Genome-Wide Association Analysis in Primary Sclerosing Cholangitis

被引：267

作者：

Karlsen, Tom H. ^{[1
]}

Franke, Andre ^{[2
]}

Melum, Espen ^{[1
]}

Kaser, Arthur ^{[3
]}

Hov, Johannes Roksund ^{[1
]}

Balschun, Tobias ^{[2
]}

Lie, Benedicte A. ^{[4
]}

Bergquist, Annika ^{[5
]}

Schramm, Christoph ^{[6
]}

Weismueller, Tobias J. ^{[7
]}

Gotthardt, Daniel

Rust, Christian ^{[9
]}

Philipp, Eva E. R.

Fritz, Teresa ^{[3
]}

Henckaerts, Liesbet ^{[10
]}

Weersma, Rinse K. ^{[11
,12
]}

Stokkers, Pieter ^{[13
]}

Ponsioen, Cyriel Y. ^{[13
]}

Wijmenga, Cisca ^{[12
,14
]}

Sterneck, Martina ^{[6
]}

Nothnagel, Michael ^{[15
]}

Hampe, Jochen ^{[16
]}

Teufel, Andreas ^{[17
]}

Runz, Heiko ^{[18
]}

Rosenstiel, Philip ^{[2
]}

Stiehl, Adolf ^{[8
]}

Vermeire, Severine ^{[10
]}

Beuers, Ulrich ^{[13
]}

Manns, Michael P. ^{[7
]}

Schrumpf, Erik ^{[1
]}

Boberg, Kirsten Muri ^{[1
]}

Schreiber, Stefan ^{[2
,16
]}

机构：

[1] Univ Oslo, Rikshosp, Dept Med, Univ Hosp, N-0027 Oslo, Norway

[2] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany

[3] Innsbruck Med Univ, Dept Gastroenterol & Hepatol, Innsbruck, Austria

[4] Univ Oslo, Rikshosp, Univ Hosp, Inst Immunol, N-0027 Oslo, Norway

[5] Karolinska Univ, Huddinge Hosp, Dept Gastroenterol & Hepatol, Stockholm, Sweden

[6] Univ Med Ctr Hamburg Eppendorf, Dept Med 1, Hamburg, Germany

[7] Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, D-3000 Hannover, Germany

[8] Univ Heidelberg Hosp, Dept Med, Heidelberg, Germany

[9] Univ Munich, Dept Med 2, Munich, Germany

[10] Univ Hosp Gasthuisberg, Dept Gastroenterol, B-3000 Louvain, Belgium

[11] Univ Med Ctr Groningen, Dept Gastroenterol & Hepatol, Groningen, Netherlands

[12] Univ Groningen, NL-9700 AB Groningen, Netherlands

[13] Univ Amsterdam, Acad Med Ctr, Dept Gastroenterol & Hepatol, NL-1105 AZ Amsterdam, Netherlands

[14] Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[15] Univ Kiel, Inst Med Informat & Stat, Kiel, Germany

[16] Univ Kiel, Dept Gen Internal Med, Kiel, Germany

[17] Johannes Gutenberg Univ Mainz, Dept Med 1, D-6500 Mainz, Germany

[18] Univ Heidelberg Hosp, Dept Human Genet, Heidelberg, Germany

来源：

GASTROENTEROLOGY | 2010年 / 138卷 / 03期

关键词：

Inflammation; Glypican; 6; G-Protein-Coupled Bile Acid Receptor 1; Macrophage Stimulating 1 (Hepatocyte Growth Factor-Like); INFLAMMATORY-BOWEL-DISEASE; ACID RECEPTOR TGR5; ULCERATIVE-COLITIS; INCREASED RISK; LOCI; MULTIPLE; EXPRESSION; SUSCEPTIBILITY; IDENTIFICATION; CONTRIBUTE;

D O I：

10.1053/j.gastro.2009.11.046

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

BACKGROUND & AIMS: We aimed to characterize the genetic susceptibility to primary sclerosing cholangitis (PSC) by means of a genome-wide association analysis of single nucleotide polymorphism (SNP) markers. METHODS: A total of 443,816 SNPs on the Affymetrix SNP Array 5.0 (Affymetrix, Santa Clara, CA) were genotyped in 285 Norwegian PSC patients and 298 healthy controls. Associations detected in this discovery panel were re-examined in independent case-control panels from Scandinavia (137 PSC cases and 368 controls), Belgium/The Netherlands (229 PSC cases and 735 controls), and Germany (400 cases and 1832 controls). RESULTS: The strongest associations were detected near HLA-B at chromosome 6p21 (rs3099844: odds ratio [OR], 4.8; 95% confidence interval [CI], 3.6-6.5; P = 2.6 X 10(-26); and rs2844559: OR, 4.7; 95% CI, 3.5-6.4; P = 4.2 X 10(-26) in the discovery panel). Outside the HLA complex, rs9524260 at chromosome 13q31 showed significant associations in 3 of 4 study panels. Lentiviral silencing of glypican 6, encoded at this locus, led to the up-regulation of proinflammatory markers in a cholangiocyte cell line. Of 15 established ulcerative colitis susceptibility loci, significant replication was obtained at chromosomes 2q35 and 3p21 (rs12612347: OR, 1.26; 95% CI, 1.06-1.50; and rs3197999: OR, 1.22; 95% CI, 1.02-1.47, respectively), with circumstantial evidence supporting the G-protein-coupled bile acid receptor 1 and macrophage-stimulating 1, respectively, as the likely disease genes. CONCLUSIONS: Strong HLA associations and a subset of genes involved in bile homeostasis and other inflammatory conditions constitute key components of the genetic architecture of PSC.

引用

页码：1102 / 1111

页数：10

共 35 条

[21] Genetic polymorphisms associated with inflammatory bowel disease do not confer risk for primary sclerosing cholangitis [J].

Karlsen, Tom H. ;

Hampe, Jochen ;

Wiencke, Kristine ;

Schrumpf, Erik ;

Thorsby, Erik ;

Lie, Benedicte A. ;

Broome, Ulrika ;

Schreiber, Stefan ;

Boberg, Kirsten Muri .

AMERICAN JOURNAL OF GASTROENTEROLOGY, 2007, 102 (01) :115-121

[22] Expression and function of the bile acid receptor TGR5 in Kupffer cells [J].

Keitel, Verena ;

Donner, Markus ;

Winandy, Stefanie ;

Kubitz, Ralf ;

Haeussinger, Dieter .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2008, 372 (01) :78-84

[23] The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells [J].

Keitel, Verena ;

Reinehr, Roland ;

Gatsios, Petros ;

Rupprecht, Claudia ;

Goerg, Boris ;

Selbach, Oliver ;

Haeussinger, Dieter ;

Kubitz, Ralf .

HEPATOLOGY, 2007, 45 (03) :695-704

[24] The Membrane-Bound Bile Acid Receptor TGR5 Is Localized in the Epithelium of Human Gallbladders [J].

Keitel, Verena ;

Cupisti, Kenko ;

Ullmer, Christoph ;

Knoefel, Wolfram T. ;

Kubitz, Ralf ;

Haeussinger, Dieter .

HEPATOLOGY, 2009, 50 (03) :861-870

[25] PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis [J].

Loftus, EV ;

Harewood, GC ;

Loftus, CG ;

Tremaine, WJ ;

Harmsen, WS ;

Zinsmeister, AR ;

Jewell, DA ;

Sandborn, WJ .

GUT, 2005, 54 (01) :91-96

[26] Identification of membrane-type receptor for bile acids (M-BAR) [J].

Maruyama, T ;

Miyamoto, Y ;

Nakamura, T ;

Tamai, Y ;

Okada, H ;

Sugiyama, E ;

Nakamura, T ;

Itadani, H ;

Tanaka, K .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2002, 298 (05) :714-719

[27] Primary sclerosing cholangitis in childhood is associated with abnormalities in cystic fibrosis-mediated chloride channel function [J].

Pall, Harpreft ;

Ziflenski, Julian ;

Jonas, Maureen M. ;

Dasilva, Deborah A. ;

Potvin, Kimberly M. ;

Yuan, Xiao-Wei ;

Huang, Qiuju ;

Freedman, Steven D. .

JOURNAL OF PEDIATRICS, 2007, 151 (03) :255-259

[28] PLINK: A tool set for whole-genome association and population-based linkage analyses [J].

Purcell, Shaun ;

Neale, Benjamin ;

Todd-Brown, Kathe ;

Thomas, Lori ;

Ferreira, Manuel A. R. ;

Bender, David ;

Maller, Julian ;

Sklar, Pamela ;

de Bakker, Paul I. W. ;

Daly, Mark J. ;

Sham, Pak C. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2007, 81 (03) :559-575

[29] HLA ANTIGENS AND IMMUNOREGULATORY T-CELLS IN ULCERATIVE-COLITIS ASSOCIATED WITH HEPATOBILIARY DISEASE [J].

SCHRUMPF, E ;

FAUSA, O ;

FORRE, O ;

DOBLOUG, JH ;

RITLAND, S ;

THORSBY, E .

SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY, 1982, 17 (02) :187-191

[30] Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study [J].

Silverberg, Mark S. ;

Cho, Judy H. ;

Rioux, John D. ;

McGovern, Dermot P. B. ;

Wu, Jing ;

Annese, Vito ;

Achkar, Jean-Paul ;

Goyette, Philippe ;

Scott, Regan ;

Xu, Wei ;

Barmada, M. Michael ;

Klei, Lambertus ;

Daly, Mark J. ;

Abraham, Clara ;

Bayless, Theodore M. ;

Bossa, Fabrizio ;

Griffiths, Anne M. ;

Ippoliti, Andrew F. ;

Lahaie, Raymond G. ;

Latiano, Anna ;

Pare, Pierre ;

Proctor, Deborah D. ;

Regueiro, Miguel D. ;

Steinhart, A. Hillary ;

Targan, Stephan R. ;

Schumm, L. Philip ;

Kistner, Emily O. ;

Lee, Annette T. ;

Gregersen, Peter K. ;

Rotter, Jerome I. ;

Brant, Steven R. ;

Taylor, Kent D. ;

Roeder, Kathryn ;

Duerr, Richard H. .

NATURE GENETICS, 2009, 41 (02) :216-220

← 1 2 3 4 →