EoE genetic susceptibility is mediated by synergistic interactions between EoE-specific and general atopic disease loci

Publication date: Available online 10 November 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): L.J. Martin, H. He, M.H. Collins, J.P. Abonia, J.M. Biagini Myers, M. Eby, H.E. Johansson, L.C. Kottyan, G.K. Khurana Hershey, M.E. Rothenberg
BackgroundEosinophilic esophagitis (EoE) is an esophageal inflammatory disease associated with atopic diseases. TSLP and CAPN14 genetic variation contribute to EoE, but how this relates to atopy is unclear. The purpose of this study was to explore the relationship between EoE, atopy and genetic risk.MethodsEoE-atopy enrichment was tested using 700 EoE cases and 801 community controls. Probing 372 SNPs in 63 atopy-genes, we evaluated EoE associations using 412 non-atopic and 868 atopic disease controls. Interaction and stratified analyses of EoE-specific and atopy SNPs were performed.ResultsAtopic disease was enriched in EoE (p < 0.0001). Comparing EoE and non-atopic controls, EoE associated strongly with IL4/KIF3A (p = 2.8×10^-6; odds ratio (OR) = 1.85), moderately with TSLP (p = 1.5×10^-4; OR = 1.43), and nominally with CAPN14 (p = 0.029; OR = 1.35). Comparing EoE to atopic disease controls, EoE associated strongly with ST2 (p = 3.5×10^-6; OR = 1.79) and nominally with IL4/KIF3A (p = 0.019, OR = 1.25); TSLP's association persisted (p = 4.7×10^-5; OR = 1.37), and CAPN14's association strengthened (p = 0.0001; OR = 1.71). Notably, there was gene-gene interaction between TSLP and IL4 SNPs (p = 0.0074). Children with risk alleles for both genes were at higher risk for EoE (p = 2.0×10^-10; OR = 3.67).ConclusionsEoE genetic susceptibility is mediated by EoE-specific and general atopic disease loci which may have synergistic effects. These results may aid in identifying potential therapeutics and predicting EoE susceptibility.Clinical Implications.EoE susceptibility is mediated by multiple genes, which have synergistic effects. These genes include both EoE-specific and general atopic disease loci. Identifying these effects may help customize treatments.

Teaser

TSLP is a susceptibility locus for EoE. We demonstrate that TSLP and IL4 variants interact, partially explaining the high degree of co-morbid atopy. These findings will improve risk prediction and may help identify novel therapeutics.


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