Estudio de las deleciones de los genes GSTM1 y GSTT1 y del polimorfismo Ile105Val del gen GSTP1 en pacientes con enfermedad ósea de Paget

Abstract

Background: Paget's disease of bone (PDB) is a disorder focussed on the bone with an increase in the number, size and activity of the osteoclasts. Some epidemiological data support the theory of its relationship with toxic or infectious environmental agents, whose interaction with some predisposing genetic alterations may lead to PDB. The glutathione S-transferases (GST) are involved in the metabolism of toxins, by catalysing the nucleophilic attack of the physiological substrate, reduced glutathione or GSH (g-Glu-Cys-Gly) on the electrophilic centre of a great number of toxic structures. We studied whether the variability of the GSTM1, GSTP1 and GSTT1 genes is related to the risk of developing PDB. Patients and methods: We analysed 148 patients diagnosed with PDB, and 207 control individuals matched in sex and age with no history of bone alterations. Using genomic DNA obtained from peripheral blood the presence-absence of the GSTM1 and GSTT1 genes was studied by means of multiplex PCR. The study of the Ile105Val GSTP1 gene was carried out using PCR and subsequent digestion with the restriction enzyme BsmAI. The distribution of genotypes was analysed by means of the Pearson chi-square test. When statistically significant differences were found we carried out a multivariate logistical regression to determine the risk which the presence of a particular genotype could generate. We used the CSPSS 21.0 program. Differences were considered to be statistically significant when the value of p<0.05. Results: We found differences in the distribution of the presence-absence of the deletion in the GSTM1 gene; not being a carrier for the deletion or being a heterozygous carrier in the GSTM1 gene confers a lower risk of developing PDB (OR=0.56, 95% CI: 0.36-0.87; p=0.011). In the study of the GSTT1 and GSTP1 genes there were no significant differences. Conclusion: The detoxifying activity diminishes when two copies of the GSTM1 gene with deletions are inherited by reducing in enzyme activity, which has been associated with a greater susceptibility to some cancers, alcoholic hepatopathy and other inflammatory problems. We are not aware of any description of its association with PDB. PDB is observed more frequently in carriers of the homozygous deletion in the GSTM1 gene. This fact could explain the epidemiological findings which link PDB to exposure to certain environmental agents.

Frequency of CYP1A1*2A polymorphisms and deletion of the GSMT1 gene in a Peruvian mestizo population

“…The GSTM1 gene is located on the short arm of chromosome 1 in region 13.3 (1p13.3), and has four polymor-phisms, called GSTM1*A, GSTM1*B, both due to changes in a single nitrogen base; GSTM1*1 × 2 which is a duplication and the GSTM1*0 generated by a deletion (Heredia et al 2017). These genes encode different glutathione S-transferase (GST) isoenzymes classified into seven families (GST alpha, kappa, mu, pi, sigma, theta and zeta) that differ from each other due to their sequencing and functional activity (Strange et al 2001;Usategui-Martín et al 2014). GSTM1 (GST mu), GSTP1 (GST pi) and GSTT1 (GST theta) are the most frequent, which are expressed in the gastrointestinal tract (Board and Menon 2013;Usategui-Martín et al 2014;Rosero et al 2016;García-Martínez et al 2017).…”

“…These genes encode different glutathione S-transferase (GST) isoenzymes classified into seven families (GST alpha, kappa, mu, pi, sigma, theta and zeta) that differ from each other due to their sequencing and functional activity (Strange et al 2001;Usategui-Martín et al 2014). GSTM1 (GST mu), GSTP1 (GST pi) and GSTT1 (GST theta) are the most frequent, which are expressed in the gastrointestinal tract (Board and Menon 2013;Usategui-Martín et al 2014;Rosero et al 2016;García-Martínez et al 2017). GSTM1mu is encoded by five genes that constitute the isoforms GSTM1, GSTM2, GSTM3, GSTM4, and GSTM5 (Xu 1998).…”

“…The GSTM1*0 variant is the product of a homozygous deletion, due to an unequal recombination between two highly conserved regions of 4.2 kb that are located at the 5' and 3' ends of the gene respectively, generating a null allele that expresses an enzyme without activity (Board and Menon 2013;Rosero et al 2016;Heredia et al 2017), which leads to genomic instability that predisposes to various types of cancer (Heredia et al 2017;Satinder et al 2017). Figure 1 outlines the action of the CYP1A1 enzyme (expressed by the CYP1A1 gene) on benzopyrene (Route A), which converts it into a bioactive metabolite (7,8-dihydroxy-9,10-oxy-benzopyrene) that binds to the guanine of DNA generating the benzopyrene guanine adduct that induces mutagenic and carcinogenic processes (Lee et al 2006;Acevedo et al 2014;Wongpratate et al 2020); at the same time, the mechanism of conjugation of 4,5-benzopyrene epoxide (Route B) and 7,8,9,10-tetrahydroxy-7,8,9,10-tetrahydro benzopyrene (Route C) is represented by action of reduced glutathione (GSH g-Glu-Cys-Gly) which is expressed by GSTM1; additionally, GSH conjugates different reactive oxygen species (ROS), protecting cells from cytotoxic effects and oxidative stress (Board and Menon 2013;Usategui-Martín et al 2014;García-Martínez et al 2017).…”

Enfermedad ósea de Paget

“…On the other hand, recent experimental data suggest that one or a number of environmental factors may be required to induce the complete pagetic phenotype in the presence of the SQSMT1 mutation. Since environmental factors, some of them toxic, play a significant role in the development of PDB, and as the response to these factors is genetically conditioned, presented in this number is a work by Dr Usategui-Martín et al 19 , designed to determine whether the variability of some of the genes involved in the metabolism of exogenous toxins are related to the risk of developing PDB.…”