Author(s): Walker G.J.; Heap G.A.; Heerasing N.M.; Hendy P.; Singh A.; So K.; Goodhand J.R.; Kennedy N.A.; Ahmad T.; Bewshea C.M.; Harrison J.W.; Jones S.E.; Ward R.; Weedon M.N.; Voskuil M.D.; Festen E.A.M.; Weersma R.K.; Andersen V.; Anderson C.A.; Barrett J.C.; Ananthakrishnan A.N.; Beaugerie L.; Seksik P.; Sokol H.; Cole A.T.; Cummings F.R.; Daly M.J.; Koskela J.; Rivas M.A.; Xavier R.; Ellul P.; Fedorak R.N.; Florin T.H.; Gaya D.R.; Halfvarson J.; Hart A.L.; Irving P.M.; Lindsay J.O.; Mansfield J.C.; McGovern D.; Parkes M.; Torrente F.; Pollok R.C.G.; Ramakrishnan S.; Rampton D.S.; Russell R.K.; Schultz M.; Sebastian S.; Subramaniam K.; Todd A.; Annese V.; Holden A.L.; Andrews J.; Auth M.; Babu S.; Bampton P.; Banim P.; Barnes T.; Basude D.; Beckly J.; Bell A.; Bell S.; Bhandari P.; Bloom S.; Border D.; Bredin F.; Brookes M.J.; Brown M.; Calvert C.; Campbell D.; Chanchlani N.; Chaudhary B.; Chaudhary R.; Chung-Faye G.; Colleypriest B.; Connor S.; Cooney R.; Cooper S.; Creed T.J.; Croft N.; Cullen S.; D’Amato M.; D’Inca R.; Dalal H.; Daneshmend T.K.; Das D.; Delaney M.; DeSilva S.; Dhar A.; Dharmasiri S.; Direkze N.; Dunckley P.; Elphick D.; Everett S.M.; Feeney M.; Fell J.; Foley S.; Franke A.; Gavin D.; Gee I.; Ghosh D.; Goldsmith C.; Gorard D.; Gordon J.N.; Gore S.; Green J.; Grimes D.; Hamill G.; Harbord M.; Hart J.; Hawkey C.; Iqbal T.; Ireland A.; Johnson M.; Jones C.; Kanegasundaram S.; Karban A.; Katsanos K.H.; Tsianos E.; Kiparissi F.; Kirkham S.; Lal S.; Langlands S.; Lawrance I.C.; Lees C.W.; Lev-Tzion R.; Levison S.; Lewis S.J.; Li A.; Limdi J.; Lin S.; Thomas A.; Lobo A.; Lockett M.; Loehry J.; MacDonald C.; MacFaul G.; Mahmood T.; Mahmood Z.; Mann S.; Mawdsley J.; Mazhar Z.; McGovern J.F.; McNair A.; Modi A.; Monahan K.; Moran A.; Morris M.-A.; Tremelling M.; Mortimore M.; Mowat C.; Muhammed R.; Murray C.D.R.; Olivier H.; Orchard T.R.; Panter S.; Patel V.; Phillips R.; Prasad N.; Preston C.; Radford-Smith G.; Rajasekhar P.; Roy D.; Saich R.; Satsangi J.; Schreiber S.; Sen S.; Shah N.; Shenderay R.; Shenoy A.; Shutt J.; Silverberg M.; Simmons A.; Simmons J.; Singh S.; Smith M.; Snook J.A.; Tighe M.; Sonwalker S.; Stevens C.R.; Sturniolo G.; Subramanian S.; Vani D.; Walsh A.; Watermeyer G.; Watts D.; Watts G.; Weaver S.; Wesley E.; Willmott A.; Yearsley K.; Zambar V.; Zeissig S.

Source: JAMA – Journal of the American Medical Association; Feb 2019; vol. 321 (no. 8); p. 753-761

Publication Date: Feb 2019

Publication Type(s): Article

Available¬† at JAMA – Journal of the American Medical Association –¬† from Edge Hill Aintree LIRC (lib302411) Local Print Collection

Abstract: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(s): To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). Design, Setting, and Participant(s): 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 x 109/L or less or a decline in absolute neutrophil cell count to 1.0 x 109/L or less leading to a dose reduction or drug withdrawal. Result(s): 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 x 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 [95% CI, 5.1 to 286.1], P = 1.3 x 10-8), which was replicated in a different cohort (2.7% [2/73] affected vs 0.2% [2/840] unaffected patients; OR, 11.8 [95% CI, 1.6 to 85.0], P =.03). Carriage of any of 3 coding NUDT15 variants was associated with an increased risk (OR, 27.3 [95% CI, 9.3 to 116.7], P = 1.1 x 10-7) of TIM, independent of TPMT genotype and thiopurine dose. Conclusions and Relevance: Among patients of European ancestry with IBD, variants in NUDT15 were associated with increased risk of TIM. These findings suggest that NUDT15 genotyping may be considered prior to initiation of thiopurine therapy; however, further study including additional validation in independent cohorts is required.Copyright © 2019 American Medical Association. All rights reserved.

Database: EMBASE

Leave a Reply

Your email address will not be published. Required fields are marked *