The genetic etiology of eosinophilic esophagitis

Abstract

Eosinophilic esophagitis (EoE) is a chronic allergic disease associated with marked mucosal eosinophil accumulation. Multiple studies have reported a strong familial component to EoE, with the presence of EoE increasing the risk for other family members with EoE. Epidemiologic studies support an important role for environmental risk factors as modulators of genetic risk. In a small percentage of cases, including patients who have Mendelian diseases with co-occurrent EoE, rare genetic variation with large effect sizes could mediate EoE and explain multigenerational incidence in families. Common genetic risk variants mediate genetic risk for the majority of patients with EoE. Across the 31 reported independent EoE risk loci (P < 10^-5), most of the EoE risk variants are located in between genes (36.7%) or within the introns of genes (42.4%). Although some variants do change the amino acid sequence of genes (2.2%), only 3 of the 31 EoE risk loci harbor an amino acid-changing variant. Thus most EoE risk loci are outside of the coding regions of genes, suggesting a key role for gene regulation in patients with EoE, which is consistent with most other complex diseases.

Keywords: Eosinophilic esophagitis; genetics; genome-wide association study; heritability; single nucleotide polymorphism.

Figure 1.

Annotation of genetic variants associated with EoE. All genetic variants in high linkage disequilibrium (LD) with reported Tag SNPs at EoE risk loci (see Table 1) were identified using European and European American haplotypes in the 1000 genomes project . 544 variants across the 31 independent risk loci were identified. The variants were annotated based on their position within the genome and in the context of genes.

Figure 2.. Genetic risk of EoE.

Genetic risk variants are polymorphic places in the genome in which a risk allele is enriched in groups of patients with EoE compared to healthy controls. These variants are largely located in the non-coding region of the genome and do not affect the amino acid usage in proteins. Often, the way these noncoding variants increase risk of EoE is through changing DNA regulatory activity, leading to genotype-dependent expression of a gene. In some cases, these genes with allele-dependent expression (such as TSLP) affect the physiology of epithelial cells in the esophagus. These physiological changes can lead to EoE in patients.