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. Because only a few genetic loci have been identified in EoE, the genetic underpinning of EoE remains largely elusive.

Objective

We sought to identify genetic loci associated with EoE.

Methods

Four EoE cohorts were genotyped using the Illumina single nucleotide polymorphism array platform, totaling 1,930 cases and 13,634 controls of European ancestry. Genotype imputation was performed with the Michigan Imputation Server using the Trans-Omics for Precision Medicine reference panel including whole-genome sequencing data from more than 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 6 are common variant loci, including 5q31.1 (rs2106984, P = 4.16 × 10⁻⁸; odds ratio [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 single nucleotide polymorphism at the 8q22.1 locus. We also identified 5 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.

中文翻译：

---

全基因组关联荟萃分析确定了新的嗜酸性粒细胞性食管炎位点

背景

嗜酸性粒细胞性食管炎 (EoE) 是一种以嗜酸性粒细胞浸润为特征的食管慢性炎症性疾病。累积的证据表明，EoE 的风险涉及遗传和环境因素的复杂相互作用。因为在 EoE 中只发现了几个基因位点，所以 EoE 的遗传基础在很大程度上仍然难以捉摸。

客观的

我们试图确定与 EoE 相关的基因位点。

方法

使用 Illumina 单核苷酸多态性阵列平台对四个 EoE 队列进行了基因分型，共计 1,930 个病例和 13,634 个欧洲血统对照。使用 Trans-Omics for Precision Medicine 参考面板的 Michigan Imputation Server 进行基因型插补，包括来自 100,000 多人的全基因组测序数据。进行荟萃分析以确定与 EoE 相关的潜在新基因位点。

结果

我们的研究确定了 11 个新的全基因组显着位点，其中 6 个是常见变异位点，包括 5q31.1（rs2106984，P  = 4.16 × 10 ^-8；优势比 [OR]，1.26，RAD50），15q22.2（rs2279293 , P  = 1.23 × 10 ^-10；OR, 0.69, RORA ) 和 15q23 (rs56062135, P  = 2.91 × 10 ^-11 ; OR, 1.29, SMAD3 )，它们以前与过敏性疾病有关。有趣的是， MATN2中的一个低频同义突变基因被鉴定为 8q22.1 位点最显着的单核苷酸多态性。我们还在 EoE 病例中确定了 5 个性别特异性位点，包括 9p24.1 处的炎症性肠病相关位点（rs62541556，P  = 4.4 × 10 ^-8；OR，1.11，JAK2）。

结论

我们的研究结果表明 EoE 和其他免疫介导的疾病之间存在共同的遗传基础，并为治疗靶点识别和优先排序提供了新的候选基因。