Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease.

Autor:	Walker GJ; Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England.; IBD Pharmacogenetics Group, University of Exeter, Exeter, England., Harrison JW; University of Exeter Medical School, Exeter, England., Heap GA; Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England.; IBD Pharmacogenetics Group, University of Exeter, Exeter, England., Voskuil MD; Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, the Netherlands., Andersen V; Medical Department, Regional Hospital Viborg, Viborg, Denmark., Anderson CA; Wellcome Trust Sanger Institute, Hinxton, England., Ananthakrishnan AN; Department of Gastroenterology, Massachusetts General Hospital, Boston., Barrett JC; Wellcome Trust Sanger Institute, Hinxton, England., Beaugerie L; Department of Gastroenterology, Saint-Antoine Hospital and Sorbonne Universite, Paris, France., Bewshea CM; IBD Pharmacogenetics Group, University of Exeter, Exeter, England., Cole AT; Derby Digestive Diseases Centre, Royal Derby Hospital, Derby Teaching Hospitals NHS Foundation Trust, Derby, England., Cummings FR; Department of Gastroenterology, Southampton General Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, England., Daly MJ; Broad Institute, Harvard University, Cambridge, Massachusetts., Ellul P; Department of Gastroenterology, Mater Dei Hospital, Msida, Malta., Fedorak RN; Division of Gastroenterology, University of Alberta, Edmonton, Canada., Festen EAM; Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, the Netherlands., Florin TH; Mater Research Institute, University of Queensland, South Brisbane, Australia., Gaya DR; Department of Gastroenterology, Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde, Glasgow, Scotland., Halfvarson J; Division of Gastroenterology, Örebro University, Örebro, Sweden., Hart AL; Department of Gastroenterology, St Mark's Hospital, London North West Healthcare NHS Trust, Harrow, England., Heerasing NM; Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England.; IBD Pharmacogenetics Group, University of Exeter, Exeter, England., Hendy P; Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England.; IBD Pharmacogenetics Group, University of Exeter, Exeter, England., Irving PM; Department of Gastroenterology, Guy's and St Thomas' NHS Foundation Trust, London, England., Jones SE; University of Exeter Medical School, Exeter, England., Koskela J; Broad Institute, Harvard University, Cambridge, Massachusetts., Lindsay JO; Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine, Queen Mary University of London, London, England., Mansfield JC; Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, England., McGovern D; F. Widjaja Foundation Inflammatory Bowel Disease and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California., Parkes M; Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England., Pollok RCG; Department of Gastroenterology, St George's Healthcare NHS Trust, Tooting, England., Ramakrishnan S; Gastrointestinal and Liver Services, Warrington and Halton Hospitals NHS Foundation Trust, Warrington, England., Rampton DS; Department of Gastroenterology, Royal London Hospital, Barts Health NHS Trust, London, England., Rivas MA; Broad Institute, Harvard University, Cambridge, Massachusetts., Russell RK; Department of Paediatric Gastroenterology, Royal Hospital for Children, NHS Greater Glasgow and Clyde, Glasgow, Scotland., Schultz M; Dunedin Hospital, Dunedin, New Zealand., Sebastian S; Gastroenterology and Hepatology, Hull and East Yorkshire Hospitals NHS Trust, Hull, England., Seksik P; Department of Gastroenterology, Saint-Antoine Hospital and Sorbonne Universite, Paris, France., Singh A; Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England., So K; Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England., Sokol H; Department of Gastroenterology, Saint-Antoine Hospital and Sorbonne Universite, Paris, France., Subramaniam K; Canberra Hospital, Canberra, Australia., Todd A; Department of Haematology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England., Annese V; Division of Gastroenterology, Azienda Ospedaliero Universitaria Careggi, Florence, Italy., Weersma RK; Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, the Netherlands., Xavier R; Broad Institute, Harvard University, Cambridge, Massachusetts., Ward R; University of Exeter Medical School, Exeter, England., Weedon MN; University of Exeter Medical School, Exeter, England., Goodhand JR; Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England.; IBD Pharmacogenetics Group, University of Exeter, Exeter, England., Kennedy NA; Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England.; IBD Pharmacogenetics Group, University of Exeter, Exeter, England., Ahmad T; Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, England.; IBD Pharmacogenetics Group, University of Exeter, Exeter, England.
Jazyk:	angličtina
Zdroj:	JAMA [JAMA] 2019 Feb 26; Vol. 321 (8), pp. 773-785.
DOI:	10.1001/jama.2019.0709
Abstrakt:	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.
Databáze:	MEDLINE
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