Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis

Abstract

Background The genetic etiology 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 EE patients. 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 (SNP)s that associated with EE apart from allergy. Methods We utilized a custom array containing 738 SNPs in 53 genes implicated in allergic and/or immune responses to genotype 220 allergic or 246 non-allergic controls and a discovery cohort of 170 EE patients. 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 LD adjusted significance and only when EE cases were compared with allergic controls (rs10062929, P = 4.11 × 10−5, odds ratio = 0.35). A non-synonymous polymorphism in the TSLP receptor on Xp22.3 and Yp11.3 was significantly associated with disease only in male EE patients. Primary esophageal epithelial cells expressed TSLP mRNA following Toll-like receptor 3 (TLR3) stimulation. Conclusion These data collectively identify TSLP as a candidate gene critically involved in EE susceptibility beyond its role in promoting Th2 responses.