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P661. Case–control study and meta-analysis of glutathione S-transferase polymorphisms in patients with inflammatory bowel disease

M. Broekman, C. Bos, R.H. te Morsche, F. Hoentjen, H.M. Roelofs, W.H. Peters, G.J. Wanten, D.J. de Jong, Radboud UMC, Gastroenterology & Hepatology, Nijmegen, Netherlands

Background

Glutathione S-transferases (GSTs) are important in the detoxification of a wide variety of exogenous and endogenous compounds, including reactive oxygen species (ROS). Since ROS are involved in the aetiology of inflammatory bowel diseases (IBD), polymorphisms in GSTs might modulate the risk for Crohn's disease (CD) or ulcerative colitis (UC). In more detail, the null alleles GSTM1*0 and GSTT1*0, which cannot be detected by immunochips used in genome wide association studies, lead to a failed protein synthesis. For GSTP, the single nucleotide substitutions A>G at codon 105 and C>T at codon 114, are considered as the most important polymorphisms and lead to a reduced enzyme function. Previous studies highlighting GST polymorphisms in IBD patients showed divergent results, therefore we conducted a case–control study and a meta-analysis of GST polymorphisms in GST Mu (GSTM1), GST Pi (GSTP1) and GST Theta (GSTT1) in IBD patients.

Methods

Genomic DNA of 552 patients with CD, 223 patients with UC and 972 healthy controls from our centre was genotyped for polymorphisms in GSTM1, GSTP1 and GSTT1 using polymerase chain reaction techniques. Results of the case–control study were included in the meta-analysis. A search on Pubmed and EMBASE was conducted comprising the search terms: GST, glutathione S-transferase, IBD, Crohn's disease and ulcerative colitis. Case–control studies examining GST polymorphisms in patients with IBD compared to healthy controls were included, provided that absolute numbers of genotype distributions were given. With the most common homozygous GSTP1 genotype or homozygous + heterozygous GSTM1 or GSTT1 genotypes set as reference, data were pooled and weighed odds ratios (OR) were calculated with a random effect model using RevMan® V5.2 software.

Results

The search for the meta-analysis identified 118 articles. After screening for title and abstract 10 articles remained. Three were excluded because of Chinese language (n = 2) or overlapping data (n = 1). A total of 1613 patients with CD, 1759 patients with UC and 4098 healthy controls, including our data, was used for further analysis. Pooled analysis showed an increased susceptibility for UC with the homozygous GSTT1*0 genotype (OR 2.27, 95% CI 1.31–3.92). In contrast to GSTT1, the GSTP1 114 Ala/Val + Val/Val genotypes had lower risk for UC (OR 0.70, 95% CI 0.54–0.90). For CD, pooled analysis showed a slight protective effect for the combination of homozygous GSTM1*0 + GSTT1*0 genotype (OR 0.73, 95% CI 0.55–0.98).

Conclusion

The homozygous GSTT1*0 genotype, associated with a decreased detoxification of ROS, may increase the susceptibility for UC, whereas the GSTP1 114 genotypes associated with reduced enzyme activity, may result in a lower risk for UC.