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

5.00
Hdl Handle:
http://hdl.handle.net/11287/593811
Title:
HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants
Authors:
Heap, Graham A.; Weedon, M. N.; Bewshea, Claire M.; Singh, A.; Chen, M.; Satchwell, J. B.; Vivian, J. P.; So, K.; Dubois, P. C.; Andrews, J. M.; Annese, V.; Bampton, P.; Barnardo, M.; Bell, S.; Cole, A.; Connor, S. J.; Creed, T.; Cummings, F. R.; D'Amato, M.; Daneshmend, T. K.; Fedorak, R. N.; Florin, T. H.; Gaya, D. R.; Greig, E.; Halfvarson, J.; Hart, Anthony; Irving, P. M.; Jones, G.; Karban, A.; Lawrance, I. C.; Lee, J. C.; Lees, C.; Lev-Tzion, R.; Lindsay, J. O.; Mansfield, J.; Mawdsley, J.; Mazhar, Z.; Parkes, M.; Parnell, K.; Orchard, T. R.; Radford-Smith, G.; Russell, R. K.; Reffitt, D.; Satsangi, J.; Silverberg, M. S.; Sturniolo, G. C.; Tremelling, M.; Tsianos, E. V.; van Heel, D. A.; Walsh, A.; Watermeyer, G.; Weersma, R. K.; Zeissig, S.; Rossjohn, J.; Holden, A. L.; International Serious Adverse Events, Consortium; I. B. D. Pharmacogenetics Study Group; Ahmad, Tariq
Abstract:
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 HLA 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.
Citation:
Nat Genet. 2014 Oct;46(10):1131-4.
Publisher:
Nature
Journal:
Nature genetics
Issue Date:
1-Oct-2014
URI:
http://hdl.handle.net/11287/593811
DOI:
10.1038/ng.3093
PubMed ID:
25217962
Additional Links:
http://dx.doi.org/10.1038/ng.3093
Type:
Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't
Language:
eng
ISSN:
1546-1718
Appears in Collections:
2014 RD&E publications; Honorary contracts publications

Full metadata record

DC FieldValue Language
dc.contributor.authorHeap, Graham A.en
dc.contributor.authorWeedon, M. N.en
dc.contributor.authorBewshea, Claire M.en
dc.contributor.authorSingh, A.en
dc.contributor.authorChen, M.en
dc.contributor.authorSatchwell, J. B.en
dc.contributor.authorVivian, J. P.en
dc.contributor.authorSo, K.en
dc.contributor.authorDubois, P. C.en
dc.contributor.authorAndrews, J. M.en
dc.contributor.authorAnnese, V.en
dc.contributor.authorBampton, P.en
dc.contributor.authorBarnardo, M.en
dc.contributor.authorBell, S.en
dc.contributor.authorCole, A.en
dc.contributor.authorConnor, S. J.en
dc.contributor.authorCreed, T.en
dc.contributor.authorCummings, F. R.en
dc.contributor.authorD'Amato, M.en
dc.contributor.authorDaneshmend, T. K.en
dc.contributor.authorFedorak, R. N.en
dc.contributor.authorFlorin, T. H.en
dc.contributor.authorGaya, D. R.en
dc.contributor.authorGreig, E.en
dc.contributor.authorHalfvarson, J.en
dc.contributor.authorHart, Anthonyen
dc.contributor.authorIrving, P. M.en
dc.contributor.authorJones, G.en
dc.contributor.authorKarban, A.en
dc.contributor.authorLawrance, I. C.en
dc.contributor.authorLee, J. C.en
dc.contributor.authorLees, C.en
dc.contributor.authorLev-Tzion, R.en
dc.contributor.authorLindsay, J. O.en
dc.contributor.authorMansfield, J.en
dc.contributor.authorMawdsley, J.en
dc.contributor.authorMazhar, Z.en
dc.contributor.authorParkes, M.en
dc.contributor.authorParnell, K.en
dc.contributor.authorOrchard, T. R.en
dc.contributor.authorRadford-Smith, G.en
dc.contributor.authorRussell, R. K.en
dc.contributor.authorReffitt, D.en
dc.contributor.authorSatsangi, J.en
dc.contributor.authorSilverberg, M. S.en
dc.contributor.authorSturniolo, G. C.en
dc.contributor.authorTremelling, M.en
dc.contributor.authorTsianos, E. V.en
dc.contributor.authorvan Heel, D. A.en
dc.contributor.authorWalsh, A.en
dc.contributor.authorWatermeyer, G.en
dc.contributor.authorWeersma, R. K.en
dc.contributor.authorZeissig, S.en
dc.contributor.authorRossjohn, J.en
dc.contributor.authorHolden, A. L.en
dc.contributor.authorInternational Serious Adverse Events, Consortiumen
dc.contributor.authorI. B. D. Pharmacogenetics Study Groupen
dc.contributor.authorAhmad, Tariqen
dc.date.accessioned2016-01-19T12:35:13Zen
dc.date.available2016-01-19T12:35:13Zen
dc.date.issued2014-10-01en
dc.identifier.citationNat Genet. 2014 Oct;46(10):1131-4.en
dc.identifier.issn1546-1718en
dc.identifier.pmid25217962en
dc.identifier.doi10.1038/ng.3093en
dc.identifier.urihttp://hdl.handle.net/11287/593811en
dc.description.abstractPancreatitis 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 HLA 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.en
dc.language.isoengen
dc.publisherNatureen
dc.relation.urlhttp://dx.doi.org/10.1038/ng.3093en
dc.titleHLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressantsen
dc.typeJournal Articleen
dc.typeMulticenter Studyen
dc.typeResearch Support, Non-U.S. Gov'ten
dc.identifier.journalNature geneticsen

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