The GSTP1 gene variant rs1695 is not associated with an increased risk of multiple sclerosis

Abstract

We analyzed the allelic and genotypic frequencies of the glutathione-S-transferase P1 (GSTP1) rs1695 single nucleotide polymorphism (SNP) in 290 patients with multiple sclerosis (MS) and in 310 healthy controls. We found no significant association between the rs1695 variant and MS. Among MS patients, there was no relationship between the rs1695 variant and either gender, clinical type of MS or the age of onset of MS. These results suggest that the GSTP1 rs1695 polymorphism is not a risk factor for MS.Genome-wide association studies in samples from MS patients have identified more than 100 loci with genome-wide significance, but most of these loci had a modest odds ratio (OR) in the range of 1.1-1.3; only HLA (especially the HLA-DRB1*15:01 haplotype) had a strong association with MS risk. Glutathione S-transferases (GSTs) are a superfamily of dimeric phase 2 metabolic enzymes that catalyze the conjugation of reduced glutathione with electrophilic groups of carcinogens, herbicides/pesticides, and other compounds. GSTP1 also plays a role in inflammatory processes (http://www.ncbi.nlm.nih.gov/ pubmed/23596995). In humans, the GSTs are divided into a number of major classes that have distinct substrate specificities and tissue distributions. Polymorphisms in the GSTM1, GSTP1 and GSTT1 genes are known to alter gene function. The rs1695 variant of the GSTP1 gene (chromosome 11q13; Gene identity 2950, MIM 134660; http://www.ncbi.nlm.nih.gov/gene/2950) causes an amino-acid substitution and reduces the catalytic activity of the enzyme (http://www.ncbi.nlm.nih.gov/pubmed/ 9600848, http://www.ncbi.nlm.nih.gov/pubmed/16488119 and http://www.ncbi.nlm.nih.gov/pubmed/22401947). The rs1695 variant is the only non-synonymous polymorphism of the GSTP1 gene with a significant allele frequency in human populations and minor allele frequencies ranging from 17% to 44% (http://browser.1000genomes.org/Homo_sapiens/Variation/ Population?db5core;r511:67352189-67353189;v5rs1695;vdb 5variation;vf521985). The frequency of the GSTP1 rs1695 variant is nearly 35% in the Spanish population. 2Although GSTP1 polymorphisms were not identified as possible susceptibility genes by genome-wide association studies, we explored a possible relationship between GSTP1 polymorphisms and allelic gene variants and the risk of MS due to the possible role of oxidative stress and lipid peroxidation in the pathogenesis of MS 1 and the upregulation of GSTP1 gene expression found in active demyelinating MS lesions.3 Although two preliminary studies did not find a relationship between polymorphisms in either GSTM1 4,5 or GSTT1 5 and the risk for MS, another recent study showed an association between GSTT1 deletion and MS susceptibility 6 . Another study reported a relationship between GSTM1, GSTM3 and GSTP1, but not GSTT1, and the degree of disability in MS. Alexoudi et al.8 reported a similar distribution of GSTP1 genotypes in MS patients and controls but a higher frequency

No association of GSTP1 rs1695 polymorphism with amyotrophic lateral sclerosis: A case-control study in the Brazilian population

“…However, we observed that the A/G and G/G genotypes were not related to an early age of the disease ( Table 5 ). Agúndez and collaborators [ 16 ] also showed that the age of onset of Multiple Sclerosis was not statistically different between patients with rs1695 variant, which in turn is similar to our findings.…”

“…Glutathione S-Transferase Pi 1 (GSTP1) isoenzyme is most often produced in the brain where it might alter the effectiveness of neurotoxins and products of oxidative stress contributing to detoxification and cell protection [ 15 ]. Hence, the presence of GSTP1 rs1695 polymorphism may contribute to the development of neurodegenerative diseases through excessive oxidative stress associated with pathogenic mechanisms that could promote the death of the motor neurons [ 12 , 13 , 15 , 16 ].…”

“…GSTP1 rs1695 variant (chromosome 11q13; gene identity 2950, MIM 134660; https://www.ncbi.nlm.nih.gov/gene/2950 ) [ 16 ] consists of an adenine to guanine transition at position 313 (codon 105), which promotes substitution of amino acid isoleucine (Ile) for valine (Val), resulting in a lower activity of the Pi isoenzyme. Thus, carriers of the G/G genotype have a lower Pi isoenzyme activity than carriers of the A/A genotype, while heterozygotes individuals (A/G) have an intermediate activity [ 15 , 17 ].…”

Glutathione Transferase P1-1 an Enzyme Useful in Biomedicine and as Biomarker in Clinical Practice and in Environmental Pollution

“…The other studies reported in the literature focused on GSTP1 polymorphisms (see Section 3.6 and Table 1) in pathologies like systemic lupus erythematosus [86], or are meta-analysis suggesting that the GSTP1 polymorphisms are not associated with the risk of rheumatoid arthritis [87]. Another study confirmed the lack of association between GSTP1 polymorphisms and multiple sclerosis [88]. However, further studies are required for a better comprehension of the environmental factors implicated and the roles played by GSTP1 polymorphisms in the pathogenesis of autoimmune diseases.…”

Heme Oxygenase-1 and 2 Common Genetic Variants and Risk for Multiple Sclerosis

“…The study, which was conducted in accordance with the principles of the Helsinki declaration of 1975, was approved by the Ethics Committees of Clinical Investigation of the University Hospital “Príncipe de Asturias” (University of Alcalá, Alcalá de Henares, Madrid, Spain), the Infanta Cristina University Hospital (Badajoz, Spain), and Clínica Universitaria de Navarra (Pamplona, Spain). Most of the patients recruited had participated in other previous studies of genetic association with MS risk 1 24 25 26 27 28 29 30 .…”