Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 126, Issue 1, Pages 160-165Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2010.04.037
Keywords
Eosinophilic esophagitis; thymic stromal lymphopoietin; single nucleotide polymorphism; allergy; cytokine receptor-like factor 2; Toll-like receptor 3
Categories
Funding
- National Institutes of Health [U19 AI070235, R01 DK076893, HL091805]
- Public Health Service [P30 DK0789392]
- Department of Defense
- Food Allergy Project
- Buckeye Foundation
- Campaign Urging Research for Eosinophilic Disorders (CURED) Foundation
- Dana Foundation Human Immunology Consortium
- Ception Therapeutics,
- Children's Digestive Health and Nutrition Foundation
- GlaxoSmithKline
- Food Allergy and Anaphylaxis Network
- Dana Foundation
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Background: The genetic cause of eosinophilic esophagitis (EE) has been largely unexplored until a recent genome-wide association study identified a disease susceptibility locus on 5q22, a region that harbors the thymic stromal lymphopoietin (TSLP) gene. However, it is unclear whether the observed genetic associations with EE are disease-specific or confounded by the high rate of allergy in patients with EE. In addition, the genetic contributions of other allergy-associated genes to EE risk have not been explored. Objective: We aimed to delineate single nucleotide polymorphisms (SNPs) that associated with EE apart from allergy. Methods: We used a custom array containing 738 SNPs in 53 genes implicated in allergic responses, immune responses, or both to genotype 220 allergic or 246 nonallergic control subjects and a discovery cohort of 170 patients with EE. We replicated a statistically significant SNP association in an independent case-control cohort and examined the induction of the candidate gene in primary esophageal epithelial cells. Results: A single SNP residing in the TSLP gene reached Bonferroni linkage disequilibrium adjusted significance but only when patients with EE were compared with allergic control subjects (rs10062929; P = 4.11 x 10(-5); odds ratio, 0.35). A nonsynonymous polymorphism in the thymic stromal lymphopoietin receptor (TSLPR) gene on Xp22.3 and Yp11.3 was significantly associated with disease only in male patients with EE. Primary esophageal epithelial cells expressed TSLP mRNA after Toll-like receptor 3 stimulation. Conclusion: These data collectively identify TSLP as a candidate gene critically involved in EE susceptibility beyond its role in promoting T(H)2 responses. (J Allergy Clin Immunol 2010;126:160-5.)
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