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 HalfvarsonAilsa 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

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

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

Original languageEnglish
Pages (from-to)773-785
Number of pages13
JournalJAMA - Journal of the American Medical Association
Volume321
Issue number8
DOIs
Publication statusPublished - 26 Feb 2019

Keywords

  • Adolescent
  • Adult
  • Case-Control Studies
  • Colitis, Ulcerative/drug therapy
  • Crohn Disease/drug therapy
  • European Continental Ancestry Group
  • Exome
  • Female
  • Genome-Wide Association Study
  • Haplotypes
  • Humans
  • Leukocyte Count
  • Male
  • Methyltransferases/genetics
  • Polymorphism, Single Nucleotide
  • Pyrophosphatases/genetics
  • Sequence Analysis, DNA/methods
  • Young Adult

Fingerprint Dive into the research topics of 'Association of Genetic Variants in NUDT15 with Thiopurine-Induced Myelosuppression in Patients with Inflammatory Bowel Disease'. Together they form a unique fingerprint.

Cite this