Volume 125, Issue 2 , Pages 328-335.e11, February 2010
Genome-wide association study of asthma identifies RAD50-IL13 and HLA-DR/DQ regions
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, FEV1, forced vital capacity, and FEV1/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 TH2 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 TH2 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.
Key words: Asthma, GWAS, RAD50, IL13, HLA-DQB1, TENOR
Abbreviations used: FVC, Forced vital capacity, GC, Genomic control, GWAS, Genome-wide association study, IBS, Identity-by-state, LCR, Locus control region, LD, Linkage disequilibrium, MAF, Minor allele frequency, QC, Quality control, SNP, Single nucleotide polymorphism, TENOR, The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens
The clinical TENOR study was supported by Genentech, Inc, and Novartis Pharmaceuticals Corp, and this genetic study was funded by NIH HL76285 and HL87665.
Disclosure of potential conflict of interest: D. A. Meyers has received research support from the National Institutes of Health. S. P. Peters has consulted for Genentech and has received research support from Genentech and the National Institutes of Health/National Heart, Lung, and Blood Institute. E. R. Bleecker is a member of Genentech's TENOR Steering Committee and has received research support (but no personal income) from Genentech and the National Institutes of Health. T. Haselkorn has consulted for Genentech. The rest of the authors have declared that they have no conflict of interest.
PII: S0091-6749(09)01735-7
doi:10.1016/j.jaci.2009.11.018
© 2010 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Volume 125, Issue 2 , Pages 328-335.e11, February 2010
