Dataset Information

Influence of glutathione-related genetic variants on the oxidative stress profile of Mexican patients with psychotic disorders.

ABSTRACT:

Objective

The clinical trajectories of patients with psychotic disorders have divergent outcomes, which may result in part from glutathione (GSH)-related high-risk genotypes. We aimed to determine pharmacokinetics of clozapine, GSH levels, GSH peroxidase (GPx) activity, gene variants involved in the synthesis and metabolism of GSH, and their association with psychotic disorders in Mexican patients on clozapine monotherapy and controls.

Methods

The sample included 75 patients with psychotic disorders on clozapine therapy and 40 paired healthy controls. Plasma clozapine/N-desmethylclozapine, GSH concentrations, and GPx activity were determined, along with genotyping of GCLC and GSTP1 variants and copy number variations of GSTP1, GSTT1, and GSTM1. Clinical, molecular and biochemical data were analyzed with a logistic regression model.

Results

GSH levels were significantly reduced and, conversely, GPx activity was higher in PD patients compared to controls. GCLC_GAG-7/9 genotype (OR=4.3, CI95=1.40-14.31, p=0.019) and hetero-/homozygous genotypes of GCLC_rs761142 (OR=6.09, CI95=1.93-22.59, p=0.003) were found as risk factors for psychosis. The genetic variants were not related to clozapine/N-desmethylclozapine levels or to metabolic ratio.

Conclusions

GCLC variants were associated with the oxidative stress profile of PD patients raising opportunities for intervention to improve their antioxidant defenses. Further studies with larger samples should explore this proposal.

SUBMITTER: Mayen-Lobo YG

PROVIDER: S-EPMC10154007 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Publications

Influence of glutathione-related genetic variants on the oxidative stress profile of Mexican patients with psychotic disorders.

Mayén-Lobo Yerye G YG Alcaraz-Zubeldia Mireya M Dávila-Ortiz de Montellano David J DJ Motilla-Frías Blanca A BA García-Manteca Mayumi Y MY Ortega-Vázquez Alberto A Aviña-Cervantes Carlos L CL Crail-Meléndez Edgar D ED Ríos Camilo C López-López Marisol M Monroy-Jaramillo Nancy N

Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999) 20230511 2

<h4>Objective</h4>The clinical trajectories of patients with psychotic disorders have divergent outcomes, which may result in part from glutathione (GSH)-related high-risk genotypes. We aimed to determine pharmacokinetics of clozapine, GSH levels, GSH peroxidase (GPx) activity, gene variants involved in the synthesis and metabolism of GSH, and their association with psychotic disorders in Mexican patients on clozapine monotherapy and controls.<h4>Methods</h4>The sample included 75 patients with ...[more]

PMID: 36318479

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Project description:BackgroundRecent genome-wide association studies (GWASs) investigating bipolar disorder (BD) have detected a number of susceptibility genes. These studies have also provided novel insight into shared genetic components between BD and schizophrenia (SCZ), two major psychotic disorders. To examine the replication of the risk variants for BD and the pleiotropic effect of the variants associated with BD, we conducted a genetic association study of single nucleotide polymorphisms (SNPs) that were selected based upon previous BD GWASs, which targeted psychotic disorders (BD and SCZ) in the Japanese population.MethodsForty-eight SNPs were selected based upon previous GWASs. A two-stage analysis was conducted using first-set screening (for all SNPs: BD = 1,012, SCZ = 1,032 and control = 993) and second-set replication samples (for significant SNPs in the screening analysis: BD = 821, SCZ = 1,808 and control = 2,149). We assessed allelic association between BD, SCZ, psychosis (BD+SCZ) and the SNPs selected for the analysis.ResultsEight SNPs revealed nominal association signals for all comparisons (Puncorrected<0.05). Among these SNPs, the top two SNPs (associated with psychosis: Pcorrected = 0.048 and 0.037 for rs2251219 and rs2709722, respectively) were further assessed in the second-set samples, and we replicated the signals from the initial screening analysis (associated with psychosis: Pcorrected = 0.0070 and 0.033 for rs2251219 and rs2709722, respectively). The meta-analysis between the current and previous GWAS results showed that rs2251219 in Polybromo1 (PBRM1) was significant on genome-wide association level (P = 5×10(-8)) only for BD (P = 9.4×10(-9)) and psychosis (P = 2.0×10(-10)). Although the association of rs2709722 in Sp8 transcription factor (SP8) was suggestive in the Asian population (P = 2.1×10(-7) for psychosis), this signal weakened when the samples size was increased by including data from a Caucasian population (P = 4.3×10(-3)).ConclusionsWe found 3p21.1 (including PBRM1, strong linkage disequilibrium made it difficult to pinpoint the risk genes) and SP8 as risk loci for BD, SCZ and psychosis. Further replication studies will be required for conclusive results.

Project description:Background: Phthalate exposure may increase the risk of asthma. Little is known about whether oxidative-stress related genes may alter this association. First, this motivated us to investigate whether genetic polymorphisms of the oxidative-stress related genes glutathione S-transferase Mu 1 (GSTM1), glutathione S-transferase pi 1 (GSTP1), superoxide dismutase 2 (SOD2), catalase (CAT), myeloperoxidase (MPO), and EPHX1 in children are associated with phthalate urine concentrations. Second, we addressed the question whether these genes may affect the influence of phthalates on asthma.Methods: In a case-control study composed of 126 asthmatic children and 327 controls, urine phthalate metabolites (monoethyl phthalate (MEP), monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), and mono(2-ethyl-5-hydroxyhexyl)phthalate (MEHHP) were measured by UPLC-MS/MS at age 3. Genetic variants were analyzed by TaqMan assay. Information on asthma and environmental exposures was also collected. Analyses of variance and logistic regressions were performed. Results: Urine MEHHP levels were associated with asthma (adjusted OR 1.33, 95% CI (1.11-1.60). Children with the GSTP1 (rs1695) AA and SOD2 (rs5746136) TT genotypes had higher MEHHP levels as compared to GG and CC types, respectively. Since only SOD2 TT genotype was significantly associated with asthma (adjusted OR (95% CI): 2.78 (1.54-5.02)), we estimated whether SOD2 variants modify the association of MEHHP levels and asthma. As MEHHP concentrations were dependent on GSTP1 and SOD2, but the assessment of interaction requires independent variables, we estimated MEHHP residuals and assessed their interaction, showing that the OR for SOD2 TT was further elevated to 3.32 (1.75-6.32) when the residuals of MEHHP were high. Conclusions: Urine phthalate metabolite concentrations are associated with oxidative-stress related genetic variants. Genetic variants of SOD2, considered to be reflect oxidative stress metabolisms, might modify the association of phthalate exposure with asthma.

Dataset Information

Influence of glutathione-related genetic variants on the oxidative stress profile of Mexican patients with psychotic disorders.

Objective

Methods

Results

Conclusions

Publications

Influence of glutathione-related genetic variants on the oxidative stress profile of Mexican patients with psychotic disorders.

Similar Datasets

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