pathogenesis of asthma.

Methods: A total of 292,443 single nucleotide polymorphisms (SNPs) were tested for association with asthma in 473 The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) cases and 1892 Illumina general population controls. Asthma-related quantitative traits (total serum IgE, FEV(1), forced vital capacity, and FEV(1)/forced vital capacity) were also tested in identified candidate regions in 473 TENOR cases and 363 phenotyped controls without a history of asthma to analyze GWAS results further. Imputation was performed in identified candidate regions for analysis with denser SNP coverage.

Results: Multiple SNPs in the RAD50-IL13 region on chromosome 5q31.1 were associated with asthma: rs2244012 in intron 2 of RAD50 (P = 3.04E-07). The HLA-DR/DQ region on chromosome 6p21.3 was also associated with asthma: rs1063355 in the 3' untranslated region of HLA-DQB1 (P = 9.55E-06). Imputation identified several significant SNPs in the T(H)2 locus control region 3' of RAD50. Imputation also identified a more significant SNP, rs3998159 (P = 1.45E-06), between HLA-DQB1 and HLA-DQA2.

Conclusion: This GWAS confirmed the important role of T(H)2 cytokine and antigen presentation genes in asthma at a genome-wide level and the importance of additional investigation of these 2 regions to delineate their structural complexity and biologic function in the development of asthma.

Figure 1

Genome-wide association of 292,443 SNPs in 473 TENOR cases and 1,892 Illumina controls. Color scale of the x-axis represents chromosomes. Negative logarithm transformed GC-adjusted P values are shown on the y-axis.

Figure 2

Linkage disequilibrium (LD) and association plot of 14 SNPs in the T_H2 cytokine locus. (A) Association plot: negative logarithm transformed P values (left scale) and recombination rate (right scale). (B) LD plot: r² color scheme was used and labeled. 95% confidence intervals on D’ was used to set up blocks.

Figure 3

Linkage disequilibrium (LD) and association plot of 10 SNPs in the HLA-DR/DQ region. (A) Association plot: negative logarithm transformed P values (left scale) and recombination rate (right scale). (B) LD plot: r² color scheme was used and labeled. 95% confidence intervals on D’ was used to setup blocks. Only 10 out of 46 SNPs (with P ≤ 0.001) are shown.