Glutathione S-Transferase T1 Null Genotype is Associated with Susceptibility to Inflammatory Bowel Disease

Abstract

Background: The published literature contains conflicting results regarding the impact of the glutathione S-transferase T1 (GSTT1) null genotype on the susceptibility to inflammatory bowel disease. Therefore, we conducted a meta-analysis of observational studies to assess the association. Methods: We searched four online databases for eligible studies. The odds ratio (OR) with 95% CI was used to assess the gene-disease association. We also performed subgroup analyses by type of inflammatory bowel disease and ethnicity. Results: There were 16 individual studies from 11 publications included in the analysis. There were 3366 cases with inflammatory bowel disease and 6013 controls. The meta-analysis of all 16 studies showed the GSTT1 null genotype was associated with increased susceptibility to inflammatory bowel disease (OR = 1.98, 95%CI 1.39-2.84, P < 0.001). The subgroup analysis by ethnicity further identified an association between the GSTT1 null genotype and inflammatory bowel disease in Caucasians, Asians, and Africans. The GSTT1 null genotype was associated with both ulcerative colitis (OR = 1.96, P = 0.004) and Crohn’s disease (OR = 2.01, P = 0.022). The GSTT1 null genotype was still significantly associated with ulcerative colitis (OR = 1.63, P < 0.0001) and Crohn’s disease (OR = 1.40, P = 0.023) after adjusting for study heterogeneity. Conclusion: The GSTT1 null genotype is significantly associated with an increased susceptibility to inflammatory bowel disease and is a risk factor for both ulcerative colitis and Crohn’s disease.

Glutathione S‐transferase theta 1 protects against colitis through goblet cell differentiation via interleukin‐22

“…A surplus production of oxidative molecules can induce inflammation, injury, and death in intestinal epithelial cells (IECs) and cause mucosal barrier dysfunction . In line with these findings, impairment of intestinal glutathione (GSH) synthesis in patients with IBD has been reported . Glutathione S‐transferases (GSTs), found in microbes, plants, and animals, are a family of enzymes involved in the scavenging of oxidative free radicals such as reactive oxygen species (ROS) through conjugation with glutathione, their major cellular ROS scavenger.…”

“…3,4 In line with these findings, impairment of intestinal glutathione (GSH) synthesis in patients with IBD has been reported. 5 Glutathione S-transferases (GSTs), found in microbes, plants, and animals, are a family of enzymes involved in the scavenging of oxidative free radicals such as reactive oxygen species (ROS) through conjugation with glutathione, their major cellular ROS scavenger. These enzymes are ubiquitously expressed with especially high levels in the intestine, and they catalyze the conjugation of reduced GSH to a wide variety of substrates via the sulfhydryl group.…”

“…6 Of the members of GSTs, glutathione S-transferase theta 1 (GSTT1), and GSTM1 in particular have become a recent target of active investigation into their role in increased susceptibility to IBD, Behçet's disease (BD), or other autoimmune diseases such as primary sclerosing cholangitis when either of the two GSTTs lose their function. 2,7,8 Deletion of the GSTT1 gene, a 50 kb genomic sequence containing the entire gene located on chromosome 22q11.2, results in a GSTT1-null genotype, 5,9 fails protein synthesis, and can decrease the ability to detoxify damaging compounds. 10 The GSTT1 null genotype leads to the absence of a functional GSTT1 enzyme 9,11 and results in increased susceptibility to a number of diseases, including IBD.…”

“…10 The GSTT1 null genotype leads to the absence of a functional GSTT1 enzyme 9,11 and results in increased susceptibility to a number of diseases, including IBD. 5,[12][13][14] However, the molecular mechanisms responsible for the role of GSTT1 in IBD remain to be investigated.…”

Whole-Genome DNA Methylation Profiling of CD14+ Monocytes Reveals Disease Status and Activity Differences in Crohn’s Disease Patients

“…Similarly, PRAP1 was found to be hypermethylated and downregulated in mucosal biopsies obtained from treatment naïve UC patients relative to control patients [63]. At the level of genomics, a meta-analysis suggested that the GSTT1 null mutation was significantly associated with susceptibility to IBD [64]. Unaffected ileal samples obtained from carriers of the NOD2 CD-risk allele displayed increased gene expression of DRD4 [65], whereas Nod2 double knockout mouse macrophages displayed a higher Ms4a3 expression relative to wildtype after lipopolysaccharide…”