GSTM1/GSTT1 double-null genotype increases risk of treatment-resistant schizophrenia: A genetic association study in Brazilian patients

Abstract

BackgroundThe role of oxidative stress in schizophrenia has been demonstrated, particularly in subjects with treatment-resistant schizophrenia (TRS). In such patients, the decreased levels of antioxidants in conjunction with the increased generation of reactive oxygen species in the brain exposes the neurons to a higher risk of damage.Methods and findingsWe evaluated the association of deletion polymorphisms of two genes of the antioxidant Glutathione S-Transferase family, GSTT1 and GSTM1, with susceptibility to TRS. A total of 54 TRS patients (mean age 38.7 years) and 78 healthy control subjects (mean age 39.0 years) were enrolled in this study. The subjects were matched by sex, age, and smoking and alcohol consumption habits. In the case group, the frequencies of GSTT1-null and GSTM1-null genotypes were 24.1 and 51.9%, respectively, whereas for the control group, the frequencies were 12.8 and 46.2%, respectively. Analysis performed with respect to the risk of developing TRS associated with the GSTT1 and GSTM1 deletion polymorphisms, resulted in odds ratio (OR) values of 2.1 and 1.2, respectively. However, the association was not found to be significant (p = 0.1229 and p = 0.5916, respectively). The analysis performed with respect to the combined genotypes of GSTT1 and GSTM1 revealed that the double-null genotype confers a 4.6-fold increased risk of developing TRS (p = 0.0412).ConclusionThe results of the present study indicate that a combination of GST deficiencies may play a role in enhanced susceptibility to TRS, and the present genotype of one of these genes may buffer the deficiency caused by the lack (null genotype) of the other. The results suggest that combined deletion polymorphisms of GSTT1 and GSTM1 can have implications in the prediction of the clinical course of the disease.

<p>Association Between Glutathione S-Transferase (GST) Polymorphisms and Schizophrenia in a Chinese Han Population</p>

“…47 In addition, Pinheiro et al showed that the double null genotype (GSTT1-null /GSTM1-null) was significantly associated with the development of SCZ; this combined genotype resulted in a 4.6-fold increased risk of developing SCZ. 48 This result was consistent with the complex genetic theory of SCZ, highlighting the effects of several genetic interactions and suggested that the combination of GST polymorphisms may play a role in susceptibility to SCZ. 49 As Milica et al said, we can understand the relationship between GST polymorphism and SCZ from the perspective of vascular injury.…”

Research Article Genetic and biochemical biomarkers related to oxidative stress in patients with schizophrenia

“…On the other hand, in this series a lower frequency of combination GSTT1-null/GSTM1-present was found in patients compared to controls, in disagreement with two meta-analyses (Kim et al, 2015;Koga et al, 2016). It is possible that the presence of one of these genotypes could attenuate the impairment caused by the absence of the other, explaining the differences in clinical profile and response to drug treatment (Pinheiro et al, 2017), which should be investigated in further studies on gene-gene and geneenvironment interactions (Hu et al, 2016).…”

“…The prevalence of familial history of schizophrenia adds relevance to genetic factors for the disease (Pinheiro et al, 2017). In this context, the association of the GSTM1 genotype in East Asian patients with schizophrenia, but not for GSTT1 (Kim et al, 2015) is emphasized, whereas in our study the genotypes of the two polymorphisms were similar between the groups.…”

“…In this case, it should be expected worse conditions mainly in the treatment-resistant group considering the type and period of treatment with atypical antipsychotic. Other researchers have pointed out that this combination can alter antioxidant enzyme levels, increasing lipid peroxidation and consequently oxidative damage in the brain (Pinheiro et al, 2017).…”

“…Schizophrenia, a severe mental disorder, is characterized by neurological, behavioral and emotional changes. The disease affects 1% of the world population, mainly individuals under 25 years of age (Kim et al, 2015;Pinheiro et al, 2017;Shojaeimotlagh et al, 2019). Genetic, environmental and metabolic factors have been associated with this disorder (Boskovic et al, 2011;Emiliani et al, 2014;Mak et al, 2019;Shojaeimotlagh et al, 2019).…”