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

doi:10.1001/jama.2019.0709

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 (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

118 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 language	English
Pages (from-to)	773-785
Number of pages	13
Journal	JAMA - Journal of the American Medical Association
Volume	321
Issue number	8
DOIs	https://doi.org/10.1001/jama.2019.0709
Publication status	Published - 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

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, Walker, G. J., Harrison, J. W., Heap, G. A., Voskuil, M. D., Andersen, V., Anderson, C. A., Ananthakrishnan, A. N., Barrett, J. C., Beaugerie, L., Bewshea, C. M., Cole, A. T., Cummings, F. R., Daly, M. J., Ellul, P., Fedorak, R. N., Festen, E. A. M., Florin, T. H., Gaya, D. R., ... Ahmad, T. (2019). Association of Genetic Variants in NUDT15 with Thiopurine-Induced Myelosuppression in Patients with Inflammatory Bowel Disease. JAMA - Journal of the American Medical Association, 321(8), 773-785. https://doi.org/10.1001/jama.2019.0709

@article{c63d704dd9ff46e1849bd16a1e38294f,

title = "Association of Genetic Variants in NUDT15 with Thiopurine-Induced Myelosuppression in Patients with Inflammatory Bowel Disease",

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. ",

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",

author = "Walker, {Gareth J.} and Harrison, {James W.} and Heap, {Graham A.} and Voskuil, {Michiel D.} and Vibeke Andersen and Anderson, {Carl A.} and Ananthakrishnan, {Ashwin N.} and Barrett, {Jeffrey C.} and Laurent Beaugerie and Bewshea, {Claire M.} and Cole, {Andy T.} and Cummings, {Fraser R.} and Daly, {Mark J.} and Pierre Ellul and Fedorak, {Richard N.} and Festen, {Eleonora A. M.} and Florin, {Timothy H.} and Gaya, {Daniel R.} and Jonas Halfvarson and Hart, {Ailsa L.} and Heerasing, {Neel M.} and Peter Hendy and Irving, {Peter M.} and Jones, {Samuel E.} and Jukka Koskela and Lindsay, {James O.} and Mansfield, {John C.} and Dermot McGovern and Miles Parkes and Pollok, {Richard C. G.} and Subramaniam Ramakrishnan and Rampton, {David S.} and Rivas, {Manuel A.} and Russell, {Richard K.} and Michael Schultz and Shaji Sebastian and Philippe Seksik and Abhey Singh and Kenji So and Harry Sokol and Kavitha Subramaniam and Anthony Todd and Vito Annese and Weersma, {Rinse K.} and Ramnik Xavier and Rebecca Ward and Weedon, {Michael N.} and Goodhand, {James R.} and Kennedy, {Nicholas A.} and Tariq Ahmad and Craig Mowat",

year = "2019",

month = feb,

day = "26",

doi = "10.1001/jama.2019.0709",

language = "English",

volume = "321",

pages = "773--785",

journal = "JAMA - Journal of the American Medical Association",

issn = "0098-7484",

publisher = "American Medical Association",

number = "8",

}

Walker, GJ, Harrison, JW, Heap, GA, Voskuil, MD, Andersen, V, Anderson, CA, Ananthakrishnan, AN, Barrett, JC, Beaugerie, L, Bewshea, CM, Cole, AT, Cummings, FR, Daly, MJ, Ellul, P, Fedorak, RN, Festen, EAM, Florin, TH, Gaya, DR, Halfvarson, J, Hart, AL, Heerasing, NM, Hendy, P, Irving, PM, Jones, SE, Koskela, J, Lindsay, JO, Mansfield, JC, McGovern, D, Parkes, M, Pollok, RCG, Ramakrishnan, S, Rampton, DS, Rivas, MA, Russell, RK, Schultz, M, Sebastian, S, Seksik, P, Singh, A, So, K, Sokol, H, Subramaniam, K, Todd, A, Annese, V, Weersma, RK, Xavier, R, Ward, R, Weedon, MN, Goodhand, JR & Kennedy, NA & Ahmad, T 2019, 'Association of Genetic Variants in NUDT15 with Thiopurine-Induced Myelosuppression in Patients with Inflammatory Bowel Disease', JAMA - Journal of the American Medical Association, vol. 321, no. 8, pp. 773-785. https://doi.org/10.1001/jama.2019.0709

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 - Mowat, Craig

PY - 2019/2/26

Y1 - 2019/2/26

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 × 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.

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 × 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.

KW - Adolescent

KW - Adult

KW - Case-Control Studies

KW - Colitis, Ulcerative/drug therapy

KW - Crohn Disease/drug therapy

KW - European Continental Ancestry Group

KW - Exome

KW - Female

KW - Genome-Wide Association Study

KW - Haplotypes

KW - Humans

KW - Leukocyte Count

KW - Male

KW - Methyltransferases/genetics

KW - Polymorphism, Single Nucleotide

KW - Pyrophosphatases/genetics

KW - Sequence Analysis, DNA/methods

KW - Young Adult

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 -

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

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