Kottyan Leah C, Davis Benjamin P, Sherrill Joseph D, Liu Kan, Rochman Mark, Kaufman Kenneth, Weirauch Matthew T, Vaughn Samuel, Lazaro Sara, Rupert Andrew M, Kohram Mojtaba, Stucke Emily M, Kemme Katherine A, Magnusen Albert, He Hua, Dexheimer Phillip, Chehade Mirna, Wood Robert A, Pesek Robbie D, Vickery Brian P, Fleischer David M, Lindbad Robert, Sampson Hugh A, Mukkada Vincent A, Putnam Phil E, Abonia J Pablo, Martin Lisa J, Harley John B, Rothenberg Marc E
1] Center for Autoimmune Genomics and Etiology, Department of Pediatrics, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA. [2] US Department of Veterans Affairs Medical Center, Cincinnati, Ohio, USA. [3] Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA. [4].
1] Department of Pediatrics, Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA. [2].
Nat Genet. 2014 Aug;46(8):895-900. doi: 10.1038/ng.3033. Epub 2014 Jul 13.
Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder associated with allergic hypersensitivity to food. We interrogated >1.5 million genetic variants in EoE cases of European ancestry and subsequently in a multi-site cohort with local and out-of-study control subjects. In addition to replicating association of the 5q22 locus (meta-analysis P=1.9×10(-16)), we identified an association at 2p23 spanning CAPN14 (P=2.5×10(-10)). CAPN14 was specifically expressed in the esophagus, was dynamically upregulated as a function of disease activity and genetic haplotype and after exposure of epithelial cells to interleukin (IL)-13, and was located in an epigenetic hotspot modified by IL-13. Genes neighboring the top 208 EoE-associated sequence variants were enriched for esophageal expression, and multiple loci for allergic sensitization were associated with EoE susceptibility (4.8×10(-2)<P<5.1×10(-11)). We propose a model to explain the tissue-specific nature of EoE that involves the interplay of allergic sensitization with an EoE-specific, IL-13-inducible esophageal response involving CAPN14.
嗜酸性粒细胞性食管炎（EoE）是一种与食物过敏超敏反应相关的慢性炎症性疾病。我们对欧洲血统的EoE病例中的超过150万个基因变异进行了研究，随后在一个包含本地和非研究对照受试者的多中心队列中进行了研究。除了重复5q22位点的关联（荟萃分析P = 1.9×10⁻¹⁶）外，我们还在2p23上鉴定了一个跨越钙蛋白酶14（CAPN14）的关联（P = 2.5×10⁻¹⁰）。CAPN14在食管中特异性表达，随着疾病活动和遗传单倍型以及上皮细胞暴露于白细胞介素（IL）-13后动态上调，并且位于由IL-13修饰的表观遗传热点中。与前208个EoE相关序列变异相邻的基因在食管表达中富集，并且多个过敏致敏位点与EoE易感性相关（4.8×10⁻² < P < 5.1×10⁻¹¹）。我们提出了一个模型来解释EoE的组织特异性本质，该模型涉及过敏致敏与涉及CAPN14的EoE特异性、IL-13诱导的食管反应之间的相互作用。
