HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants

被引：158

作者：

Heap, Graham A. ^{[1
,2
]}

Weedon, Michael N. ^{[2
]}

Bewshea, Claire M. ^{[1
,2
]}

Singh, Abhey ^{[1
]}

Chen, Mian ^{[3
]}

Satchwel, Jack B. ^{[3
]}

Vivian, Julian P. ^{[4
]}

So, Kenji ^{[1
]}

Dubois, Patrick C. ^{[5
]}

Andrews, Jane M. ^{[6
,7
]}

Annese, Vito ^{[8
]}

Bampton, Peter ^{[9
]}

Barnardo, Martin ^{[3
]}

Bell, Sally ^{[10
]}

Cole, Andy ^{[11
]}

Connor, Susan J. ^{[12
]}

Creed, Tom ^{[13
]}

Cummings, Fraser R. ^{[14
]}

D'Amato, Mauro ^{[15
]}

Daneshmend, Tawfique K. ^{[1
]}

Fedorak, Richard N. ^{[16
]}

Florin, Timothy H. ^{[17
]}

Gaya, Daniel R. ^{[18
]}

Greig, Emma ^{[19
]}

Halfvarson, Jonas ^{[20
,21
]}

Hart, Alisa ^{[22
,23
]}

Irving, Peter M. ^{[24
]}

Jones, Gareth ^{[25
]}

Karban, Amir ^{[26
]}

Lawrance, Ian C. ^{[27
]}

Lee, James C. ^{[28
]}

Lees, Charlie ^{[25
]}

Lev-Tzion, Raffi ^{[29
]}

Lindsay, James ^{[30
]}

Mansfield, John ^{[31
]}

Mawdsley, Joel ^{[32
]}

Mazhar, Zia ^{[33
]}

Parkes, Miles ^{[28
]}

Parnell, Kirstie ^{[2
]}

Orchard, Timothy R. ^{[34
]}

Radford-Smith, Graham ^{[35
,36
,37
]}

Russell, Richard K. ^{[38
]}

Reffitt, David ^{[39
]}

Satsangi, Jack ^{[25
]}

Silverberg, Mark S. ^{[40
]}

Sturniolo, Giacomo C. ^{[41
]}

Tremelling, Mark ^{[42
]}

Tsianos, Epameinondas V. ^{[43
,44
]}

van Heel, David A. ^{[45
]}

Walsh, Alissa ^{[46
]}

机构：

[1] Royal Devon & Exeter Hosp, IBD Pharmacogenet, Exeter EX2 5DW, Devon, England

[2] Univ Exeter, Precis Med Exeter, Exeter, Devon, England

[3] Oxford Univ Hosp Natl Hlth Serv NHS Trust, Oxford Transplant Ctr, Oxford, England

[4] Monash Univ, Sch Biomed Sci, Dept Biochem & Mol Biol, Clayton, Vic, Australia

[5] Kings Coll Hosp London, Dept Gastroenterol, London, England

[6] IBD Serv, Dept Gastroenterol, Adelaide, SA, Australia

[7] Univ Adelaide, Royal Adelaide Hosp, Adelaide, SA, Australia

[8] Univ Careggi, Azienda Osped, Div Gastroenterol, Florence, Italy

[9] Flinders Univ South Australia, Flinders Med Ctr, Adelaide, SA, Australia

[10] St Vincent Hosp, Dept Gastroenterol, Fitzroy, Vic, Australia

[11] Royal Derby Hosp, Derby, England

[12] Liverpool Hosp, Dept Gastroenterol & Hepatol, Sydney, NSW, Australia

[13] Univ Hosp Bristol NHS Fdn Trust, Joint Clin Res Unit, Bristol, Avon, England

[14] Univ Hosp Southampton NHS Fdn Trust, Dept Gastroenterol, Southampton, Hants, England

[15] Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden

[16] Univ Alberta, Div Gastroenterol, Edmonton, AB, Canada

[17] Univ Queensland, Sch Med, South Brisbane, Qld, Australia

[18] Glasgow Royal Infirm, Gastroenterol Unit, Glasgow G4 0SF, Lanark, Scotland

[19] Taunton & Somerset NHS Fdn Trust, Dept Gastroenterol, Taunton, Somerset, England

[20] Orebro Univ Hosp, Div Gastroenterol, Orebro, Sweden

[21] Univ Orebro, Sch Hlth & Med Sci, Orebro, Sweden

[22] St Marks Hosp, Dept Med, London EC1V 2PS, England

[23] North West London Hosp NHS Trust, Acad Inst, London, England

[24] Guys & St Thomas NHS Fdn Trust, Dept Gastroenterol, London, England

[25] Western Gen Hosp, Dept Gastroenterol, Edinburgh EH4 2XU, Midlothian, Scotland

[26] Rambam Med Ctr, Dept Gastroenterol, Haifa, Israel

[27] Univ Western Australia, Fremantle Hosp, Ctr Inflammatory Bowel Dis, Fremantle, WA, Australia

[28] Cambridge Univ Hosp NHS Trust, Dept Gastroenterol, Cambridge, England

[29] Shaare Zedek Med Ctr, Paediatr Gastroenterol & Nutr Unit, Jerusalem, Israel

[30] Barts & London NHS Trust, Dept Gastroenterol, London, England

[31] Newcastle Univ Hosp NHS Trust, Dept Gastroenterol, Newcastle Upon Tyne, Tyne & Wear, England

[32] West Middlesex Univ Hosp NHS Trust, Dept Gastroenterol, Isleworth, England

[33] Basildon & Thurrock Hosp NHS Trust, Dept Gastroenterol, Basildon, Essex, England

[34] Imperial Coll Healthcare NHS, Dept Med, London, England

[35] Royal Brisbane & Womens Hosp, Dept Gastroenterol, Brisbane, Qld, Australia

[36] IBD Grp, Queensland Inst Med Res, Brisbane, Qld, Australia

[37] Univ Queensland, Sch Med, Brisbane, Qld, Australia

[38] Yorkhill Hosp, Dept Paediat Gastroenterol, Glasgow, Lanark, Scotland

[39] Lewisham & Greenwich NHS Trust, Dept Gastroenterol, London, England

[40] Mt Sinai Hosp, Zane Cohen Ctr Digest Dis, Inflammatory Bowel Dis Grp, Toronto, ON M5G 1X5, Canada

[41] Univ Padua, Padua, Italy

[42] Norfolk & Norwich Hosp NHS Trust, Dept Gastroenterol, Norwich, Norfolk, England

[43] Univ Ioannina, Fac Med, Div Internal Med 1, GR-45110 Ioannina, Greece

[44] Univ Ioannina, Fac Med, Div Gastroenterol, GR-45110 Ioannina, Greece

[45] Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, London, England

[46] St Vincents Hosp, Dept Gastroenterol, Sydney, NSW 2010, Australia

[47] Groote Schuur Hosp, Gastrointestinal Clin, ZA-7925 Cape Town, South Africa

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

[49] Univ Med Ctr Schleswig Holstein, Dept Internal Med, Kiel, Germany

[50] Int Serious Adverse Events Consortium, Chicago, IL USA

来源：

NATURE GENETICS | 2014年 / 46卷 / 10期

基金：

英国惠康基金;

关键词：

THERAPY; AZATHIOPRINE; COMPLICATION; GENOTYPE; DISEASE;

D O I：

10.1038/ng.3093

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 x 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the H LA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.

引用

页码：1131 / 1134

页数：4

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