Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

被引：35

作者：

Alberts, Rudi ^{[1
,2
]}

de Vries, Elisabeth M. G. ^{[3
]}

Goode, Elizabeth C. ^{[4
,5
]}

Jiang, Xiaojun ^{[6
,7
]}

Sampaziotis, Fotis ^{[8
,9
,10
]}

Rombouts, Krista ^{[11
]}

Bottcher, Katrin ^{[11
]}

Folseraas, Trine ^{[6
,7
]}

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

Mason, Andrew L. ^{[14
]}

Wang, Weiwei ^{[14
]}

Alexander, Graeme ^{[15
]}

Alvaro, Domenico ^{[16
]}

Bergquist, Annika ^{[17
]}

Bjorkstrom, Niklas K. ^{[18
]}

Beuers, Ulrich ^{[3
]}

Bjornsson, Einar ^{[19
]}

Boberg, Kirsten Muri ^{[6
,20
,21
]}

Bowlus, Christopher L. ^{[22
]}

Bragazzi, Maria C. ^{[23
]}

Carbone, Marco ^{[24
]}

Chazouilleres, Olivier ^{[25
]}

Cheung, Angela ^{[26
]}

Dalekos, Georgios ^{[27
,28
]}

Eaton, John ^{[29
]}

Eksteen, Bertus ^{[30
]}

Ellinghaus, David ^{[31
]}

Farkkila, Martti ^{[32
]}

Festen, Eleonora A. M. ^{[1
,2
]}

Floreani, Annarosa ^{[33
]}

Franceschet, Irene ^{[34
]}

Gotthardt, Daniel Nils ^{[35
]}

Hirschfield, Gideon M. ^{[36
]}

van Hoek, Bart ^{[37
]}

Holm, Kristian ^{[6
,7
]}

Hohenester, Simon ^{[38
]}

Hov, Johannes Roksund ^{[6
,7
]}

Imhann, Floris ^{[1
,2
]}

Invernizzi, Pietro ^{[24
]}

Juran, Brian D. ^{[29
]}

Lenzen, Henrike ^{[12
]}

Lieb, Wolfgang ^{[39
,40
]}

Liu, Jimmy Z. ^{[41
]}

Marschall, Hanns-Ulrich ^{[42
]}

Marzioni, Marco ^{[43
]}

Melum, Espen ^{[6
,7
]}

Milkiewicz, Piotr ^{[44
]}

Mueller, Tobias ^{[45
]}

Pares, Albert ^{[46
]}

Rupp, Christian ^{[47
]}

机构：

[1] Univ Groningen, Dept Gastroenterol & Hepatol, POB 30-001, NL-9700 RB Groningen, Netherlands

[2] Univ Med Ctr Groningen, POB 30-001, NL-9700 RB Groningen, Netherlands

[3] Acad Med Ctr, Dept Gastroenterol & Hepatol, Amsterdam, Netherlands

[4] Univ East Anglia, Norwich Med Sch, Fac Med & Hlth Sci, Norwich, Norfolk, England

[5] Univ Cambridge, Acad Dept Med Genet, Cambridge, England

[6] Natl Hosp Norway, Oslo Univ Hosp, Norwegian PSC Res Ctr, Div Canc Med Surg & Transplantat, Oslo, Norway

[7] Natl Hosp Norway, Oslo Univ Hosp, Res Inst Internal Med, Oslo, Norway

[8] Univ Cambridge, Wellcome Trust Med Res Council Stem Cell Inst, Anne McLaren Lab, Dept Surg, Cambridge, England

[9] Univ Cambridge, Dept Surg, Cambridge, England

[10] NIHR Cambridge Biomed Res Ctr, Cambridge, England

[11] UCL, Inst Liver & Digest Hlth, Royal Free Hosp, London, England

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

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

[14] Univ Alberta, Div Gastroenterol & Hepatol, Edmonton, AB, Canada

[15] Univ Cambridge, Div Hepatol, Dept Med, Cambridge, England

[16] Sapienza Univ Rome, Div Gastroenterol, Dept Clin Med, Rome, Italy

[17] Karolinska Inst, Karolinska Univ Hosp, Ctr Digest Dis, Stockholm, Sweden

[18] Karolinska Inst, Karolinska Univ Hosp, Ctr Infect Med, Dept Med Huddinge, Stockholm, Sweden

[19] Landspitali Univ Hosp, Div Gastroenterol & Hepatol, Dept Internal Med, Reykjavik, Iceland

[20] Univ Oslo, KG Jebsen Inflammat Res Ctr, Oslo, Norway

[21] Univ Oslo, Inst Clin Med, Oslo, Norway

[22] Univ Calif Davis, Div Gastroenterol & Hepatol, Davis, CA 95616 USA

[23] Sapienza Univ Rome, Medicosurg Sci & Biotechnol, Rome, Italy

[24] Univ Milano Bicocca, Dept Med & Surg, Program Autoimmune Liver Dis, Int Ctr Digest Hlth, Milan, Italy

[25] Hop St Antoine, AP HP, Dept Hepatol, Paris, France

[26] Univ Hlth Network, Toronto Gen Hosp, Gen Internal Med, Toronto, ON, Canada

[27] Univ Thessaly, Dept Med, Sch Med, Larisa, Greece

[28] Univ Thessaly, Res Lab Internal Med, Sch Med, Larisa, Greece

[29] Mayo Clin Minnesota, Div Gastroenterol & Hepatol, Rochester, MN USA

[30] Univ Calgary, Snyder Inst Chron Dis, Dept Med, Calgary, AB, Canada

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

[32] Helsinki Univ Hosp, Div Gastroenterol, Dept Med, Helsinki, Finland

[33] Univ Padua, Dept Surg Oncol & Gastroenterol Sci, Padua, Italy

[34] Univ Padua, Dept Surg Oncol & Gastroenterol, Padua, Italy

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

[36] Univ Birmingham, NIHR Biomed Res Unit, Liver Res Ctr, Birmingham, W Midlands, England

[37] Leiden Univ, Med Ctr, Dept Gastroenterol & Hepatol, Leiden, Netherlands

[38] Univ Munich, Liver Ctr Munich, Dept Med 2, Munich, Germany

[39] Univ Kiel, Popgen Biobank, Univ Hosp Schleswig Holstein, Kiel, Germany

[40] Univ Kiel, Inst Epidemiol, Kiel, Germany

[41] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge, England

[42] Sahlgrens Acad, Inst Med, Dept Mol & Clin Med, Gothenburg, Sweden

[43] Univ Politecn Marche, Osped Riuniti Univ Hosp, Dept Gastroenterol, Ancona, Italy

[44] Med Univ Warsaw, Liver & Internal Med Unit, Warsaw, Poland

[45] Charite Univ Med Berlin, Dept Internal Med Hepatol & Gastroenterol, Campus Virchow Klinikum, Berlin, Germany

[46] Univ Barcelona, Hosp Clin, Liver Unit, IDIBAPS,CIBERehd, Barcelona, Spain

[47] Univ Hosp Heidelberg, Dept Internal Med 4, Heidelberg, Germany

[48] Krankenhaus Barmherzige Bruder, Dept Med 1, Munich, Germany

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

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

来源：

GUT | 2018年 / 67卷 / 08期

关键词：

GENOME-WIDE ASSOCIATION; HEPATIC STELLATE CELLS; RISK LOCI; ULCERATIVE-COLITIS; LIVER FIBROSIS; MULTIPLE; EPIDEMIOLOGY; ACTIVATION; MALIGNANCY; CIRRHOSIS;

D O I：

10.1136/gutjnl-2016-313598

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07x10(-9)). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

引用

页码：1517 / 1524

页数：8

共 38 条

[1]

Genetic Modifiers of Liver Disease in Cystic Fibrosis [J].

Bartlett, Jaclyn R. ;

Friedman, Kenneth J. ;

Ling, Simon C. ;

Pace, Rhonda G. ;

Bell, Scott C. ;

Bourke, Billy ;

Castaldo, Giuseppe ;

Castellani, Carlo ;

Cipolli, Marco ;

Colombo, Carla ;

Colombo, John L. ;

Debray, Dominique ;

Fernandez, Adriana ;

Lacaille, Florence ;

Macek, Milan, Jr. ;

Rowland, Marion ;

Salvatore, Francesco ;

Taylor, Christopher J. ;

Wainwright, Claire ;

Wilschanski, Michael ;

Zemkova, Dana ;

Hannah, William B. ;

Phillips, M. James ;

Corey, Mary ;

Zielenski, Julian ;

Dorfman, Ruslan ;

Wang, Yunfei ;

Zou, Fei ;

Silverman, Lawrence M. ;

Drumm, Mitchell L. ;

Wright, Fred A. ;

Lange, Ethan M. ;

Durie, Peter R. ;

Knowles, Michael R. ;

Clancy, J. P. ;

Sindel, L. J. ;

Roberts, D. M. ;

Roberts, V. ;

Radford, P. J. ;

Argel, N. ;

Morgan, W. J. ;

Douthit, J. L. ;

Schellhase, D. E. ;

Anderson, P. ;

Taggart, A. ;

Morrissey, B. ;

Platzker, A. C. G. ;

Woo, M. S. ;

Fukushima, L. ;

Hsu, E. .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2009, 302 (10) :1076-1083

[2]

CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].

BENJAMINI, Y ;

HOCHBERG, Y .

JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300

[3]

Increased risk of primary sclerosing cholangitis and ulcerative colitis in first-degree relatives of patients with primary sclerosing cholangitis [J].

Bergquist, Annika ;

Montgomery, Scott M. ;

Bahmanyar, Shahram ;

Olsson, Rolf ;

Danielsson, Ake ;

Lindgren, Stefan ;

Prytz, Hanne ;

Hultcrantz, Rolf ;

Loof, Lars ;

Sandberg-Gertzen, Hanna ;

Almer, Sven ;

Askling, Johan ;

Ehlin, Anna ;

Ekbom, Anders .

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY, 2008, 6 (08) :939-943

[4]

EASL Clinical Practice Guidelines: Management of cholestatic liver diseases [J].

Beuers, Ulrich ;

Boberg, Kirsten M. ;

Chapman, Roger W. ;

Chazouilleres, Olivier ;

Invernizzi, Pietro ;

Jones, David E. J. ;

Lammert, Frank ;

Pares, Albert ;

Trauner, Michael .

JOURNAL OF HEPATOLOGY, 2009, 51 (02) :237-267

[5]

Primary sclerosing cholangitis and malignancy [J].

Boberg, Kirsten Muri ;

Lind, Guro E. .

BEST PRACTICE & RESEARCH CLINICAL GASTROENTEROLOGY, 2011, 25 (06) :753-764

[6]

Population-Based Epidemiology, Malignancy Risk, and Outcome of Primary Sclerosing Cholangitis [J].

Boonstra, Kirsten ;

Weersma, Rinse K. ;

van Erpecum, Karel J. ;

Rauws, Erik A. ;

Spanier, B. W. Marcel ;

Poen, Alexander C. ;

van Nieuwkerk, Karin M. ;

Drenth, Joost P. ;

Witteman, Ben J. ;

Tuynman, Hans A. ;

Naber, Anton H. ;

Kingma, Paul J. ;

van Buuren, Henk R. ;

van Hoek, Bart ;

Vleggaar, Frank P. ;

van Geloven, Nan ;

Beuers, Ulrich ;

Ponsioen, Cyriel Y. .

HEPATOLOGY, 2013, 58 (06) :2045-2055

[7]

Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: A systematic review [J].

Boonstra, Kirsten ;

Beuers, Ulrich ;

Ponsioen, Cyriel Y. .

JOURNAL OF HEPATOLOGY, 2012, 56 (05) :1181-1188

[8]

ASSOCIATION OF PRIMARY SCLEROSING CHOLANGITIS WITH HLA-B8 [J].

CHAPMAN, RW ;

VARGHESE, Z ;

GAUL, R ;

PATEL, G ;

KOKINON, N ;

SHERLOCK, S .

GUT, 1983, 24 (01) :38-41

[9]

Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis [J].

Cheng, Jason H. ;

She, Hongyun ;

Han, Yuan-Ping ;

Wang, Jiaohong ;

Xiong, Shigang ;

Asahina, Kinji ;

Tsukamoto, Hidekazu .

AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2008, 294 (01) :G39-G49

[10]

Genome-Wide Association Study Identifies Variants Associated With Autoimmune Hepatitis Type 1 [J].

de Boer, Ynto S. ;

van Gerven, Nicole M. F. ;

Zwiers, Antonie ;

Verwer, Bart J. ;

van Hoek, Bart ;

van Erpecum, Karel J. ;

Beuers, Ulrich ;

van Buuren, Henk R. ;

Drenth, Joost P. H. ;

den Ouden, Jannie W. ;

Verdonk, Robert C. ;

Koek, Ger H. ;

Brouwer, Johannes T. ;

Guichelaar, Maureen M. J. ;

Vrolijk, Jan M. ;

Kraal, Georg ;

Mulder, Chris J. J. ;

van Nieuwkerk, Carin M. J. ;

Fischer, Janett ;

Berg, Thomas ;

Stickel, Felix ;

Sarrazin, Christoph ;

Schramm, Christoph ;

Lohse, Ansgar W. ;

Weiler-Normann, Christina ;

Lerch, Markus M. ;

Nauck, Matthias ;

Voelzke, Henry ;

Homuth, Georg ;

Bloemena, Elisabeth ;

Verspaget, Hein W. ;

Kumar, Vinod ;

Zhernakova, Alexandra ;

Wijmenga, Cisca ;

Franke, Lude ;

Bouma, Gerd .

GASTROENTEROLOGY, 2014, 147 (02) :443-+

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