Genetic variants at the 16p13 locus confer risk for eosinophilic esophagitis

Abstract

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus triggered by immune hypersensitivity to food. Herein, we tested whether genetic risk factors for known, non-allergic, immune-mediated diseases, particularly those involving autoimmunity, were associated with EoE risk. We used the high-density Immunochip platform, encoding 200,000 genetic variants for major auto-immune disease. Accordingly, 1214 subjects with EoE of European ancestry and 3734 population controls were genotyped and assessed using data directly generated or imputed from the previously published GWAS. We found lack of association of EoE with the genetic variants in the major histocompatibility complex (MHC) class I, II, and III genes and nearly all other loci using a highly powered study design with dense genotyping throughout the locus. Importantly, we identified an EoE risk locus at 16p13 with genome-wide significance (P_combined=2.05 × 10^-9, odds ratio = 0.76-0.81). This region is known to encode for the genes CLEC16A, DEXI, and CIITI, which are expressed in immune cells and esophageal epithelial cells. Suggestive EoE risk were also seen 5q23 (intergenic) and 7p15 (JAZF1). Overall, we have identified an additional EoE risk locus at 16p13 and highlight a shared and unique genetic etiology of EoE with a spectrum of immune-associated diseases.

Fig. 1

Manhattan plot of the P values obtained from the Immunochip association analysis. Data are from 1210 subjects with eosinophilic esophagitis (EoE) and 3734 controls over 79,405 genetic variants with minor allele frequencies (MAFs) greater than 1% in the subjects with EoE. The −log₁₀ value of each probability is shown as a function of genomic position on the autosomes. Genome-wide significance (red dashed line; P ≤ 5 × 10⁻⁸) and suggestive significance (solid blue line; P ≤ 1 × 10⁻⁷) are indicated

Fig. 2

Genetic association of variants at the 16p13 loci with EoE risk. a P values (−log₁₀) from the genetic association analysis of genotyped and imputed variants are plotted against the genomic position of each genotyped (blue) and imputed (red) single-nucleotide polymorphism (SNP) on the x axis on chromosome 16. b P values (−log₁₀) from the genetic association analysis adjusting for the association of rs12924112 of genotyped and imputed variants are plotted against the genomic position of each genotyped (blue) and imputed (red) SNP on the x axis on chromosome 16. Genes in the region are shown below. Position is given relative to Build 37 of the reference genome. Black lines indicate the recombination rates determined using subjects of European ancestry from the 1000 Genomes Project

Fig. 3

Expression of genes at the 16p13 locus. a RNAseq expression of CLEC16A, DEXI, and CIITA mRNA from esophageal biopsies (Control n = 10, EoE n = 10). No significant differences were identified between Control and EoE. b RNAseq expression of genes from esophageal epithelial cells in air-liquid interface culture system with or without IL-13 stimulation for 5 days (n = 3 wells per group). For a and b, bars represent the mean and error bars represent the standard deviation. No significant differences were identified between no treatment and IL-13 treatment. c Barcode x-score relative microarray expression of CLEC16A, DEXI, and CIITA in various human immune cell subsets downloaded from http://biospgs.org/ (ref. [48]). Reads per killobase of transcript per million mapped reads, RPKM. Data are representative from multiple cellular subtypes in the Primary Cell Atlas dataset