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

Inflamm Bowel Dis. 2018 Nov 29;24(12):2606-2612. doi: 10.1093/ibd/izy163.


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.

MeSH terms

  • Adult
  • Azathioprine / therapeutic use*
  • Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor / genetics*
  • Cohort Studies
  • Female
  • Guanine Nucleotides / blood
  • Humans
  • Inflammatory Bowel Diseases / blood
  • Inflammatory Bowel Diseases / drug therapy
  • Inflammatory Bowel Diseases / enzymology*
  • Male
  • Mercaptopurine / analogs & derivatives
  • Mercaptopurine / blood
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Thionucleotides / blood
  • Young Adult


  • Guanine Nucleotides
  • Thionucleotides
  • 6-thioguanylic acid
  • 6-methylthiopurine
  • Mercaptopurine
  • Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor
  • Azathioprine