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

Author information

1
Department of Surgical Sciences (Dunedin), University of Otago, Otago, New Zealand.
2
Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, the Netherlands.
3
Department of Internal Medicine, Gastroenterology and Geriatrics, Atrium-ORBIS Medical Center, Heerlen-Sittard, the Netherlands.
4
QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
5
Centre for Inflammatory Bowel Disease, Saint John of God Hospital, Subiaco, WA, Australia.
6
Harry Perkins Institute of Medical Research, School of Medicine and Pharmacology, University of Western Australia, Murdoch, WA, Australia.
7
Flinders Medical Centre, Flinders University of South Australia, Bedford Park, South Australia, Australia.
8
Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
9
Department of Gastroenterology, St Vincent's Hospital, Melbourne, Victoria, Australia.
10
Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand.
11
Centre for Biomarker Research, School of Applied Sciences, University of Huddersfield, Huddersfield, UK.
12
Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand.
13
Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.

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.

PMID:
29788244
DOI:
10.1093/ibd/izy163
[Indexed for MEDLINE]

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