Nonsynonymous Polymorphism in Guanine Monophosphate Synthetase Is a Risk Factor for Unfavorable Thiopurine Metabolite Ratios in Patients With Inflammatory Bowel Disease

Rebecca L Roberts, Mary C Wallace, Margien L Seinen, Adriaan A Van Bodegraven, Krupa Krishnaprasad, Gregory T Jones, Andre M Van Rij, Angela Baird, Ian C Lawrance, Ruth Prosser, Peter Bampton, Rachel Grafton, Lisa A Simms, Corrie Studd, Sally J Bell, Martin A Kennedy, Jacob Halliwell, Richard B Gearry, Graham Radford-smith, Jane M Andrews & 2 others Patrick C Mchugh, Murray L Barclay

Research output: Contribution to journalArticle

Abstract

Background: Up to 20% of patients with inflammatory bowel disease (IBD) who are refractory to thiopurine therapy preferentially produce 6-methylmercaptopurine (6-MMP) at the expense of 6-thioguanine nucleotides (6-TGN), resulting in a high 6-MMP:6-TGN ratio (>20). The objective of this study was to evaluate whether genetic variability in guanine monophosphate synthetase (GMPS) contributes to preferential 6-MMP metabolizer phenotype. Methods: Exome sequencing was performed in a cohort of IBD patients with 6-MMP:6-TGN ratios of >100 to identify nonsynonymous single nucleotide polymorphisms (nsSNPs). In vitro assays were performed to measure GMPS activity associated with these nsSNPs. Frequency of the nsSNPs was measured in a cohort of 530 Caucasian IBD patients. Results: Two nsSNPs in GMPS (rs747629729, rs61750370) were detected in 11 patients with very high 6-MMP:6-TGN ratios. The 2 nsSNPs were predicted to be damaging by in silico analysis. In vitro assays demonstrated that both nsSNPs resulted in a significant reduction in GMPS activity (P < 0.05). The SNP rs61750370 was significantly associated with 6-MMP:6-TGN ratios ≥100 (odds ratio, 5.64; 95% confidence interval, 1.01-25.12; P < 0.031) in a subset of 264 Caucasian IBD patients. Conclusions: The GMPS SNP rs61750370 may be a reliable risk factor for extreme 6MMP preferential metabolism.

Original languageEnglish
Pages (from-to)2606-2612
Number of pages7
JournalInflammatory Bowel Diseases
Volume24
Issue number12
Early online date16 May 2018
DOIs
Publication statusPublished - Dec 2018

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Guanine
Ligases
Inflammatory Bowel Diseases
Single Nucleotide Polymorphism
Exome
Computer Simulation
6-methylthiopurine
Odds Ratio
6-thioguanylic acid
Confidence Intervals
Phenotype

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Roberts, R. L., Wallace, M. C., Seinen, M. L., Van Bodegraven, A. A., Krishnaprasad, K., Jones, G. T., ... Barclay, M. L. (2018). Nonsynonymous Polymorphism in Guanine Monophosphate Synthetase Is a Risk Factor for Unfavorable Thiopurine Metabolite Ratios in Patients With Inflammatory Bowel Disease. Inflammatory Bowel Diseases, 24(12), 2606-2612. https://doi.org/10.1093/ibd/izy163
Roberts, Rebecca L ; Wallace, Mary C ; Seinen, Margien L ; Van Bodegraven, Adriaan A ; Krishnaprasad, Krupa ; Jones, Gregory T ; Van Rij, Andre M ; Baird, Angela ; Lawrance, Ian C ; Prosser, Ruth ; Bampton, Peter ; Grafton, Rachel ; Simms, Lisa A ; Studd, Corrie ; Bell, Sally J ; Kennedy, Martin A ; Halliwell, Jacob ; Gearry, Richard B ; Radford-smith, Graham ; Andrews, Jane M ; Mchugh, Patrick C ; Barclay, Murray L. / Nonsynonymous Polymorphism in Guanine Monophosphate Synthetase Is a Risk Factor for Unfavorable Thiopurine Metabolite Ratios in Patients With Inflammatory Bowel Disease. In: Inflammatory Bowel Diseases. 2018 ; Vol. 24, No. 12. pp. 2606-2612.
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title = "Nonsynonymous Polymorphism in Guanine Monophosphate Synthetase Is a Risk Factor for Unfavorable Thiopurine Metabolite Ratios in Patients With Inflammatory Bowel Disease",
abstract = "Background: Up to 20{\%} of patients with inflammatory bowel disease (IBD) who are refractory to thiopurine therapy preferentially produce 6-methylmercaptopurine (6-MMP) at the expense of 6-thioguanine nucleotides (6-TGN), resulting in a high 6-MMP:6-TGN ratio (>20). The objective of this study was to evaluate whether genetic variability in guanine monophosphate synthetase (GMPS) contributes to preferential 6-MMP metabolizer phenotype. Methods: Exome sequencing was performed in a cohort of IBD patients with 6-MMP:6-TGN ratios of >100 to identify nonsynonymous single nucleotide polymorphisms (nsSNPs). In vitro assays were performed to measure GMPS activity associated with these nsSNPs. Frequency of the nsSNPs was measured in a cohort of 530 Caucasian IBD patients. Results: Two nsSNPs in GMPS (rs747629729, rs61750370) were detected in 11 patients with very high 6-MMP:6-TGN ratios. The 2 nsSNPs were predicted to be damaging by in silico analysis. In vitro assays demonstrated that both nsSNPs resulted in a significant reduction in GMPS activity (P < 0.05). The SNP rs61750370 was significantly associated with 6-MMP:6-TGN ratios ≥100 (odds ratio, 5.64; 95{\%} confidence interval, 1.01-25.12; P < 0.031) in a subset of 264 Caucasian IBD patients. Conclusions: The GMPS SNP rs61750370 may be a reliable risk factor for extreme 6MMP preferential metabolism.",
keywords = "azathioprine, 6-mercaptopurine, 6-thioguanine nucleotides (6-TGN ), 6-methylmercaptopurine (6-MMP), guanosine monophosphate synthetase (GMPS)",
author = "Roberts, {Rebecca L} and Wallace, {Mary C} and Seinen, {Margien L} and {Van Bodegraven}, {Adriaan A} and Krupa Krishnaprasad and Jones, {Gregory T} and {Van Rij}, {Andre M} and Angela Baird and Lawrance, {Ian C} and Ruth Prosser and Peter Bampton and Rachel Grafton and Simms, {Lisa A} and Corrie Studd and Bell, {Sally J} and Kennedy, {Martin A} and Jacob Halliwell and Gearry, {Richard B} and Graham Radford-smith and Andrews, {Jane M} and Mchugh, {Patrick C} and Barclay, {Murray L}",
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pages = "2606--2612",
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Roberts, RL, Wallace, MC, Seinen, ML, Van Bodegraven, AA, Krishnaprasad, K, Jones, GT, Van Rij, AM, Baird, A, Lawrance, IC, Prosser, R, Bampton, P, Grafton, R, Simms, LA, Studd, C, Bell, SJ, Kennedy, MA, Halliwell, J, Gearry, RB, Radford-smith, G, Andrews, JM, Mchugh, PC & Barclay, ML 2018, 'Nonsynonymous Polymorphism in Guanine Monophosphate Synthetase Is a Risk Factor for Unfavorable Thiopurine Metabolite Ratios in Patients With Inflammatory Bowel Disease', Inflammatory Bowel Diseases, vol. 24, no. 12, pp. 2606-2612. https://doi.org/10.1093/ibd/izy163

Nonsynonymous Polymorphism in Guanine Monophosphate Synthetase Is a Risk Factor for Unfavorable Thiopurine Metabolite Ratios in Patients With Inflammatory Bowel Disease. / Roberts, Rebecca L; Wallace, Mary C; Seinen, Margien L; Van Bodegraven, Adriaan A; Krishnaprasad, Krupa; Jones, Gregory T; Van Rij, Andre M; Baird, Angela; Lawrance, Ian C; Prosser, Ruth; Bampton, Peter; Grafton, Rachel; Simms, Lisa A; Studd, Corrie; Bell, Sally J; Kennedy, Martin A; Halliwell, Jacob; Gearry, Richard B; Radford-smith, Graham; Andrews, Jane M; Mchugh, Patrick C; Barclay, Murray L.

In: Inflammatory Bowel Diseases, Vol. 24, No. 12, 12.2018, p. 2606-2612.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Nonsynonymous Polymorphism in Guanine Monophosphate Synthetase Is a Risk Factor for Unfavorable Thiopurine Metabolite Ratios in Patients With Inflammatory Bowel Disease

AU - Roberts, Rebecca L

AU - Wallace, Mary C

AU - Seinen, Margien L

AU - Van Bodegraven, Adriaan A

AU - Krishnaprasad, Krupa

AU - Jones, Gregory T

AU - Van Rij, Andre M

AU - Baird, Angela

AU - Lawrance, Ian C

AU - Prosser, Ruth

AU - Bampton, Peter

AU - Grafton, Rachel

AU - Simms, Lisa A

AU - Studd, Corrie

AU - Bell, Sally J

AU - Kennedy, Martin A

AU - Halliwell, Jacob

AU - Gearry, Richard B

AU - Radford-smith, Graham

AU - Andrews, Jane M

AU - Mchugh, Patrick C

AU - Barclay, Murray L

PY - 2018/12

Y1 - 2018/12

N2 - Background: Up to 20% of patients with inflammatory bowel disease (IBD) who are refractory to thiopurine therapy preferentially produce 6-methylmercaptopurine (6-MMP) at the expense of 6-thioguanine nucleotides (6-TGN), resulting in a high 6-MMP:6-TGN ratio (>20). The objective of this study was to evaluate whether genetic variability in guanine monophosphate synthetase (GMPS) contributes to preferential 6-MMP metabolizer phenotype. Methods: Exome sequencing was performed in a cohort of IBD patients with 6-MMP:6-TGN ratios of >100 to identify nonsynonymous single nucleotide polymorphisms (nsSNPs). In vitro assays were performed to measure GMPS activity associated with these nsSNPs. Frequency of the nsSNPs was measured in a cohort of 530 Caucasian IBD patients. Results: Two nsSNPs in GMPS (rs747629729, rs61750370) were detected in 11 patients with very high 6-MMP:6-TGN ratios. The 2 nsSNPs were predicted to be damaging by in silico analysis. In vitro assays demonstrated that both nsSNPs resulted in a significant reduction in GMPS activity (P < 0.05). The SNP rs61750370 was significantly associated with 6-MMP:6-TGN ratios ≥100 (odds ratio, 5.64; 95% confidence interval, 1.01-25.12; P < 0.031) in a subset of 264 Caucasian IBD patients. Conclusions: The GMPS SNP rs61750370 may be a reliable risk factor for extreme 6MMP preferential metabolism.

AB - Background: Up to 20% of patients with inflammatory bowel disease (IBD) who are refractory to thiopurine therapy preferentially produce 6-methylmercaptopurine (6-MMP) at the expense of 6-thioguanine nucleotides (6-TGN), resulting in a high 6-MMP:6-TGN ratio (>20). The objective of this study was to evaluate whether genetic variability in guanine monophosphate synthetase (GMPS) contributes to preferential 6-MMP metabolizer phenotype. Methods: Exome sequencing was performed in a cohort of IBD patients with 6-MMP:6-TGN ratios of >100 to identify nonsynonymous single nucleotide polymorphisms (nsSNPs). In vitro assays were performed to measure GMPS activity associated with these nsSNPs. Frequency of the nsSNPs was measured in a cohort of 530 Caucasian IBD patients. Results: Two nsSNPs in GMPS (rs747629729, rs61750370) were detected in 11 patients with very high 6-MMP:6-TGN ratios. The 2 nsSNPs were predicted to be damaging by in silico analysis. In vitro assays demonstrated that both nsSNPs resulted in a significant reduction in GMPS activity (P < 0.05). The SNP rs61750370 was significantly associated with 6-MMP:6-TGN ratios ≥100 (odds ratio, 5.64; 95% confidence interval, 1.01-25.12; P < 0.031) in a subset of 264 Caucasian IBD patients. Conclusions: The GMPS SNP rs61750370 may be a reliable risk factor for extreme 6MMP preferential metabolism.

KW - azathioprine

KW - 6-mercaptopurine

KW - 6-thioguanine nucleotides (6-TGN )

KW - 6-methylmercaptopurine (6-MMP)

KW - guanosine monophosphate synthetase (GMPS)

UR - http://www.scopus.com/inward/record.url?scp=85057549588&partnerID=8YFLogxK

U2 - 10.1093/ibd/izy163

DO - 10.1093/ibd/izy163

M3 - Article

VL - 24

SP - 2606

EP - 2612

JO - Inflammatory Bowel Diseases

JF - Inflammatory Bowel Diseases

SN - 1078-0998

IS - 12

ER -