Gareth J Walker1,2, James W Harrison3, Graham A Heap1,2, Michiel D Voskuil4, Vibeke Andersen5, Carl A Anderson6, Ashwin N Ananthakrishnan7, Jeffrey C Barrett6, Laurent Beaugerie8, Claire M Bewshea2, Andy T Cole9, Fraser R Cummings10, Mark J Daly11, Pierre Ellul12, Richard N Fedorak13, Eleonora A M Festen4, Timothy H Florin14, Daniel R Gaya15, Jonas Halfvarson16, Ailsa L Hart17, Neel M Heerasing1,2, Peter Hendy1,2, Peter M Irving18, Samuel E Jones3, Jukka Koskela11, James O Lindsay19, John C Mansfield20, Dermot McGovern21, Miles Parkes22, Richard C G Pollok23, Subramaniam Ramakrishnan24, David S Rampton25, Manuel A Rivas11, Richard K Russell26, Michael Schultz27, Shaji Sebastian28, Philippe Seksik8, Abhey Singh1, Kenji So1, Harry Sokol8, Kavitha Subramaniam29, Anthony Todd30, Vito Annese31, Rinse K Weersma4, Ramnik Xavier11, Rebecca Ward3, Michael N Weedon3, James R Goodhand1,2, Nicholas A Kennedy1,2, Tariq Ahmad1,2. 1. Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England. 2. IBD Pharmacogenetics Group, University of Exeter, Exeter, England. 3. University of Exeter Medical School, Exeter, England. 4. Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, the Netherlands. 5. Medical Department, Regional Hospital Viborg, Viborg, Denmark. 6. Wellcome Trust Sanger Institute, Hinxton, England. 7. Department of Gastroenterology, Massachusetts General Hospital, Boston. 8. Department of Gastroenterology, Saint-Antoine Hospital and Sorbonne Universite, Paris, France. 9. Derby Digestive Diseases Centre, Royal Derby Hospital, Derby Teaching Hospitals NHS Foundation Trust, Derby, England. 10. Department of Gastroenterology, Southampton General Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, England. 11. Broad Institute, Harvard University, Cambridge, Massachusetts. 12. Department of Gastroenterology, Mater Dei Hospital, Msida, Malta. 13. Division of Gastroenterology, University of Alberta, Edmonton, Canada. 14. Mater Research Institute, University of Queensland, South Brisbane, Australia. 15. Department of Gastroenterology, Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde, Glasgow, Scotland. 16. Division of Gastroenterology, Örebro University, Örebro, Sweden. 17. Department of Gastroenterology, St Mark's Hospital, London North West Healthcare NHS Trust, Harrow, England. 18. Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, England. 19. Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London, London, England. 20. Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, England. 21. F. Widjaja Foundation Inflammatory Bowel Disease and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California. 22. Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England. 23. Department of Gastroenterology, St George's Healthcare NHS Trust, Tooting, England. 24. Gastrointestinal and Liver Services, Warrington and Halton Hospitals NHS Foundation Trust, Warrington, England. 25. Department of Gastroenterology, Royal London Hospital, Barts Health NHS Trust, London, England. 26. Department of Paediatric Gastroenterology, Royal Hospital for Children, NHS Greater Glasgow and Clyde, Glasgow, Scotland. 27. Dunedin Hospital, Dunedin, New Zealand. 28. Gastroenterology and Hepatology, Hull and East Yorkshire Hospitals NHS Trust, Hull, England. 29. Canberra Hospital, Canberra, Australia. 30. Department of Haematology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England. 31. Division of Gastroenterology, Azienda Ospedaliero Universitaria Careggi, Florence, Italy.
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: 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.
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.
Authors: J F Colombel; N Ferrari; H Debuysere; P Marteau; J P Gendre; B Bonaz; J C Soulé; R Modigliani; Y Touze; P Catala; C Libersa; F Broly Journal: Gastroenterology Date: 2000-06 Impact factor: 22.682
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