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

• Published in: Journal of allergy and clinical immunology Vol. 125; no. 2; pp. 328 - 335.e11
• Main Authors: Li, Xingnan, Howard, Timothy D., Zheng, Siqun L., Haselkorn, Tmirah, Peters, Stephen P., Meyers, Deborah A., Bleecker, Eugene R.
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.02.2010; Elsevier; Elsevier Limited
• Subjects: Acid Anhydride Hydrolases; Adult; Allergy and Immunology; Asthma; Asthma - genetics; Biological and medical sciences; Chromosomes; Chronic obstructive pulmonary disease, asthma; Deoxyribonucleic acid; DNA; DNA Repair Enzymes - genetics; DNA-Binding Proteins - genetics; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genealogy; Genes; Genetic Predisposition to Disease - genetics; Genome-Wide Association Study; Genomes; Genomics; Genotype; GWAS; HLA-DQ Antigens - genetics; HLA-DQB1; HLA-DR Antigens - genetics; Humans; IL13; Immunopathology; Interleukin-13 - genetics; Male; Medical sciences; Middle Aged; Pneumology; Polymorphism, Single Nucleotide; RAD50; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Statistical analysis; Studies; TENOR; TENOR; GWAS; IL13; Asthma; RAD50; FVC; QC; MAF; SNP; LD; LCR; IBS; GC; HLA-DQB1; Genomic control; Forced vital capacity; Linkage disequilibrium; Genome-wide association study; The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens; Identity-by-state; Quality control; Single nucleotide polymorphism; Minor allele frequency; Locus control region; Lung disease; Immunopathology; HLA-System; Respiratory disease; Cytokine; Class II histocompatibility antigen; Interleukin 13; HLA-DR-Locus; HLA-DQ-Locus; Association; Immunology; HGA-DQB1; Bronchus disease; Obstructive pulmonary disease; Genome
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2009.11.018

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. 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. 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. 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 H2 locus control region 3′ of RAD50. Imputation also identified a more significant SNP, rs3998159 ( P = 1.45E-06), between HLA-DQB1 and HLA-DQA2. This GWAS confirmed the important role of T H2 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.