Genome-Wide Association Study Identifies Variants Associated With Autoimmune Hepatitis Type 1

被引：232

作者：

de Boer, Ynto S. ^{[1
]}

van Gerven, Nicole M. F. ^{[1
]}

Zwiers, Antonie ^{[1
,2
]}

Verwer, Bart J. ^{[1
]}

van Hoek, Bart ^{[3
]}

van Erpecum, Karel J. ^{[4
]}

Beuers, Ulrich ^{[5
]}

van Buuren, Henk R. ^{[6
]}

Drenth, Joost P. H. ^{[7
]}

den Ouden, Jannie W. ^{[8
]}

Verdonk, Robert C. ^{[9
,10
]}

Koek, Ger H. ^{[11
]}

Brouwer, Johannes T. ^{[12
]}

Guichelaar, Maureen M. J. ^{[13
]}

Vrolijk, Jan M. ^{[14
]}

Kraal, Georg ^{[2
]}

Mulder, Chris J. J. ^{[1
]}

van Nieuwkerk, Carin M. J. ^{[1
]}

Fischer, Janett ^{[15
]}

Berg, Thomas ^{[15
]}

Stickel, Felix ^{[16
]}

Sarrazin, Christoph ^{[17
]}

Schramm, Christoph ^{[18
]}

Lohse, Ansgar W. ^{[18
,25
]}

Weiler-Normann, Christina ^{[18
]}

Lerch, Markus M. ^{[19
]}

Nauck, Matthias ^{[20
]}

Voelzke, Henry ^{[21
]}

Homuth, Georg ^{[22
,23
]}

Bloemena, Elisabeth ^{[24
]}

Verspaget, Hein W. ^{[3
]}

Kumar, Vinod ^{[25
]}

Zhernakova, Alexandra ^{[25
]}

Wijmenga, Cisca ^{[25
]}

Franke, Lude ^{[25
]}

Bouma, Gerd ^{[1
,2
]}

机构：

[1] Vrije Univ Amsterdam, Med Ctr, Dept Gastroenterol & Hepatol, NL-1007 MB Amsterdam, Netherlands

[2] Vrije Univ Amsterdam, Med Ctr, Dept Mol Cell Biol & Immunol, NL-1007 MB Amsterdam, Netherlands

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

[4] Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, Utrecht, Netherlands

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

[6] Erasmus Univ, Med Ctr, Dept Gastroenterol & Hepatol, Rotterdam, Netherlands

[7] Radboud Univ Nijmegen, Med Ctr, Dept Gastroenterol & Hepatol, NL-6525 ED Nijmegen, Netherlands

[8] Haga Hosp, Dept Gastroenterol & Hepatol, The Hague, Netherlands

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

[10] St Antonius Hosp Nieuwegein, Dept Gastroenterol & Hepatol, Nieuwegein, Netherlands

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

[12] Reinier de Graaf Hosp, Dept Gastroenterol & Hepatol, Delft, Netherlands

[13] Med Spectrum Twente, Dept Gastroenterol & Hepatol, Enschede, Netherlands

[14] Rijnstate Hosp, Dept Gastroenterol & Hepatol, Arnhem, Netherlands

[15] Univ Hosp Leipzig, Sect Hepatol, Med Clin Gastroenterol & Rheumatol, Dept Internal Med Neurol & Dermatol, Leipzig, Germany

[16] Univ Bern, Inselspital, Dept Visceral Surg & Med, CH-3010 Bern, Switzerland

[17] Univ Frankfurt M, Dept Med 1, Frankfurt, Germany

[18] Univ Med Ctr Hamburg Eppendorf, Dept Med, Hamburg, Germany

[19] Univ Med Greifswald, Dept Internal Med A, Greifswald, Germany

[20] Univ Med Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany

[21] Univ Med Greifswald, Inst Community Med, Greifswald, Germany

[22] Univ Med, Interfac Inst Genet & Funct Genom, Greifswald, Germany

[23] Ernst Moritz Arndt Univ Greifswald, Greifswald, Germany

[24] Vrije Univ Amsterdam, Med Ctr, Dept Pathol, NL-1007 MB Amsterdam, Netherlands

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

来源：

GASTROENTEROLOGY | 2014年 / 147卷 / 02期

基金：

欧洲研究理事会;

关键词：

Autoimmunity; Genetics; GWAS; SH2B Adaptor Protein 3; PRIMARY BILIARY-CIRRHOSIS; NF-KAPPA-B; PRIMARY SCLEROSING CHOLANGITIS; ANTIGEN-4 GENE POLYMORPHISMS; SUSCEPTIBILITY LOCI; RISK LOCI; CONFER SUSCEPTIBILITY; JAPANESE PATIENTS; ADAPTER PROTEIN; DISEASE;

D O I：

10.1053/j.gastro.2014.04.022

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

BACKGROUND & AIMS: Autoimmune hepatitis (AIH) is an uncommon autoimmune liver disease of unknown etiology. We used a genome-wide approach to identify genetic variants that predispose individuals to AIH. METHODS: We performed a genome-wide association study of 649 adults in The Netherlands with AIH type 1 and 13,436 controls. Initial associations were further analyzed in an independent replication panel comprising 451 patients with AIH type 1 in Germany and 4103 controls. We also performed an association analysis in the discovery cohort using imputed genotypes of the major histocompatibility complex region. RESULTS: We associated AIH with a variant in the major histocompatibility complex region at rs2187668 (P = 1.5 x 10(-78)). Analysis of this variant in the discovery cohort identified HLA-DRB1*0301 (P = 5.3 x 10(-49)) as a primary susceptibility genotype and HLA-DRB1*0401 (P = 2.8 x 10(-18)) as a secondary susceptibility genotype. We also associated AIH with variants of SH2B3 (rs3184504, 12q24; P = 7.7 x 10(-8)) and CARD10 (rs6000782, 22q13.1; P = 3.0 x 10(-6)). In addition, strong inflation of association signal was found with single-nucleotide polymorphisms associated with other immune-mediated diseases, including primary sclerosing cholangitis and primary biliary cirrhosis, but not with single-nucleotide polymorphisms associated with other genetic traits. CONCLUSIONS: In a genome-wide association study, we associated AIH type 1 with variants in the major histocompatibility complex region, and identified variants of SH2B3and CARD10 as likely risk factors. These findings support a complex genetic basis for AIH pathogenesis and indicate that part of the genetic susceptibility overlaps with that for other immune-mediated liver diseases.

引用

页码：443 / +

页数：15

共 57 条

[41] Genome-wide Association Study Identifies TNFSF15 and POU2AF1 as Susceptibility Loci for Primary Biliary Cirrhosis in the Japanese Population [J].

Nakamura, Minoru ;

Nishida, Nao ;

Kawashima, Minae ;

Aiba, Yoshihiro ;

Tanaka, Atsushi ;

Yasunami, Michio ;

Nakamura, Hitomi ;

Komori, Atsumasai ;

Nakamuta, Makoto ;

Zeniya, Mikio ;

Hashimoto, Etsuko ;

Ohira, Hiromasa ;

Yamamoto, Kazuhide ;

Onji, Morikazu ;

Kaneko, Shuichi ;

Honda, Masao ;

Yamagiwa, Satoshi ;

Nakao, Kazuhiko ;

Ichida, Takafumi ;

Takikawa, Hajime ;

Seike, Masataka ;

Umemura, Takeji ;

Ueno, Yoshiyuki ;

Sakisaka, Shotaro ;

Kikuchi, Kentaro ;

Ebinuma, Hirotoshi ;

Yamashiki, Noriyo ;

Tamura, Sumito ;

Sugawara, Yasuhiko ;

Mori, Akira ;

Yagi, Shintaro ;

Shirabe, Ken ;

Taketomi, Akinobu ;

Arai, Kuniaki ;

Monoe, Kyoko ;

Ichikawa, Tatsuki ;

Taniai, Makiko ;

Miyake, Yasuhiro ;

Kumagi, Teru ;

Abe, Masanori ;

Yoshizawa, Kaname ;

Joshita, Satoru ;

Shimoda, Shinji ;

Honda, Koichi ;

Takahashi, Hiroki ;

Hirano, Katsuji ;

Takeyama, Yasuaki ;

Harada, Kenichi ;

Migita, Kiyoshi ;

Ito, Masahiro .

AMERICAN JOURNAL OF HUMAN GENETICS, 2012, 91 (04) :721-728

[42] Association of the HLA locus and TNF with type I autoimmune hepatitis susceptibility in New Zealand Caucasians [J].

Ngu, Jing H. ;

Wallace, Mary C. ;

Merriman, Tony R. ;

Gearry, Richard B. ;

Stedman, Catherine A. M. ;

Roberts, Rebecca L. .

SPRINGERPLUS, 2013, 2 :1-8

[43] Autoimmune hepatitis, HLA and extended haplotypes [J].

Oliveira, Lea Campos ;

Porta, Gilda ;

Marin, Maria Lucia C. ;

Bittencourt, Paulo Lisboa ;

Kalil, Jorge ;

Goldberg, Anna Carla .

AUTOIMMUNITY REVIEWS, 2011, 10 (04) :189-193

[44] Principal components analysis corrects for stratification in genome-wide association studies [J].

Price, Alkes L. ;

Patterson, Nick J. ;

Plenge, Robert M. ;

Weinblatt, Michael E. ;

Shadick, Nancy A. ;

Reich, David .

NATURE GENETICS, 2006, 38 (08) :904-909

[45] Association of CTLA4 single nucleotide polymorphisms with viral but not autoimmune liver disease [J].

Schott, Eckart ;

Witt, Heiko ;

Pascu, Maria ;

van Boemmel, Florian ;

Weich, Viola ;

Bergk, Alexandra ;

Halangk, Juliane ;

Mueller, Tobias ;

Puhl, Gero ;

Wiedenmann, Bertram ;

Berg, Thomas .

EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY, 2007, 19 (11) :947-951

[46] HLA CLASS-II MOLECULES AND AUTOIMMUNE HEPATITIS SUSCEPTIBILITY IN JAPANESE PATIENTS [J].

SEKI, T ;

OTA, M ;

FURUTA, S ;

FUKUSHIMA, H ;

KONDO, T ;

HINO, K ;

MIZUKI, N ;

ANDO, A ;

TSUJI, K ;

INOKO, H ;

KIYOSAWA, K .

GASTROENTEROLOGY, 1992, 103 (03) :1041-1047

[47] Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci [J].

Stahl, Eli A. ;

Raychaudhuri, Soumya ;

Remmers, Elaine F. ;

Xie, Gang ;

Eyre, Stephen ;

Thomson, Brian P. ;

Li, Yonghong ;

Kurreeman, Fina A. S. ;

Zhernakova, Alexandra ;

Hinks, Anne ;

Guiducci, Candace ;

Chen, Robert ;

Alfredsson, Lars ;

Amos, Christopher I. ;

Ardlie, Kristin G. ;

Barton, Anne ;

Bowes, John ;

Brouwer, Elisabeth ;

Burtt, Noel P. ;

Catanese, Joseph J. ;

Coblyn, Jonathan ;

Coenen, Marieke J. H. ;

Costenbader, Karen H. ;

Criswell, Lindsey A. ;

Crusius, J. Bart A. ;

Cui, Jing ;

de Bakker, Paul I. W. ;

De Jager, Philip L. ;

Ding, Bo ;

Emery, Paul ;

Flynn, Edward ;

Harrison, Pille ;

Hocking, Lynne J. ;

Huizinga, Tom W. J. ;

Kastner, Daniel L. ;

Ke, Xiayi ;

Lee, Annette T. ;

Liu, Xiangdong ;

Martin, Paul ;

Morgan, Ann W. ;

Padyukov, Leonid ;

Posthumus, Marcel D. ;

Radstake, Timothy R. D. J. ;

Reid, David M. ;

Seielstad, Mark ;

Seldin, Michael F. ;

Shadick, Nancy A. ;

Steer, Sophia ;

Tak, Paul P. ;

Thomson, Wendy .

NATURE GENETICS, 2010, 42 (06) :508-U56

[48] Universal risk factors for multifactorial diseases - LifeLines: a three-generation population-based study [J].

Stolk, Ronald P. ;

Rosmalen, Judith G. M. ;

Postma, Dirkje S. ;

de Boer, Rudolf A. ;

Navis, Gerjan ;

Slaets, Joris P. J. ;

Ormel, Johan ;

Wolffenbuttel, Bruce H. R. .

EUROPEAN JOURNAL OF EPIDEMIOLOGY, 2008, 23 (01) :67-74

[49] Cytotoxic T Lymphocyte Antigen-4+49A/G polymorphism does not affect susceptibility to autoimmune hepatitis [J].

van Gerven, Nicole M. F. ;

de Boer, Ynto S. ;

Zwiers, Antonie ;

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, G. ;

Mulder, Chris J. J. ;

van Nieuwkerk, Carin. M. J. ;

Bouma, Gerd .

LIVER INTERNATIONAL, 2013, 33 (07) :1039-1043

[50] A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21 [J].

van Heel, David A. ;

Franke, Lude ;

Hunt, Karen A. ;

Gwilliam, Rhian ;

Zhernakova, Alexandra ;

Inouye, Mike ;

Wapenaar, Martin C. ;

Barnardo, Martin C. N. M. ;

Bethel, Graeme ;

Holmes, Geoffrey K. T. ;

Feighery, Con ;

Jewell, Derek ;

Kelleher, Dermot ;

Kumar, Parveen ;

Travis, Simon ;

Walters, Julian R. F. ;

Sanders, David S. ;

Howdle, Peter ;

Swift, Jill ;

Playford, Raymond J. ;

McLaren, William M. ;

Mearin, M. Luisa ;

Mulder, Chris J. ;

McManus, Ross ;

McGinnis, Ralph ;

Cardon, Lon R. ;

Deloukas, Panos ;

Wijmenga, Cisca .

NATURE GENETICS, 2007, 39 (07) :827-829

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