GSTM1andGSTM5Genetic Polymorphisms and Expression in Age-Related Macular Degeneration

Abstract

Purpose Previously, two cytosolic antioxidant enzymes, Glutathione S-transferase Mu 1 (GSTM1) and Mu 5 (GSTM5), were reduced in retinas with Age-related Macular Degeneration (AMD). This study compared genomic copy number variations (gCNV) of these two antioxidant enzymes in AMD vs. controls. Methods Genomic copy number (gCN) assays were performed using Taqman Gene Copy Number Assays (Applied Biosystems) in technical quadruplicate for both GSTM1 and GSTM5. Peripheral leukocyte RNA levels were compared to controls in technical triplicates. Statistical comparisons were performed in SAS v9.2 (SAS Institute Inc. Cary, NC). Results A large percentage of patients in both AMD and age-matched control groups had no copies of GSTM1 (0/0). The mean gCN of GSTM1 was 1.40 (range 0 – 4) and 1.61 (range 0 – 5) for AMD and control, respectively (p = 0.29). A greater percentage of control patients had > 3 gCNs of GSTM1 compared to AMD, respectively (15.3% vs. 3.0%, p = 0.004). The gCN of GSTM5 was 2 in all samples except one control sample. The relative quantification of GSTM1 and GSTM5 mRNA from peripheral blood leukocytes in patients showed significant differences in relative expression in AMD vs. control (p < 0.05). Peripheral blood leukocyte mRNA and gCN were not significantly correlated (p = 0.27). Conclusion Since high copy numbers of GSTM1 are found more frequently in controls than in AMD, it is possible that high copy number leads to increased retinal antioxidant defense. Genomic polymorphisms of GSTM1 and GSTM5 do not significantly affect the peripheral blood leukocyte mRNA levels.

Sexually Dimorphic Effects of Early-Life Exposures to Endocrine Disruptors: Sex-Specific Epigenetic Reprogramming as a Potential Mechanism

“…The most striking effect of prenatal Pb exposure was the significant lower levels of 5hmc in the conserved genes GSTM1 (13%) and GSTM5 (21%). These genes are highly involved in the detoxification of electrophilic compounds like carcinogens, therapeutic drugs and environmental toxicants [62]. Also of interest, the gene ontology of the genes implicated in the DMRs of 5mc in males fell mainly into the functional categories of telencephalon development and glial cell differentiation, while females fell mostly into the regulation of cellular division.…”

Evaluation of associations of GSTM1/GSTT1 null genotypes with the susceptibility to age-related macular degeneration: A meta-analysis

“…The application of the above-mentioned criteria yielded five reports. [13][14][15][16][17] Study of Hunter et al 17 had been reported two case-control groups, therefore, considered as two studies. The following data were extracted: author's name, publication year, country, ethnicity of the participants and the frequencies of the genotypes for each polymorphism in ARMD patients and control subjects.…”

“…Considering that the null genotypes of GSTT1 and GSTM1 were associated with several multifactorial human complex diseases. [5][6][7][8][9][10][11][12] There were studies investigated the relationship between these polymorphisms and the risk of ARMD, [13][14][15][16][17] the results were inconsistent. Considering that association studies usually were done on a relatively small samples size, in order to increase the sample size and aid the generalisation of the results to larger populations, the present meta-analysis was carried out.…”

“…[10][11][12] The relationship between the GSTM1/GSTT1 null genotypes (homozygotes for the null alleles) and the risk of ARMD have been reported and revealed inconsistent results. [13][14][15][16][17] To evaluate the relation-Relevant published articles (before December 2020) were found by searching several databases, including PubMed, Scopus, Index Copernicus, DOAJ, Academic Journals Databases, SID, Ko-reaMed, and Google scholar. The following search terms were used: GSTT1, GSTM1, null genotype, age-related macular degeneration.…”

Dietary and Lifestyle Factors Modulate the Activity of the Endogenous Antioxidant System in Patients with Age-Related Macular Degeneration: Correlations with Disease Severity

“…In our study, we did not observe a significant association between R-GSSG activity and GSH concentration in any of the tested groups; thus, the increase in R-GSSG activity in patients with AMD might be an analogous indicator of increased antioxidant activity, similarly to GPx or increased GSH transferase activity. Interestingly, conflicting results on the involvement of GSTM1 and GSTM5 (glutathione s-transferase mu 1/5) polymorphisms and gene expression in AMD pathology exist [ 51 , 52 ], once again suggesting that the necessary balance of the antioxidant system is achieved through the proper activity of several enzymes, and not a single enzyme. The tight cooperation of endogenous antioxidants is reflected in SOD activity, which functions together with GPx and CAT to convert H 2 O 2 to nontoxic products and by that protect the photoreceptors and RPE from oxidative damage [ 31 , 49 ].…”