Eosinophilic esophagitis (EoE) is a rare atopic disorder associated with esophageal dysfunction, including difficulty swallowing, food impaction, and inflammation, that develops in a small subset of people with food allergies. Genome-wide association studies (GWASs) have identified 9 independent EoE risk loci reaching genome-wide significance (p < 5 × 10⁻⁸) and 27 additional loci of suggestive significance (5 × 10⁻⁸ < p < 1 × 10⁻⁵). In the current study, we perform linkage disequilibrium (LD) expansion of these loci to nominate a set of 531 variants that are potentially causal. To systematically interrogate the gene regulatory activity of these variants, we designed a massively parallel reporter assay (MPRA) containing the alleles of each variant within their genomic sequence context cloned into a GFP reporter library. Analysis of reporter gene expression in TE-7, HaCaT, and Jurkat cells revealed cell-type-specific gene regulation. We identify 32 allelic enhancer variants, representing 6 genome-wide significant EoE loci and 7 suggestive EoE loci, that regulate reporter gene expression in a genotype-dependent manner in at least one cellular context. By annotating these variants with expression quantitative trait loci (eQTL) and chromatin looping data in related tissues and cell types, we identify putative target genes affected by genetic variation in individuals with EoE. Transcription factor enrichment analyses reveal possible roles for cell-type-specific regulators, including GATA3. Our approach reduces the large set of EoE-associated variants to a set of 32 with allelic regulatory activity, providing functional insights into the effects of genetic variation in this disease.

嗜酸性粒细胞性食管炎 (EoE) 是一种罕见的特应性疾病，与食管功能障碍相关，包括吞咽困难、食物嵌塞和炎症，发生于一小部分食物过敏人群。全基因组关联研究 (GWAS) 已确定 9 个独立的 EoE 风险位点达到全基因组显着性 (p < 5 × 10 ^-8 ) 和 27 个具有提示意义的其他位点 (5 × 10 ^-8  < p < 1 × 10 ^-5）。在当前的研究中，我们对这些位点进行连锁不平衡 (LD) 扩展，以指定一组 531 个可能存在因果关系的变异。为了系统地询问这些变体的基因调控活性，我们设计了大规模并行报告分析（MPRA），其中包含克隆到 GFP 报告基因库中的基因组序列背景中每个变体的等位基因。对 TE-7、HaCaT 和 Jurkat 细胞中报告基因表达的分析揭示了细胞类型特异性的基因调控。我们鉴定了 32 个等位基因增强子变体，代表 6 个全基因组显着的 EoE 位点和 7 个暗示性 EoE 位点，它们在至少一种细胞环境中以基因型依赖性方式调节报告基因表达。通过用相关组织和细胞类型中的表达数量性状位点 (eQTL) 和染色质循环数据注释这些变异，我们确定了 EoE 个体中受遗传变异影响的推定目标基因。转录因子富集分析揭示了细胞类型特异性调节因子（包括 GATA3）的可能作用。我们的方法将大量 EoE 相关变异减少到 32 个具有等位基因调节活性的变异，为了解遗传变异对该疾病的影响提供了功能性见解。