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

共 53 条

[1] Eosinophilic Esophagitis: Rapidly Advancing Insights [J].

Abonia, J. Pablo ;

Rothenberg, Marc E. .

ANNUAL REVIEW OF MEDICINE, VOL 63, 2012, 63 :421-434

[2] Integrating common and rare genetic variation in diverse human populations [J].

Altshuler, David M. ;

Gibbs, Richard A. ;

Peltonen, Leena ;

Dermitzakis, Emmanouil ;

Schaffner, Stephen F. ;

Yu, Fuli ;

Bonnen, Penelope E. ;

de Bakker, Paul I. W. ;

Deloukas, Panos ;

Gabriel, Stacey B. ;

Gwilliam, Rhian ;

Hunt, Sarah ;

Inouye, Michael ;

Jia, Xiaoming ;

Palotie, Aarno ;

Parkin, Melissa ;

Whittaker, Pamela ;

Chang, Kyle ;

Hawes, Alicia ;

Lewis, Lora R. ;

Ren, Yanru ;

Wheeler, David ;

Muzny, Donna Marie ;

Barnes, Chris ;

Darvishi, Katayoon ;

Hurles, Matthew ;

Korn, Joshua M. ;

Kristiansson, Kati ;

Lee, Charles ;

McCarroll, Steven A. ;

Nemesh, James ;

Keinan, Alon ;

Montgomery, Stephen B. ;

Pollack, Samuela ;

Price, Alkes L. ;

Soranzo, Nicole ;

Gonzaga-Jauregui, Claudia ;

Anttila, Verneri ;

Brodeur, Wendy ;

Daly, Mark J. ;

Leslie, Stephen ;

McVean, Gil ;

Moutsianas, Loukas ;

Nguyen, Huy ;

Zhang, Qingrun ;

Ghori, Mohammed J. R. ;

McGinnis, Ralph ;

McLaren, William ;

Takeuchi, Fumihiko ;

Grossman, Sharon R. .

NATURE, 2010, 467 (7311) :52-58

[3] Adults with eosinophilic myositis and calpain-3 mutations [J].

Amato, Anthony A. .

NEUROLOGY, 2008, 70 (09) :730-731

[4] Differential functions of calpain 1 during epithelial cell death and adipocyte differentiation in mammary gland involution [J].

Arnandis, Teresa ;

Ferrer-Vicens, Ivan ;

Torres, Luis ;

Garcia, Concha ;

Garcia-Trevijano, Elena R. ;

Zaragoza, Rosa ;

Vina, Juan R. .

BIOCHEMICAL JOURNAL, 2014, 459 :355-368

[5] Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease [J].

Barrett, Jeffrey C. ;

Hansoul, Sarah ;

Nicolae, Dan L. ;

Cho, Judy H. ;

Duerr, Richard H. ;

Rioux, John D. ;

Brant, Steven R. ;

Silverberg, Mark S. ;

Taylor, Kent D. ;

Barmada, M. Michael ;

Bitton, Alain ;

Dassopoulos, Themistocles ;

Datta, Lisa Wu ;

Green, Todd ;

Griffiths, Anne M. ;

Kistner, Emily O. ;

Murtha, Michael T. ;

Regueiro, Miguel D. ;

Rotter, Jerome I. ;

Schumm, L. Philip ;

Steinhart, A. Hillary ;

Targan, Stephan R. ;

Xavier, Ramnik J. ;

Libioulle, Cecile ;

Sandor, Cynthia ;

Lathrop, Mark ;

Belaiche, Jacques ;

Dewit, Olivier ;

Gut, Ivo ;

Heath, Simon ;

Laukens, Debby ;

Mni, Myriam ;

Rutgeerts, Paul ;

Van Gossum, Andre ;

Zelenika, Diana ;

Franchimont, Denis ;

Hugot, Jean-Pierre ;

de Vos, Martine ;

Vermeire, Severine ;

Louis, Edouard ;

Cardon, Lon R. ;

Anderson, Carl A. ;

Drummond, Hazel ;

Nimmo, Elaine ;

Ahmad, Tariq ;

Prescott, Natalie J. ;

Onnie, Clive M. ;

Fisher, Sheila A. ;

Marchini, Jonathan ;

Ghori, Jilur .

NATURE GENETICS, 2008, 40 (08) :955-962

[6] Validation of comparative genomic hybridization arrays for the detection of genomic rearrangements of the calpain-3 and dysferlin genes [J].

Bartoli, M. ;

Negre, P. ;

Wein, N. ;

Bourgeois, P. ;

Pecheux, C. ;

Levy, N. ;

Krahn, Martin .

CLINICAL GENETICS, 2012, 81 (01) :99-101

[7] Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis [J].

Blanchard, C ;

Wang, N ;

Stringer, KF ;

Mishra, A ;

Fulkerson, PC ;

Abonia, JP ;

Jameson, SC ;

Kirby, C ;

Konikoff, MR ;

Collins, MH ;

Cohen, MB ;

Akers, R ;

Hogan, SP ;

Assa'ad, AH ;

Putnam, PE ;

Aronow, BJ ;

Rothenberg, ME .

JOURNAL OF CLINICAL INVESTIGATION, 2006, 116 (02) :536-547

[8] Coordinate Interaction between IL-13 and Epithelial Differentiation Cluster Genes in Eosinophilic Esophagitis [J].

Blanchard, Carine ;

Stucke, Emily M. ;

Burwinkel, Karen ;

Caldwell, Julie M. ;

Collins, Margaret H. ;

Ahrens, Annette ;

Buckmeier, Bridget K. ;

Jameson, Sean C. ;

Greenberg, Allison ;

Kaul, Ajay ;

Franciosi, James P. ;

Kushner, Jonathan P. ;

Martin, Lisa J. ;

Putnam, Philip E. ;

Abonia, J. Pablo ;

Wells, Suzanne I. ;

Rothenberg, Marc E. .

JOURNAL OF IMMUNOLOGY, 2010, 184 (07) :4033-4041

[9] Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization [J].

Bonnelykke, Klaus ;

Matheson, Melanie C. ;

Pers, Tune H. ;

Granell, Raquel ;

Strachan, David P. ;

Alves, Alexessander Couto ;

Linneberg, Allan ;

Curtin, John A. ;

Warrington, Nicole M. ;

Standl, Marie ;

Kerkhof, Marjan ;

Jonsdottir, Ingileif ;

Bukvic, Blazenka K. ;

Kaakinen, Marika ;

Sleimann, Patrick ;

Thorleifsson, Gudmar ;

Thorsteinsdottir, Unnur ;

Schramm, Katharina ;

Baltic, Svetlana ;

Kreiner-Moller, Eskil ;

Simpson, Angela ;

St Pourcain, Beate ;

Coin, Lachlan ;

Hui, Jennie ;

Walters, Eugene H. ;

Tiesler, Carla M. T. ;

Duffy, David L. ;

Jones, Graham ;

Ring, Susan M. ;

McArdle, Wendy L. ;

Price, Loren ;

Robertson, Colin F. ;

Pekkanen, Juha ;

Tang, Clara S. ;

Thiering, Elisabeth ;

Montgomery, Grant W. ;

Hartikainen, Anna-Liisa ;

Dharmage, Shyamali C. ;

Husemoen, Lise L. ;

Herder, Christian ;

Kemp, John P. ;

Elliot, Paul ;

James, Alan ;

Waldenberger, Melanie ;

Abramson, Michael J. ;

Fairfax, Benjamin P. ;

Knight, Julian C. ;

Gupta, Ramneek ;

Thompson, Philip J. ;

Holt, Patrick .

NATURE GENETICS, 2013, 45 (08) :902-U290

[10] Calpainopathy and eosinophilic myositis [J].

Brown, RH ;

Amato, A .

ANNALS OF NEUROLOGY, 2006, 59 (06) :875-877

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