Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci

被引：172

作者：

Folseraas, Trine ^{[1
,2
,3
]}

Melum, Espen ^{[1
,2
,3
]}

Rausch, Philipp ^{[4
,5
]}

Juran, Brian D. ^{[6
]}

Ellinghaus, Eva ^{[7
]}

Shiryaev, Alexey ^{[1
,2
,3
]}

Laerdahl, Jon K. ^{[8
,9
,10
]}

Ellinghaus, David ^{[7
]}

Schramm, Christoph ^{[11
]}

Weismueller, Tobias J. ^{[12
,13
]}

Gotthard, Daniel Nils ^{[14
]}

Hov, Johannes Roksund ^{[1
,2
,3
]}

Clausen, Ole Petter ^{[3
,15
]}

Weersma, Rinse K. ^{[16
,17
]}

Janse, Marcel ^{[16
,17
]}

Boberg, Kirsten Muri ^{[1
]}

Bjornsson, Einar ^{[18
,19
]}

Marschall, Hanns-Ulrich ^{[18
,19
]}

Cleynen, Isabelle ^{[20
]}

Rosenstiel, Philip ^{[7
]}

Holm, Kristian ^{[1
]}

Teufel, Andreas ^{[21
]}

Rust, Christian ^{[22
]}

Gieger, Christian ^{[23
]}

Wichmann, H-Erich ^{[24
,25
,26
]}

Bergquist, Annika ^{[27
]}

Ryu, Euijung ^{[28
]}

Ponsioen, Cyriel Y. ^{[29
]}

Runz, Heiko ^{[30
]}

Sterneck, Martina ^{[31
]}

Vermeire, Severine ^{[20
]}

Beuers, Ulrich ^{[29
]}

Wijmenga, Cisca ^{[17
,32
]}

Schrumpf, Erik ^{[1
,3
]}

Manns, Michael P. ^{[12
,13
]}

Lazaridis, Konstantinos N. ^{[6
]}

Schreiber, Stefan ^{[7
,33
]}

Baines, John F. ^{[4
,5
]}

Franke, Andre ^{[7
]}

Karlsen, Tom H. ^{[1
,2
,34
]}

机构：

[1] Rigshosp, Oslo Univ Hosp, Dept Transplantat Med, Norwegian PSC Res Ctr, N-0424 Oslo, Norway

[2] Rigshosp, Oslo Univ Hosp, Internal Med Res Inst, N-0424 Oslo, Norway

[3] Univ Oslo, Fac Med, Oslo, Norway

[4] Univ Kiel, Inst Expt Med, Kiel, Germany

[5] Max Planck Inst Evolutionary Biol, Plon, Germany

[6] Mayo Clin, Coll Med, Div Gastroenterol & Hepatol, Ctr Basic Res Digest Dis, Rochester, MN USA

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

[8] Rigshosp, Oslo Univ Hosp, Dept Microbiol, N-0424 Oslo, Norway

[9] Rigshosp, Oslo Univ Hosp, Ctr Mol Biol & Neurosci CMBN, N-0424 Oslo, Norway

[10] Univ Oslo, Dept Informat, Bioinformat Core Facil, N-0316 Oslo, Norway

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

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

[13] Hannover Med Sch, Integrated Res & Treatment Ctr Transplantat IFB T, D-3000 Hannover, Germany

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

[15] Rigshosp, Oslo Univ Hosp, Div Pathol, N-0424 Oslo, Norway

[16] Univ Groningen, Univ Med Ctr Groningen, Dept Gastroenterol & Hepatol, NL-9713 AV Groningen, Netherlands

[17] Univ Groningen, Groningen, Netherlands

[18] Univ Hosp, Gothenburg, Sweden

[19] Sahlgrens Acad, Inst Med, Dept Internal Med, Gothenburg, Sweden

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

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

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

[23] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Genet Epidemiol, Neuherberg, Germany

[24] German Res Ctr Environm Hlth, Helmholtz Ctr Munich, Inst Epidemiol 1, Neuherberg, Germany

[25] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany

[26] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany

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

[28] Mayo Clin, Coll Med, Div Biomed Stat & Informat, Rochester, MN USA

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

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

[31] Univ Med Ctr Hamburg Eppendorf, Dept Hepatobiliary Surg & Transplantat, Hamburg, Germany

[32] Univ Med Ctr Groningen, Dept Genet, NL-9713 AV Groningen, Netherlands

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

[34] Univ Bergen, Inst Med, Div Gastroenterol, Bergen, Norway

来源：

JOURNAL OF HEPATOLOGY | 2012年 / 57卷 / 02期

关键词：

Primary sclerosing cholangitis; Genome-wide association study; Single nucleotide polymorphism; Immunogenetics; T-LYMPHOCYTE ATTENUATOR; NON-SECRETOR STATUS; SUSCEPTIBILITY LOCI; B-LYMPHOCYTE; BLOOD-GROUP; FUT2; POPULATION; DISEASES; GENE; METAANALYSIS;

D O I：

10.1016/j.jhep.2012.03.031

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background & Aims: A limited number of genetic risk factors have been reported in primary sclerosing cholangitis (PSC). To discover further genetic susceptibility factors for PSC, we followed up on,a second tier of single nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS). Methods: We analyzed 45 SNPs in 1221 PSC cases and 3508 controls. The association results from the replication analysis and the original GWAS (715 PSC cases and 2962 controls) were combined in a meta-analysis comprising 1936 PSC cases and 6470 controls. We performed an analysis of bile microbial community composition in 39 PSC patients by 16S rRNA sequencing. Results: Seventeen SNPs representing 12 distinct genetic loci achieved nominal significance (p(replication) <0.05) in the replication. The most robust novel association was detected at chromosome 1p36 (rs3748816; p(combined) = 2.1 x 10(-8)) where the MMEL1 and TNFRSF14 genes represent potential disease genes. Eight additional novel loci showed suggestive evidence of association (p(repl) <0.05). FUT2 at chromosome 19q13 (rs602662; p(comb) = 1.9 x 10(-6), rs281377; p(comb) = 2.1 x 10(-6) and rs601338; p(comb) = 2.7 x 10(-6)) is notable clue to its implication in altered susceptibility to infectious agents. We found that FUT2 secretor status and genotype defined by rs601338 significantly influence biliary microbial community composition in PSC patients. Conclusions: We identify multiple new PSC risk loci by extended analysis of a PSC GWAS. FUT2 genotype needs to be taken into account when assessing the influence of microbiota on biliary pathology in PSC. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

引用

页码：366 / 375

页数：10

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