Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease

被引：225

作者：

Kottyan, Leah C. ^{[1
,2
,3
]}

Davis, Benjamin P. ^{[3
]}

Sherrill, Joseph D. ^{[3
]}

Liu, Kan ^{[3
]}

Rochman, Mark ^{[3
]}

Kaufman, Kenneth ^{[1
,2
]}

Weirauch, Matthew T. ^{[1
,4
]}

Vaughn, Samuel ^{[1
]}

Lazaro, Sara ^{[1
,2
]}

Rupert, Andrew M.

Kohram, Mojtaba ^{[4
]}

Stucke, Emily M. ^{[3
]}

Kemme, Katherine A. ^{[3
]}

Magnusen, Albert ^{[1
,2
]}

He, Hua ^{[5
]}

Dexheimer, Phillip ^{[4
]}

Chehade, Mirna ^{[6
]}

Wood, Robert A. ^{[7
]}

Pesek, Robbie D. ^{[8
]}

Vickery, Brian P. ^{[9
]}

Fleischer, David M. ^{[10
]}

Lindbad, Robert ^{[11
]}

Sampson, Hugh A. ^{[6
]}

Mukkada, Vincent A. ^{[12
]}

Putnam, Phil E. ^{[12
]}

Abonia, J. Pablo ^{[3
]}

Martin, Lisa J. ^{[5
]}

Harley, John B. ^{[1
,2
]}

Rothenberg, Marc E. ^{[3
]}

机构：

[1] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Ctr Autoimmune Genom & Etiol,Div Rheumatol, Cincinnati, OH USA

[2] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA

[3] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Allergy & Immunol, Cincinnati, OH 45220 USA

[4] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Div Biomed Informat, Cincinnati, OH USA

[5] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Human Genet, Cincinnati, OH USA

[6] Icahn Sch Med Mt Sinai, Dept Pediat, New York, NY 10029 USA

[7] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA

[8] Univ Arkansas Med Sci, Arkansas Childrens Hosp, Dept Pediat, Little Rock, AR 72205 USA

[9] Univ N Carolina, Dept Pediat, Chapel Hill, NC USA

[10] Natl Jewish Hlth, Dept Pediat, Denver, CO USA

[11] EMMES Corp, Rockville, MD USA

[12] Univ Cincinnati, Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Cincinnati, OH USA

来源：

NATURE GENETICS | 2014年 / 46卷 / 08期

关键词：

INTERLEUKIN-4; RECEPTOR-ALPHA; GENE-EXPRESSION; SUSCEPTIBILITY LOCI; CHROMOSOME; 11Q13.5; ATOPIC-DERMATITIS; DIETARY THERAPY; METAANALYSIS; VARIANTS; COMMON; DIFFERENTIATION;

D O I：

10.1038/ng.3033

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 x 10(-16)), we identified an association at 2p23 spanning CAPN14 (P = 2.5 x 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 x 10(-2) < P < 5.1 x 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.

引用

页码：895 / 900

页数：6

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