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

International Serious Adverse Events Consortium; Graham A Heap; Michael N Weedon; Claire M Bewshea; Abhey Singh; Mian Chen; Jack B Satchwell; Julian P Vivian; Kenji So; Patrick C Dubois; Jane M Andrews; Vito Annese; Peter Bampton; Martin Barnardo; Sally Bell; Andy Cole; Susan J Connor; Tom Creed; Fraser R Cummings; Mauro D'Amato; Tawfique K Daneshmend; Richard N Fedorak; Timothy H Florin; Daniel R Gaya; Emma Greig; Jonas Halfvarson; Alisa Hart; Peter M Irving; Gareth Jones; Amir Karban; Ian C Lawrance; James C Lee; Charlie Lees; Raffi Lev-Tzion; James O Lindsay; John Mansfield; Joel Mawdsley; Zia Mazhar; Miles Parkes; Kirstie Parnell; Timothy R Orchard; Graham Radford-Smith; Richard K Russell; David Reffitt; Jack Satsangi; Mark S Silverberg; Giacomo C Sturniolo; Mark Tremelling; Epameinondas V Tsianos; David A van Heel; Alissa Walsh

doi:10.1038/ng.3093

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

International Serious Adverse Events Consortium, Graham A Heap, Michael N Weedon, Claire M Bewshea, Abhey Singh, Mian Chen, Jack B Satchwell, Julian P Vivian, Kenji So, Patrick C Dubois, Jane M Andrews, Vito Annese, Peter Bampton, Martin Barnardo, Sally Bell, Andy Cole, Susan J Connor, Tom Creed, Fraser R Cummings, Mauro D'AmatoTawfique K Daneshmend, Richard N Fedorak, Timothy H Florin, Daniel R Gaya, Emma Greig, Jonas Halfvarson, Alisa Hart, Peter M Irving, Gareth Jones, Amir Karban, Ian C Lawrance, James C Lee, Charlie Lees, Raffi Lev-Tzion, James O Lindsay, John Mansfield, Joel Mawdsley, Zia Mazhar, Miles Parkes, Kirstie Parnell, Timothy R Orchard, Graham Radford-Smith, Richard K Russell, David Reffitt, Jack Satsangi, Mark S Silverberg, Giacomo C Sturniolo, Mark Tremelling, Epameinondas V Tsianos, David A van Heel, Alissa Walsh

Research output: Contribution to journal › Article › peer-review

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 × 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.

Original language	English
Pages (from-to)	1131-4
Number of pages	4
Journal	Nature Genetics
Volume	46
Issue number	10
DOIs	https://doi.org/10.1038/ng.3093
Publication status	Published - Oct 2014

Keywords / Materials (for Non-textual outputs)

6-Mercaptopurine
Azathioprine
Gene Frequency
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
HLA-DQ alpha-Chains
HLA-DRB1 Chains
Haplotypes
Humans
Immunosuppressive Agents
Inflammatory Bowel Diseases
Models, Molecular
Molecular Structure
Pancreatitis
Polymorphism, Single Nucleotide
Protein Binding
Protein Structure, Tertiary
Risk Factors

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10.1038/ng.3093

Cite this

International Serious Adverse Events Consortium, Heap, G. A., Weedon, M. N., Bewshea, C. 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., ... Walsh, A. (2014). HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants. Nature Genetics, 46(10), 1131-4. https://doi.org/10.1038/ng.3093

@article{c846aa479bf247449e6b88767002ff1c,

title = "HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants",

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 × 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.",

keywords = "6-Mercaptopurine, Azathioprine, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, HLA-DQ alpha-Chains, HLA-DRB1 Chains, Haplotypes, Humans, Immunosuppressive Agents, Inflammatory Bowel Diseases, Models, Molecular, Molecular Structure, Pancreatitis, Polymorphism, Single Nucleotide, Protein Binding, Protein Structure, Tertiary, Risk Factors",

author = "{International Serious Adverse Events Consortium} and Heap, {Graham A} and Weedon, {Michael N} and Bewshea, {Claire M} and Abhey Singh and Mian Chen and Satchwell, {Jack B} and Vivian, {Julian P} and Kenji So and Dubois, {Patrick C} and Andrews, {Jane M} and Vito Annese and Peter Bampton and Martin Barnardo and Sally Bell and Andy Cole and Connor, {Susan J} and Tom Creed and Cummings, {Fraser R} and Mauro D'Amato and Daneshmend, {Tawfique K} and Fedorak, {Richard N} and Florin, {Timothy H} and Gaya, {Daniel R} and Emma Greig and Jonas Halfvarson and Alisa Hart and Irving, {Peter M} and Gareth Jones and Amir Karban and Lawrance, {Ian C} and Lee, {James C} and Charlie Lees and Raffi Lev-Tzion and Lindsay, {James O} and John Mansfield and Joel Mawdsley and Zia Mazhar and Miles Parkes and Kirstie Parnell and Orchard, {Timothy R} and Graham Radford-Smith and Russell, {Richard K} and David Reffitt and Jack Satsangi and Silverberg, {Mark S} and Sturniolo, {Giacomo C} and Mark Tremelling and Tsianos, {Epameinondas V} and {van Heel}, {David A} and Alissa Walsh",

year = "2014",

month = oct,

doi = "10.1038/ng.3093",

language = "English",

volume = "46",

pages = "1131--4",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "10",

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International Serious Adverse Events Consortium, Heap, GA, Weedon, MN, Bewshea, CM, Singh, A, Chen, M, Satchwell, JB, Vivian, JP, So, K, Dubois, PC, Andrews, JM, Annese, V, Bampton, P, Barnardo, M, Bell, S, Cole, A, Connor, SJ, Creed, T, Cummings, FR, D'Amato, M, Daneshmend, TK, Fedorak, RN, Florin, TH, Gaya, DR, Greig, E, Halfvarson, J, Hart, A, Irving, PM, Jones, G, Karban, A, Lawrance, IC, Lee, JC, Lees, C, Lev-Tzion, R, Lindsay, JO, Mansfield, J, Mawdsley, J, Mazhar, Z, Parkes, M, Parnell, K, Orchard, TR, Radford-Smith, G, Russell, RK, Reffitt, D, Satsangi, J, Silverberg, MS, Sturniolo, GC, Tremelling, M, Tsianos, EV, van Heel, DA & Walsh, A 2014, 'HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants', Nature Genetics, vol. 46, no. 10, pp. 1131-4. https://doi.org/10.1038/ng.3093

TY - JOUR

T1 - HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants

AU - International Serious Adverse Events Consortium

AU - Heap, Graham A

AU - Weedon, Michael N

AU - Bewshea, Claire M

AU - Singh, Abhey

AU - Chen, Mian

AU - Satchwell, Jack B

AU - Vivian, Julian P

AU - So, Kenji

AU - Dubois, Patrick C

AU - Andrews, Jane M

AU - Annese, Vito

AU - Bampton, Peter

AU - Barnardo, Martin

AU - Bell, Sally

AU - Cole, Andy

AU - Connor, Susan J

AU - Creed, Tom

AU - Cummings, Fraser R

AU - D'Amato, Mauro

AU - Daneshmend, Tawfique K

AU - Fedorak, Richard N

AU - Florin, Timothy H

AU - Gaya, Daniel R

AU - Greig, Emma

AU - Halfvarson, Jonas

AU - Hart, Alisa

AU - Irving, Peter M

AU - Jones, Gareth

AU - Karban, Amir

AU - Lawrance, Ian C

AU - Lee, James C

AU - Lees, Charlie

AU - Lev-Tzion, Raffi

AU - Lindsay, James O

AU - Mansfield, John

AU - Mawdsley, Joel

AU - Mazhar, Zia

AU - Parkes, Miles

AU - Parnell, Kirstie

AU - Orchard, Timothy R

AU - Radford-Smith, Graham

AU - Russell, Richard K

AU - Reffitt, David

AU - Satsangi, Jack

AU - Silverberg, Mark S

AU - Sturniolo, Giacomo C

AU - Tremelling, Mark

AU - Tsianos, Epameinondas V

AU - van Heel, David A

AU - Walsh, Alissa

PY - 2014/10

Y1 - 2014/10

N2 - 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 × 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.

AB - 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 × 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.

KW - 6-Mercaptopurine

KW - Azathioprine

KW - Gene Frequency

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Genotype

KW - HLA-DQ alpha-Chains

KW - HLA-DRB1 Chains

KW - Haplotypes

KW - Humans

KW - Immunosuppressive Agents

KW - Inflammatory Bowel Diseases

KW - Models, Molecular

KW - Molecular Structure

KW - Pancreatitis

KW - Polymorphism, Single Nucleotide

KW - Protein Binding

KW - Protein Structure, Tertiary

KW - Risk Factors

U2 - 10.1038/ng.3093

DO - 10.1038/ng.3093

M3 - Article

C2 - 25217962

SN - 1061-4036

VL - 46

SP - 1131

EP - 1134

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

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

Abstract

Keywords / Materials (for Non-textual outputs)

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