Eosinophilic esophagitis (EoE) genetic susceptibility is mediated by synergistic interactions between EoE-specific and general atopic disease loci - 04/05/18
Abstract |
Background |
Eosinophilic esophagitis (EoE) is an esophageal inflammatory disease associated with atopic diseases. Thymic stromal lymphopoietin (TSLP) and calpain 14 (CAPN14) genetic variations contribute to EoE, but how this relates to atopy is unclear.
Objective |
The purpose of this study was to explore the relationship between EoE, atopy, and genetic risk.
Methods |
EoE-atopy enrichment was tested by using 700 patients with EoE and 801 community control subjects. Probing 372 single nucleotide polymorphisms (SNPs) in 63 atopy genes, we evaluated EoE associations using 412 nonatopic and 868 atopic disease control subjects. Interaction and stratified analyses of EoE-specific and atopy-related SNPs were performed.
Results |
Atopic disease was enriched in patients with EoE (P < .0001). Comparing patients with EoE and nonatopic control subjects, EoE associated strongly with IL-4/kinesin family member 3A (IL4/KIF3A) (P = 2.8 × 10−6; odds ratio [OR], 1.87), moderately with TSLP (P = 1.5 × 10−4; OR, 1.43), and nominally with CAPN14 (P = .029; OR, 1.35). Comparing patients with EoE with atopic disease control subjects, EoE associated strongly with ST2 (P = 3.5 × 10−6; OR, 1.77) and nominally with IL4/KIF3A (P = .019; OR, 1.25); TSLP's association persisted (P = 4.7 × 10−5; OR, 1.37), and CAPN14's association strengthened (P = .0001; OR, 1.71). Notably, there was gene-gene interaction between TSLP and IL4 SNPs (P = .0074). Children with risk alleles for both genes were at higher risk for EoE (P = 2.0 × 10−10; OR, 3.67).
Conclusions |
EoE genetic susceptibility is mediated by EoE-specific and general atopic disease loci, which can have synergistic effects. These results might aid in identifying potential therapeutics and predicting EoE susceptibility.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Genetic association, atopy, eosinophilic esophagitis
Abbreviations used : AD, AIM, AR, CAPN14, EoE, IL4/KIF3A, LD, OR, PC, SNP, TSLP
Plan
| Supported in part by National Institutes of Health grants U19 AI70235, R01 AI124355, R01 DK107502, and P30 AR070549; the Sunshine Charitable Foundation and its supporters, Denise A. Bunning and David G. Bunning; the American Partnership for Eosinophilic Disorders (APFED); the Buckeye Foundation; the Campaign Urging Research for Eosinophilic Diseases (CURED) Foundation; and the Cincinnati Children's Research Foundation and its Cincinnati Genomic Control Cohort. |
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| Disclosure of potential conflict of interest: L. J. Martin's, H. He's, and M. Eby's institutions received a grant from the National Institutes of Health (NIH) for this work. M. H. Collins's institution received a grant from the NIH for this work, she personally received consultancy fees from Regeneron and Banner Life Sciences, and her institution received support from Shire contract for pathology central review and Regeneron contract for pathology central review. J. P. Abonia's institution received grants from the NIH/National Institute of Allergy and Infectious Diseases (NIAID; CEGIR) U54AI117804, Patient-Centered Outcomes Research Institute (PCORI) SC14-1403-11593, and NIH/NIAID (CoFAR) 2U19 AI066738-06 for this work. J. M. Biagini Myers' institute received a grant and support for travel from the NIH for this study and grants from the NIH for other works. H. Johansson's institute received a grant from the NIH for this work. L. C. Kottyan's institute received grant R01 DK107502, P30 AR070549 for this work. G. Khurana Hershey's institution received a grant from the NIH for this and other works. M. E. Rothenberg's institution received a grant from the NIH for this work and grants from US-Israel Binational Grant and PCORI for other works; his institution owns patents inventorship, ownership by Cincinnati Children's Hospital, and he personally received consultancy fees from Celgene, Genentech, Immune Pharmaceuticals, NKT Therapeutics, Spoon Guru, and PulmOneTherapeutics; payment for lectures from Merck; and stock options from PulmOne, NKT Therapeutics, and Spoon Guru, Immune Pharmaceuticals. |
Vol 141 - N° 5
P. 1690-1698 - mai 2018 Retour au numéro
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