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.
