Imperial College London
Professor Timothy Orchard

ProfessorTimothyOrchard

Faculty of Medicine, Department of Metabolism, Digestion and Reproduction

Professor of Gastroenterology
 
 
 
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t.orchard

 
 
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Location

 

GI UnitNorfolk PlaceSt Mary's Campus

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Summary

 

Publications

Citation

BibTex format

@article{Walker:2019:10.1001/jama.2019.0709,
author = {Walker, GJ and Harrison, JW and Heap, GA and Voskuil, MD and Andersen, V and Anderson, CA and Ananthakrishnan, AN and Barrett, JC and Beaugerie, L and Bewshea, CM and Cole, AT and Cummings, FR and Daly, MJ and Ellul, P and Fedorak, RN and Festen, EAM and Florin, TH and Gaya, DR and Halfvarson, J and Hart, AL and Heerasing, NM and Hendy, P and Irving, PM and Jones, SE and Koskela, J and Lindsay, JO and Mansfield, JC and McGovern, D and Parkes, M and Pollok, RCG and Ramakrishnan, S and Rampton, DS and Rivas, MA and Russell, RK and Schultz, M and Sebastian, S and Seksik, P and Singh, A and So, K and Sokol, H and Subramaniam, K and Todd, A and Annese, V and Weersma, RK and Xavier, R and Ward, R and Weedon, MN and Goodhand, JR and Kennedy, NA and Ahmad, T and Holden, AL and Andrews, J and Auth, M and Babu, S and Bampton, P and Banim, P and Barnes, T and Basude, D and Beckly, J and Bell, A and Bell, S and Bhandari, P and Bloom, S and Border, D and Bredin, F and Brookes, MJ and Brown, M and C},
doi = {10.1001/jama.2019.0709},
journal = {JAMA: Journal of the American Medical Association},
pages = {773--785},
title = {Association of genetic variants in NUDT15 with thiopurine-induced myelosuppression in patients with inflammatory bowel disease},
url = {http://dx.doi.org/10.1001/jama.2019.0709},
volume = {321},
year = {2019}
}
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TY  - JOUR
AB  - Importance  Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM).Objective  To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD).Design, Setting, and Participants  Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients.Exposures  Genetic variants associated with TIM.Main Outcomes and Measures  Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal.Results  Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10−9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2
AU  - Walker,GJ
AU  - Harrison,JW
AU  - Heap,GA
AU  - Voskuil,MD
AU  - Andersen,V
AU  - Anderson,CA
AU  - Ananthakrishnan,AN
AU  - Barrett,JC
AU  - Beaugerie,L
AU  - Bewshea,CM
AU  - Cole,AT
AU  - Cummings,FR
AU  - Daly,MJ
AU  - Ellul,P
AU  - Fedorak,RN
AU  - Festen,EAM
AU  - Florin,TH
AU  - Gaya,DR
AU  - Halfvarson,J
AU  - Hart,AL
AU  - Heerasing,NM
AU  - Hendy,P
AU  - Irving,PM
AU  - Jones,SE
AU  - Koskela,J
AU  - Lindsay,JO
AU  - Mansfield,JC
AU  - McGovern,D
AU  - Parkes,M
AU  - Pollok,RCG
AU  - Ramakrishnan,S
AU  - Rampton,DS
AU  - Rivas,MA
AU  - Russell,RK
AU  - Schultz,M
AU  - Sebastian,S
AU  - Seksik,P
AU  - Singh,A
AU  - So,K
AU  - Sokol,H
AU  - Subramaniam,K
AU  - Todd,A
AU  - Annese,V
AU  - Weersma,RK
AU  - Xavier,R
AU  - Ward,R
AU  - Weedon,MN
AU  - Goodhand,JR
AU  - Kennedy,NA
AU  - Ahmad,T
AU  - Holden,AL
AU  - Andrews,J
AU  - Auth,M
AU  - Babu,S
AU  - Bampton,P
AU  - Banim,P
AU  - Barnes,T
AU  - Basude,D
AU  - Beckly,J
AU  - Bell,A
AU  - Bell,S
AU  - Bhandari,P
AU  - Bloom,S
AU  - Border,D
AU  - Bredin,F
AU  - Brookes,MJ
AU  - Brown,M
AU  - Calvert,C
AU  - Campbell,D
AU  - Chanchlani,N
AU  - Chaudhary,B
AU  - Chaudhary,R
AU  - Chung-Faye,G
AU  - Colleypriest,B
AU  - Connor,S
AU  - Cooney,R
AU  - Cooper,S
AU  - Creed,TJ
AU  - Croft,N
AU  - Cullen,S
AU  - D'Amato,M
AU  - Dalal,H
AU  - Daneshmend,TK
AU  - Das,D
AU  - Delaney,M
AU  - Desilva,S
AU  - Dhar,A
AU  - Dharmasiri,S
AU  - Direkze,N
AU  - Dunckley,P
AU  - Elphick,D
AU  - Everett,SM
AU  - Feeney,M
AU  - Fell,J
AU  - Foley,S
AU  - Franke,A
AU  - Gavin,D
AU  - Gee,I
AU  - Ghosh,D
AU  - Goldsmith,C
AU  - Gorard,D
AU  - Gordon,JN
AU  - Gore,S
AU  - Green,J
AU  - Grimes,D
AU  - Hamill,G
AU  - Harbord,M
AU  - Hart,J
AU  - Hawkey,C
AU  - Iqbal,T
AU  - Ireland,A
AU  - Johnson,M
AU  - Jones,C
AU  - Kanegasundaram,S
AU  - Karban,A
AU  - Katsanos,KH
AU  - Kiparissi,F
AU  - Kirkham,S
AU  - Lal,S
AU  - Langlands,S
AU  - Lawrance,IC
AU  - Lees,CW
AU  - Lev-Tzion,R
AU  - Levison,S
AU  - Lewis,SJ
AU  - Li,A
AU  - Limdi,J
AU  - Lin,S
AU  - Lobo,A
AU  - Lockett,M
AU  - Loehry,J
AU  - MacDonald,C
AU  - MacFaul,G
AU  - Mahmood,T
AU  - Mann,S
AU  - Mawdsley,J
AU  - Mazhar,Z
AU  - McGovern,JF
AU  - McNair,A
AU  - Modi,A
AU  - Monahan,K
AU  - Moran,A
AU  - Morris,M-A
AU  - Mortimore,M
AU  - Mowat,C
AU  - Muhammed,R
AU  - Murray,CDR
AU  - Olivier,H
AU  - Orchard,TR
AU  - Panter,S
AU  - Patel,V
AU  - Phillips,R
AU  - Prasad,N
AU  - Preston,C
AU  - Radford-Smith,G
AU  - Rajasekhar,P
AU  - Roy,D
AU  - Saich,R
AU  - Satsangi,J
AU  - Schreiber,S
AU  - Sen,S
AU  - Shah,N
AU  - Shenderay,R
AU  - Shenoy,A
AU  - Shutt,J
AU  - Silverberg,M
AU  - Simmons,A
AU  - Simmons,J
AU  - Singh,S
AU  - Smith,M
AU  - Smith,M
AU  - Smith,M
AU  - Snook,JA
AU  - Sonwalker,S
AU  - Stevens,CR
AU  - Sturniolo,G
AU  - Subramanian,S
AU  - Thomas,A
AU  - Tighe,M
AU  - Torrente,F
AU  - Tremelling,M
AU  - Tsianos,E
AU  - Vani,D
AU  - Walsh,A
AU  - Watermeyer,G W
DO  - 10.1001/jama.2019.0709
EP  - 785
PY  - 2019///
SN  - 0098-7484
SP  - 773
TI  - Association of genetic variants in NUDT15 with thiopurine-induced myelosuppression in patients with inflammatory bowel disease
T2  - JAMA: Journal of the American Medical Association
UR  - http://dx.doi.org/10.1001/jama.2019.0709
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000460191400019&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/69108
VL  - 321
ER  -
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