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 AndrewsPatrick C Mchugh, Murray L Barclay

Research output: Contribution to journalArticlepeer-review

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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