3202 Genome-Wide Association Studies of Asthma Indicate Opposite Immunopathogenesis Direction From Autoimmune Diseases

Tuesday, 6 December 2011: 13:45 - 14:00
Tulum (Cancún Center)

Xingnan Li, PhD, MS , Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston Salem, NC

Elizabeth Ampleford, PhD , Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston Salem, NC

Timothy Howard, PhD , Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston Salem, NC

Dara Torgerson, PhD , Department of Human Genetics, University of Chicago, Chicago, IL

Huashi Li, MS , Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston Salem, NC

Wendy Moore, MD , Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston Salem, NC

William Busse, MD , Department of Medicine, University of Wisconsin, Madison, WI

Mario Castro, MD, MPH , Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO

Serpil Erzurum, MD , The Lerner Research Institute, Cleveland, OH

Anne Fitzpatrick, PhD , Department of Pediatrics, Emory University School of Medicine, Atlanta, GA

Benjamin Gaston, MD , Department of Pediatrics, University of Virginia Health Systems, Charlottesville, VA

Elliot Israel, MD , Brigham & Women's Hospital, Harvard University, Boston, MA

Nizar Jarjour, MD , Departments of Medicine and Public Health Sciences, University of Wisconsin Hospitals and Clinics, Madison, WI

W. Gerald Teague, MD , Department of Pediatrics, University of Virginia Health Systems, Charlottesville, VA

Sally Wenzel, MD , Medicine, University of Pittsburgh, Pittsburgh, PA

Gregory Hawkins, PhD , Center for Genomics and Personalized Medicine Research, Wake Forest University School of Medicine, Winston Salem, NC

Carole Ober, PhD , Department of Human Genetics, University of Chicago, Chicago, IL

Dan Nicolae, PhD , Department of Human Genetics, University of Chicago, Chicago, IL

Eugene R. Bleecker, MD , Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston Salem, NC

Deborah Meyers, PhD , Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston Salem, NC

Background: Genome-wide association studies (GWAS) of asthma and asthma-related traits, including our previous TENOR study [1], have consistently identified ORMDL3-GSDMB, IL33, IL1RL1-IL18R1, RAD50-IL13, TSLP-WDR36, and HLA-DR/DQ regions [2].

Methods: In this study, GWAS of asthma was performed in non-Hispanic white population from STAMPEED study (813 cases and 1,564 controls). Our GWAS results were compared with the published GWAS of asthma and autoimmune diseases (AD).

Results: Multiple SNPs in TNFAIP3 interacting protein 1 (TNIP1) on chromosome 5q32-q33.1 were associated with asthma in STAMPEED: rs1422673 (P = 3.44 x 10-7) and rs10036748 (P = 1.41 x 10-6). rs1422673 was weakly associated with asthma in the published GABRIEL study (P = 0.018 for meta-analysis) [2] but not in the TENOR study (P = 0.18 but same trend) [1]. TNIP1 may interact with TNFAIP3 and inhibit TNFα-induced NFκB inflammation pathway. Joint analyses were performed on six SNPs in GSDMB (rs2872507), IL33 (rs3939286), IL1RL1 (rs13431828), IL13 (rs20541), TSLP (rs1837253), and HLA-DRA (rs2395185) in STAMPEED and TENOR populations, but only limited variance can be explained (percentage of deviance = 1.5% -1.9%; the area under the receiver operating characteristic curve (AUC) = 0.58 - 0.59). Minor allele T of rs20541 in IL13 is the risk allele for asthma but the protective allele for psoriasis. Minor allele A of rs2872507 in GSDMB is the protective allele for asthma but the risk allele for rheumatoid arthritis, Crohn’s disease and ulcerative colitis. T allele of rs10036748 in TNIP1 is the minor protective allele for asthma, but the minor or major risk allele for systemic lupus erythematosus in non-Hispanic white or Chinese population, respectively.

Conclusions: Our study provides genetic evidence that asthma and AD have opposite immunopathogenesis directions.

[1] Li X, Howard TD, Zheng SL, Haselkorn T, Peters SP, Meyers DA, Bleecker ER. Genome-wide association study of asthma identifies RAD50-IL13 and HLA-DR/DQ regions. J Allergy Clin Immunol 2010;125:328-335 e311.

[2] Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M, Lathrop M, Cookson WO. A large-scale, consortium-based genomewide association study of asthma. N Engl J Med 2010;363:1211-1221.