Nonsynonymous Polymorphism in Guanine Monophosphate Synthetase Is a Risk Factor for Unfavorable Thiopurine Metabolite Ratios in Patients With Inflammatory Bowel Disease.
Inflamm Bowel Dis
; 24(12): 2606-2612, 2018 11 29.
Article
in En
| MEDLINE
| ID: mdl-29788244
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-MMP6-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-MMP6-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-MMP6-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-MMP6-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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Azathioprine
/
Inflammatory Bowel Diseases
/
Carbon-Nitrogen Ligases with Glutamine as Amide-N-Donor
Type of study:
Etiology_studies
/
Incidence_studies
/
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limits:
Adult
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Inflamm Bowel Dis
Year:
2018
Document type:
Article