Abstract

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus marked by eosinophilic infiltration. Cumulative evidence indicates that the risk of EoE involves the complex interplay of both genetic and environmental factors. As only a few genetic loci have been identified in EoE, the genetic underpinning of EoE remains largely elusive.OBJECTIVE: We aimed to identify genetic loci associated with EoE.METHODS: Four EoE cohorts were genotyped using the Illumina SNP array platform, totaling 1,930 cases and 13,634 controls of European ancestry. Genotype imputation was performed with the Michigan Imputation Server using the TOPMed reference panel including whole genome sequencing data from over 100,000 individuals. Meta-analysis was conducted to identify potential novel genetic loci associated with EoE.RESULTS: Our study identified 11 new genome-wide significant loci, of which six are common variant loci, including 5q31.1 (rs2106984, P = 4.16 * 10-8, OR = 1.26, RAD50), 15q22.2 (rs2279293, P = 1.23 * 10-10, OR = 0.69, RORA) and 15q23 (rs56062135, P = 2.91 * 10-11, OR = 1.29, SMAD3), which have been previously associated with allergic conditions. Interestingly, a low frequency synonymous mutation within the MATN2 gene was identified as the most significant SNP at the 8q22.1 locus. We also identified five sex-specific loci in the EoE cases, including an inflammatory bowel disease associated locus at 9p24.1 (rs62541556, P = 4.4 * 10-8, OR = 1.11, JAK2).CONCLUSIONS: Our findings demonstrate shared genetic underpinnings between EoE and other immune-mediated diseases, and provide novel candidate genes for therapeutic target identification and prioritization.

View details for DOI 10.1016/j.jaci.2021.08.018

View details for PubMedID 34506852