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

Gareth J. Walker; James W. Harrison; Graham A. Heap; Michiel D. Voskuil; Vibeke Andersen; Carl A. Anderson; Ashwin N. Ananthakrishnan; Jeffrey C. Barrett; Laurent Beaugerie; Claire M. Bewshea; Andy T. Cole; Fraser R. Cummings; Mark J. Daly; Pierre Ellul; Richard N. Fedorak; Eleonora A. M. Festen; Timothy H. Florin; Daniel R. Gaya; Jonas Halfvarson; Ailsa L. Hart; Neel M. Heerasing; Peter Hendy; Peter M. Irving; Samuel E. Jones; Jukka Koskela; James O. Lindsay; John C. Mansfield; Dermot McGovern; Miles Parkes; Richard C. G. Pollok; Subramaniam Ramakrishnan; David S. Rampton; Manuel A. Rivas; Richard K. Russell; Michael Schultz; Shaji Sebastian; Philippe Seksik; Abhey Singh; Kenji So; Harry Sokol; Kavitha Subramaniam; Anthony Todd; Vito Annese; Rinse K. Weersma; Ramnik Xavier; Rebecca Ward; Michael N. Weedon; James R. Goodhand; Nicholas A. Kennedy; Tariq Ahmad; Arthur L. Holden; Jane Andrews; Marcus Auth; Sathish Babu; Peter Bampton; Paul Banim; Theresa Barnes; Dharam Basude; John Beckly; Andy Bell; Sally Bell; Pradeep Bhandari; Stuart Bloom; Dave Border; Francesca Bredin; Matthew J. Brookes; Matthew Brown; Chris Calvert; David Campbell; Neil Chanchlani; Basant Chaudhary; Rakesh Chaudhary; Guy Chung-Faye; Ben Colleypriest; Susan Connor; Rachel Cooney; Sheldon Cooper; Tom J. Creed; Nick Croft; Sue Cullen; Mauro D'Amato; Helen Dalal; Tawfique K. Daneshmend; Debasish Das; Michael Delaney; Shanika Desilva; Anjan Dhar; Suranga Dharmasiri; Natalie Direkze; Paul Dunckley; David Elphick; Simon M. Everett; Mark Feeney; John Fell; Stephen Foley; Andre Franke; Daniel Gavin; Ian Gee; Deb Ghosh; Christopher Goldsmith; David Gorard; John N. Gordon; Steve Gore; John Green; David Grimes; Grace Hamill; Marcus Harbord; James Hart; Chris Hawkey; Tariq Iqbal; Alan Ireland; Matt Johnson; Colin Jones; Suren Kanegasundaram; Amir Karban; Konstantinos H. Katsanos; Fevronia Kiparissi; Sian Kirkham; Simon Lal; Sarah Langlands; Ian C. Lawrance; Charlie W. Lees; Raffi Lev-Tzion; Scott Levison; Stephen J. Lewis; Andy Li; Jimmy Limdi; Simeng Lin; Alan Lobo; Melanie Lockett; Juliette Loehry; Chris MacDonald; George MacFaul; Tariq Mahmood; Steve Mann; Joel Mawdsley; Zia Mazhar; Jane F. McGovern; Alistair McNair; Anita Modi; Kevin Monahan; Alex Moran; Mary-Anne Morris; Marianne Mortimore; Craig Mowat; Rafeeq Muhammed; Charles D. R. Murray; Hanlie Olivier; Timothy R. Orchard; Simon Panter; Vinod Patel; Rosemary Phillips; Neeraj Prasad; Cathryn Preston; Graham Radford-Smith; Praveen Rajasekhar; Dipak Roy; Rebecca Saich; Jack Satsangi; Stefan Schreiber; Sandip Sen; Neil Shah; Richard Shenderay; Acuth Shenoy; James Shutt; Mark Silverberg; Alison Simmons; Jonathan Simmons; Salil Singh; Malcolm Smith; Mark Smith; Melissa Smith; Jonathon A. Snook; Sunil Sonwalker; Christine R. Stevens; Giacomo Sturniolo; Sreedhar Subramanian; Amanda Thomas; Mark Tighe; Franco Torrente; Mark Tremelling; Epameinondas Tsianos; Deven Vani; Alissa Walsh; Gillian Watermeyer; David Watts; Gill Watts; Sean Weaver; Emma Wesley; Anne Willmott; Karen Yearsley; Veena Zambar; Sebastian Zeissig; IBD Pharmacogenetics Study Grp

doi:10.1001/jama.2019.0709

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

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

Gareth J. Walker, James W. Harrison, Graham A. Heap, Michiel D. Voskuil, Vibeke Andersen, Carl A. Anderson, Ashwin N. Ananthakrishnan, Jeffrey C. Barrett, Laurent Beaugerie, Claire M. Bewshea, …

JAMA : the journal of the American Medical Association, Vol.321(8), pp.773-785

26/02/2019

DOI: https://doi.org/10.1001/jama.2019.0709

PMCID: PMC6439872

PMID: 30806694

Abstract

General & Internal Medicine

Life Sciences & Biomedicine

Medicine, General & Internal

Science & Technology

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 x 10(9)/L or less or a decline in absolute neutrophil cell count to 1.0 x 10(9)/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 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.

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Title: Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease
Creators - without role: Gareth J. Walker - Phillips Exeter Academy
James W. Harrison - University of Exeter
Graham A. Heap - Phillips Exeter Academy
Michiel D. Voskuil - College Station Medical Center
Vibeke Andersen - College Station Medical Center
Carl A. Anderson - Wellcome Sanger Institute
Ashwin N. Ananthakrishnan - Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA
Jeffrey C. Barrett - Wellcome Sanger Institute
Laurent Beaugerie - St Antoine Hosp, Dept Gastroenterol, Paris, France
Claire M. Bewshea - University of Exeter
Andy T. Cole - Derby Teaching Hosp NHS Fdn Trust, Royal Derby Hosp, Derby Digest Dis Ctr, Derby, England
Fraser R. Cummings - Univ Hosp Southampton Fdn Trust, Southampton Gen Hosp, Dept Gastroenterol, Southampton, Hants, England
Mark J. Daly - Harvard University
Pierre Ellul - Mater Dei Hosp, Dept Gastroenterol, Msida, Malta
Richard N. Fedorak - University of Alberta
Eleonora A. M. Festen - College Station Medical Center
Timothy H. Florin - University of Queensland
Daniel R. Gaya - NHS Greater Glasgow & Clyde, Glasgow Royal Infirm, Dept Gastroenterol, Glasgow, Lanark, Scotland
Jonas Halfvarson - Univ Orebro, Div Gastroenterol, Orebro, Sweden
Ailsa L. Hart - London North West Healthcare NHS Trust
Neel M. Heerasing - Phillips Exeter Academy
Peter Hendy - Phillips Exeter Academy
Peter M. Irving - Guys & St Thomas NHS Fdn Trust, Dept Gastroenterol, London, England
Samuel E. Jones - University of Exeter
Jukka Koskela - Harvard University
James O. Lindsay - Queen Mary University of London
John C. Mansfield - Newcastle Tyne Hosp NHS Fdn Trust, Dept Gastroenterol, Newcastle Upon Tyne, Tyne & Wear, England
Dermot McGovern - College Station Medical Center
Miles Parkes - University of Cambridge
Richard C. G. Pollok - St Georges Healthcare NHS Trust, Dept Gastroenterol, Tooting, England
Subramaniam Ramakrishnan - Warrington & Halton Hosp NHS Fdn Trust, Gastrointestinal & Liver Serv, Warrington, Cheshire, England
David S. Rampton - Royal London Hosp Barts Hlth NHS Trust, Dept Gastroenterol, London, England
Manuel A. Rivas - Harvard University
Richard K. Russell - Royal Hosp Children, NHS Greater Glasgow & Clyde, Dept Paediat Gastroenterol, Glasgow, Lanark, Scotland
Michael Schultz - Dunedin Publ Hosp, Dunedin, New Zealand
Shaji Sebastian - Hull & East Yorkshire Hosp NHS Trust, Gastroenterol & Hepatol, Kingston Upon Hull, England
Philippe Seksik - St Antoine Hosp, Dept Gastroenterol, Paris, France
Abhey Singh - Phillips Exeter Academy
Kenji So - Phillips Exeter Academy
Harry Sokol - St Antoine Hosp, Dept Gastroenterol, Paris, France
Kavitha Subramaniam - ACT
Anthony Todd - Phillips Exeter Academy
Vito Annese - Florence
Rinse K. Weersma - College Station Medical Center
Ramnik Xavier - Harvard University
Rebecca Ward - University of Exeter
Michael N. Weedon - University of Exeter
James R. Goodhand - Phillips Exeter Academy
Nicholas A. Kennedy - Phillips Exeter Academy
Tariq Ahmad - Phillips Exeter Academy
Arthur L. Holden - Int Serious Adverse Event Consortium, New York, NY USA
Jane Andrews - Royal Adelaide Hosp, Adelaide, SA, Australia
Marcus Auth - Alder
Sathish Babu - Lincoln Cty Hosp, Lincoln, England
Peter Bampton - Flinders University
Paul Banim - James Paget Univ Hosp, Great Yarmouth, England
Theresa Barnes - Countess Chester Hosp, Chester, Cheshire, England
Dharam Basude - Avon
John Beckly - Royal Cornwall Hosp, Truro, England
Andy Bell - Weston Gen Hosp, Weston Super Mare, England
Sally Bell - St Vincents Hosp, Melbourne, Vic, Australia
Pradeep Bhandari - Queen Alexandra Hosp, Portsmouth, Hants, England
Stuart Bloom - Univ Coll London Hosp, London, England
Dave Border - York Teaching Hosp NHS Fdn Trust, York, N Yorkshire, England
Francesca Bredin - Kings Lynn Hosp, Kings Lynn, England
Matthew J. Brookes - The Royal Wolverhampton NHS Trust
Matthew Brown - Basingstoke & North Hampshire Hosp, Basingstoke, Hants, England
Chris Calvert - Phillips Exeter Academy
David Campbell - Sheffield Childrens Hosp, Sheffield, S Yorkshire, England
Neil Chanchlani - Phillips Exeter Academy
Basant Chaudhary - West Hertfordshire Hosp NHS Trust, Watford Gen Hosp, Watford, England
Rakesh Chaudhary - West Hertfordshire Hosp NHS Trust, Watford Gen Hosp, Watford, England
Guy Chung-Faye - Kings Coll Hosp London, London, England
Ben Colleypriest - Avon
Susan Connor - Liverpool Hosp, Liverpool, NSW, Australia
Rachel Cooney - Sandwell Hosp, Birmingham, W Midlands, England
Sheldon Cooper - Dudley Grp NHS Fdn Trust, Dudley, England
Tom J. Creed - Avon
Nick Croft - Royal London Hosp, Barts Hlth NHS Trust, Dept Gastroenterol, London, England
Sue Cullen - Stoke Mandeville Hosp, Aylesbury, Bucks, England
Mauro D'Amato - Karolinska Institutet
Helen Dalal - James Cook University
Tawfique K. Daneshmend - Phillips Exeter Academy
Debasish Das - Gen Hosp Kettering, Kettering, England
Michael Delaney - Kent & Canterbury Hosp, Canterbury, Kent, England
Shanika Desilva - Dudley Grp NHS Fdn Trust, Dudley, England
Anjan Dhar - Bishop Auckland Gen Hosp, Cty Durham & Darlington NHS Fdn Trust, Darlington, Durham, England
Suranga Dharmasiri - Univ Hosp Southampton NHS Fdn Trust, Southampton Gen Hosp, Dept Gastroenterol, Southampton, Hants, England
Natalie Direkze - Frimley Pk Hosp, Frimley, England
Paul Dunckley - Gloucestershire Hosp NHS Fdn Trust, Gloucestershire Royal Hosp, Gloucester, England
David Elphick - Chesterfield Royal Hosp NHS Fdn Trust, Chesterfield, England
Simon M. Everett - St James Univ Hosp, Leeds Teaching Hosp NHS Trust, Leeds, W Yorkshire, England
Mark Feeney - Torbay & South Devon NHS Fdn Trust, Torquay, England
John Fell - Chelsea & Westminster Hosp NHS Fdn Trust, London, England
Stephen Foley - The Mill
Andre Franke - Christian Albrechts Univ Kiel, Kiel, Germany
Daniel Gavin - Ipswich Hosp NHS Trust, Ipswich, Suffolk, England
Ian Gee - Worcestershire Royal Hosp, Worcester, MA USA
Deb Ghosh - Princess Alexandra Hosp, Harlow, Essex, England
Christopher Goldsmith - Aintree Univ Hosp NHS Fdn Trust, Liverpool, Merseyside, England
David Gorard - Stoke Mandeville Hosp, Aylesbury, Bucks, England
John N. Gordon - Hampshire Hosp NHS Fdn Trust, Royal Hampshire Cty Hosp, Winchester, Hants, England
Steve Gore - Yeovil Dist Hosp, Yeovil, England
John Green - Univ Hosp Llandough, Cardiff, S Glam, Wales
David Grimes - Royal Blackburn Hosp, Blackburn, Lancs, England
Grace Hamill - Harrogate & Dist NHS Fdn Trust, Harrogate, England
Marcus Harbord - Chelsea andWestminster Hosp NHS Fdn Trust, London, England
James Hart - Phillips Exeter Academy
Chris Hawkey - Phillips Exeter Academy
Tariq Iqbal - Queen Elizabeth Hosp, Birmingham, W Midlands, England
Alan Ireland - Royal Sussex Cty Hosp, Brighton, E Sussex, England
Matt Johnson - Luton & Dunstable Univ Hosp, Luton, Beds, England
Colin Jones - University of Exeter
Suren Kanegasundaram - Freeman Rd Hosp, Newcastle Upon Tyne, Tyne & Wear, England
Amir Karban - Rambam Hlth Care Campus, Haifa, Israel
Konstantinos H. Katsanos - Univ Hosp Ioannina, Ioannina, Greece
Fevronia Kiparissi - Ormond
Sian Kirkham - Nottingham Childrens Hosp, Nottingham, England
Simon Lal - Salford Royal NHS Fdn Trust, Salford, Lancs, England
Sarah Langlands - Frimley Pk Hosp, Frimley, England
Ian C. Lawrance - Fremantle Hosp, Fremantle, WA, Australia
Charlie W. Lees - NHS Lothian
Raffi Lev-Tzion - College Station Medical Center
Scott Levison - Manchester Royal Infirm, Manchester, Lancs, England
Stephen J. Lewis - Plymouth Hosp NHS Trust, Plymouth, Devon, England
Andy Li - Worthing Dist Hosp, Worthing, England
Jimmy Limdi - Pennine Trust, Manchester, Lancs, England
Simeng Lin - Phillips Exeter Academy
Alan Lobo - Royal Hallamshire Hosp, Sheffield, S Yorkshire, England
Melanie Lockett - North Bristol NHS Trust
Juliette Loehry - Salisbury Dist Hosp, Salisbury, Wilts, England
Chris MacDonald - North Cumbria Univ Hosp NHS Trust, Whitehaven, England
George MacFaul - Milton Keynes Univ Hosp NHS Fdn Trust, Milton Keynes, Bucks, England
Tariq Mahmood - Grantham & Dist Hosp, Grantham, England
Steve Mann - The Royal Free Hospital
Joel Mawdsley - Middlesex University
Zia Mazhar - Basildon & Thurrock Univ Hosp NHS Fdn Trust, Basildon, England
Jane F. McGovern - College Station Medical Center
Alistair McNair - Queen Elizabeth Hosp, London, England
Anita Modi - Luton & Dunstable Univ Hosp, Luton, Beds, England
Kevin Monahan - West Middlesex Univ Hosp, Middlesex, England
Alex Moran - Northern (Arctic) Federal University
Mary-Anne Morris - Norwich University
Marianne Mortimore - University of Queensland
Craig Mowat - NHS Tayside
Rafeeq Muhammed - Birmingham Childrens Hosp, Birmingham, W Midlands, England
Charles D. R. Murray - The Royal Free Hospital
Hanlie Olivier - University of Exeter
Timothy R. Orchard - Imperial Coll Healthcare NHS Trust, London, England
Simon Panter - South Tyneside Dist Hosp, South Tyneside, England
Vinod Patel - Tameside & Glossop Integrated Care NHS Fdn Trust, Ashton Under Lyne, England
Rosemary Phillips - Princess Alexandra Hosp, Harlow, Essex, England
Neeraj Prasad - Wrightington Hosp, Wrightington, England
Cathryn Preston - Bradford Royal Infirm, Bradford, W Yorkshire, England
Graham Radford-Smith - Royal Brisbane andWomens Hosp, Brisbane, Qld, Australia
Praveen Rajasekhar - Northumbria NHS Trust, Tyne And Wear, England
Dipak Roy - Tameside & Glossop Integrated Care NHS Fdn Trust, Ashton Under Lyne, England
Rebecca Saich - Basingstoke & North Hampshire Hosp, Basingstoke, Hants, England
Jack Satsangi - NHS Lothian
Stefan Schreiber - Univ Kiel, Kiel, Germany
Sandip Sen - Royal Stoke Univ Hosp, Stoke On Trent, Staffs, England
Neil Shah - Ormond
Richard Shenderay - Airedale NHS Fdn Trust, Keighley, England
Acuth Shenoy - Colchester Hosp Univ NHS Fdn Trust, Colchester, Essex, England
James Shutt - Dorset Cty Hosp NHS Fdn Trust, Dorchester, England
Mark Silverberg - Mt Sinai Hosp, Toronto, ON, Canada
Alison Simmons - University of Oxford
Jonathan Simmons - Royal Berkshire Hosp, Royal Berkshire NHS Fdn Trust, Reading, Berks, England
Salil Singh - Bolton NHS Fdn Trust, Bolton, England
Malcolm Smith - Aberdeen Royal Infirm, Aberdeen, Scotland
Mark Smith - Shrewsbury & Telford Hosp NHS Trust, Shrewsbury, Salop, England
Melissa Smith - Royal Sussex Cty Hosp, Brighton, E Sussex, England
Jonathon A. Snook - Poole Hosp NHS Fdn Trust, Poole, Dorset, England
Sunil Sonwalker - Calderdale Royal Hosp, Halifax, NS, Canada
Christine R. Stevens - Harvard University
Giacomo Sturniolo - University of Padua
Sreedhar Subramanian - ACT
Amanda Thomas - Phillips Exeter Academy
Mark Tighe - Poole Hosp NHS Fdn Trust, Poole, Dorset, England
Franco Torrente - University of Cambridge
Mark Tremelling - Norwich University
Epameinondas Tsianos - Univ Hosp Ioannina, Ioannina, Greece
Deven Vani - Mid Yorkshire Hosp NHS Trust, Wakefield, England
Alissa Walsh - St Vincents Hosp, Sydney, NSW, Australia
Gillian Watermeyer - Groote Schuur Hosp, Cape Town, South Africa
David Watts - Forth Valley Royal Hosp, Larbert, Scotland
Gill Watts - Wythenshawe Hosp, South Manchester, England
Sean Weaver - Royal Bournemouth Gen Hosp, Bournemouth, Dorset, England
Emma Wesley - Taunton & Somerset NHS Hosp, Musgrove Pk Hosp, Taunton, Somerset, England
Anne Willmott - Leicester Royal Infirmary
Karen Yearsley - Nevill Hall Hosp, Abergavenny, Wales
Veena Zambar - Leeds Gen Infirm, Leeds, W Yorkshire, England
Sebastian Zeissig - Hull & East Yorkshire Hosp NHS Trust, Gastroenterol & Hepatol, Kingston Upon Hull, England
IBD Pharmacogenetics Study Grp
Publication Details: JAMA : the journal of the American Medical Association, Vol.321(8), pp.773-785
Publisher: Amer Medical Assoc
Number of pages: 13
Grant note: P30DK043351 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) Crohn's Colitis UK MR/M00533X/1 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) WT097835MF / Wellcome Trust; European Commission P01DK046763 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA International Serious Adverse Events Consortium
Identifiers: 9926326708331
Academic Unit: Prince Sattam Bin Abdulaziz University; Prince Sultan University
Language: English
Resource Type: Journal article