TY - JOUR
T1 - Association of Genetic Variants in NUDT15 with Thiopurine-Induced Myelosuppression in Patients with Inflammatory Bowel Disease
AU - Walker, Gareth J.
AU - Harrison, James W.
AU - Heap, Graham A.
AU - Voskuil, Michiel D.
AU - Andersen, Vibeke
AU - Anderson, Carl A.
AU - Ananthakrishnan, Ashwin N.
AU - Barrett, Jeffrey C.
AU - Beaugerie, Laurent
AU - Bewshea, Claire M.
AU - Cole, Andy T.
AU - Cummings, Fraser R.
AU - Daly, Mark J.
AU - Ellul, Pierre
AU - Fedorak, Richard N.
AU - Festen, Eleonora A.M.
AU - Florin, Timothy H.
AU - Gaya, Daniel R.
AU - Halfvarson, Jonas
AU - Hart, Ailsa L.
AU - Heerasing, Neel M.
AU - Hendy, Peter
AU - Irving, Peter M.
AU - Jones, Samuel E.
AU - Koskela, Jukka
AU - Lindsay, James O.
AU - Mansfield, John C.
AU - McGovern, Dermot
AU - Parkes, Miles
AU - Pollok, Richard C.G.
AU - Ramakrishnan, Subramaniam
AU - Rampton, David S.
AU - Rivas, Manuel A.
AU - Russell, Richard K.
AU - Schultz, Michael
AU - Sebastian, Shaji
AU - Seksik, Philippe
AU - Singh, Abhey
AU - So, Kenji
AU - Sokol, Harry
AU - Subramaniam, Kavitha
AU - Todd, Anthony
AU - Annese, Vito
AU - Weersma, Rinse K.
AU - Xavier, Ramnik
AU - Ward, Rebecca
AU - Weedon, Michael N.
AU - Goodhand, James R.
AU - Kennedy, Nicholas A.
AU - Ahmad, Tariq
AU - IBD Pharmacogenetics Study Group
AU - Holden, Arthur L.
AU - Andrews, Jane
AU - Auth, Marcus
AU - Babu, Sathish
AU - Bampton, Peter
AU - Banim, Paul
AU - Barnes, Theresa
AU - Basude, Dharam
AU - Beckly, John
AU - Bell, Andy
AU - Bell, Sally
AU - Bhandari, Pradeep
AU - Bloom, Stuart
AU - Border, Dave
AU - Bredin, Francesca
AU - Brookes, Matthew J.
AU - Brown, Matthew
AU - Calvert, Chris
AU - Campbell, David
AU - Chanchlani, Neil
AU - Chaudhary, Basant
AU - Chaudhary, Rakesh
AU - Chung-Faye, Guy
AU - Colleypriest, Ben
AU - Connor, Susan
AU - Cooney, Rachel
AU - Cooper, Sheldon
AU - Creed, Tom J.
AU - Croft, Nick
AU - Cullen, Sue
AU - D'Amato, Mauro
AU - D'Inca, Renata
AU - Dalal, Helen
AU - Daneshmend, Tawfique K.
AU - Das, Debasish
AU - Delaney, Michael
AU - DeSilva, Shanika
AU - Dhar, Anjan
AU - Dharmasiri, Suranga
AU - Direkze, Natalie
AU - Dunckley, Paul
AU - Elphick, David
AU - Everett, Simon M.
AU - Feeney, Mark
AU - Fell, John
AU - Foley, Stephen
AU - Franke, Andre
AU - Gavin, Daniel
AU - Gee, Ian
AU - Ghosh, Deb
AU - Goldsmith, Christopher
AU - Gorard, David
AU - Gordon, John N.
AU - Gore, Steve
AU - Green, John
AU - Grimes, David
AU - Hamill, Grace
AU - Harbord, Marcus
AU - Hart, James
AU - Hawkey, Chris
AU - Iqbal, Tariq
AU - Ireland, Alan
AU - Johnson, Matt
AU - Jones, Colin
AU - Kanegasundaram, Suren
AU - Karban, Amir
AU - Katsanos, Konstantinos H.
AU - Kiparissi, Fevronia
AU - Kirkham, Sian
AU - Lal, Simon
AU - Langlands, Sarah
AU - Lawrance, Ian C.
AU - Lees, Charlie W.
AU - Lev-Tzion, Raffi
AU - Levison, Scott
AU - Lewis, Stephen J.
AU - Li, Andy
AU - Limdi, Jimmy
AU - Lin, Simeng
AU - Lobo, Alan
AU - Lockett, Melanie
AU - Loehry, Juliette
AU - MacDonald, Chris
AU - MacFaul, George
AU - Mahmood, Tariq
AU - Mahmood, Zahid
AU - Mann, Steve
AU - Mawdsley, Joel
AU - Mazhar, Zia
AU - McGovern, Jane F.
AU - McNair, Alistair
AU - Modi, Anita
AU - Monahan, Kevin
AU - Moran, Alex
AU - Morris, Mary Anne
AU - Mortimore, Marianne
AU - Mowat, Craig
AU - Muhammed, Rafeeq
AU - Murray, Charles D.R.
AU - Olivier, Hanlie
AU - Orchard, Timothy R.
AU - Panter, Simon
AU - Patel, Vinod
AU - Phillips, Rosemary
AU - Prasad, Neeraj
AU - Preston, Cathryn
AU - Radford-Smith, Graham
AU - Rajasekhar, Praveen
AU - Roy, Dipak
AU - Saich, Rebecca
AU - Satsangi, Jack
AU - Schreiber, Stefan
AU - Sen, Sandip
AU - Shah, Neil
AU - Shenderay, Richard
AU - Shenoy, Acuth
AU - Shutt, James
AU - Silverberg, Mark
AU - Simmons, Alison
AU - Simmons, Jonathan
AU - Singh, Salil
AU - Smith, Malcolm
AU - Smith, Mark
AU - Smith, Melissa
AU - Snook, Jonathon A.
AU - Sonwalker, Sunil
AU - Stevens, Christine R.
AU - Sturniolo, Giacomo
AU - Subramanian, Sreedhar
AU - Thomas, Amanda
AU - Tighe, Mark
AU - Torrente, Franco
AU - Tremelling, Mark
AU - Tsianos, Epameinondas
AU - Vani, Deven
AU - Walsh, Alissa
AU - Watermeyer, Gillian
AU - Watts, David
AU - Watts, Gill
AU - Weaver, Sean
AU - Wesley, Emma
AU - Willmott, Anne
AU - Yearsley, Karen
AU - Zambar, Veena
AU - Zeissig, Sebastian
AU - Nelson, Matthew R.
PY - 2019/4/23
Y1 - 2019/4/23
N2 - 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 [95% CI, 5.1 to 286.1], P = 1.3 × 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 × 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.
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 [95% CI, 5.1 to 286.1], P = 1.3 × 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 × 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.
KW - thiopurines
KW - myelosuppression
KW - NUDT15 variants
UR - http://www.scopus.com/inward/record.url?scp=85062067665&partnerID=8YFLogxK
U2 - 10.1001/jama.2019.0709
DO - 10.1001/jama.2019.0709
M3 - Article
C2 - 30806694
AN - SCOPUS:85062067665
SN - 0098-7484
VL - 321
SP - 773
EP - 785
JO - JAMA: Journal of the American Medical Association
JF - JAMA: Journal of the American Medical Association
IS - 8
ER -