Variation of genes encoding nitric oxide synthases and antioxidant enzymes as potential risks of multiple sclerosis development: a preliminary study

Abstract

Multiple sclerosis (MS) is a neurodegenerative disease characterized by a variable clinical course and diverse pathophysiology, including nitrative and oxidative stresses as well as inflammation. We aimed to detect the potential association between five selected single-nucleotide polymorphisms (SNPs) in genes encoding nitric oxide synthetases as well as antioxidant enzymes and the development of MS in a Polish population. Genomic DNA was isolated from peripheral blood collected from 142 MS patients and 140 controls. Using Taq-Man® probes, we genotyped the following SNPs: rs1879417 in NOS1, and rs2297518 in NOS2 as well as rs4880 in SOD2, rs7943316 in CAT, rs713041 in GPX4. In the case of rs2297518, the C/C genotype and C allele SNP were associated with an enhanced occurrence of MS, while the C/T, T/T genotypes, and T allele of the same polymorphism reduced this risk. Moreover, the C/C homozygote and C allele of the rs4880 SNP reduced MS risk, while the T allele increased the risk. In addition, the A/T heterozygote of rs7943316 polymorphism was associated with an increased risk of MS occurrence. We also detected that the C/C genotype and C allele of rs713041 decreased the risk of MS, whereas the T/T genotype and T allele increased this risk. In conclusion, the results of our study suggest some links between polymorphic variability in the nitrative/oxidative stress-related genes and the risk of MS development in the Polish population.

The Role of rs713041 Glutathione Peroxidase 4 (GPX4) Single Nucleotide Polymorphism on Disease Susceptibility in Humans: A Systematic Review and Meta-Analysis

“…The selected studies reported data related to GPX4 (rs713041) SNP linked to nineteen diseases; these included breast cancer [ 16 , 17 ], colorectal cancer [ 35 , 36 ], prostate cancer [ 20 , 37 ], laryngeal cancer [ 19 ], lung cancer [ 19 ], pre-eclampsia [ 38 , 39 ], hypertension [ 40 ], ischemic stroke [ 41 ], endometriosis [ 22 ], recurrent miscarriage [ 42 ], pregnancy loss [ 43 ], Graves’ disease [ 23 ], Hashimoto disease [ 23 ], acute pancreatitis [ 44 ], Alzheimer’s disease [ 24 ], depression [ 25 ], multiple sclerosis [ 26 ], type 2 diabetes mellitus [ 45 ] and Kashin-Beck disease [ 46 ]. Regarding demographics, from the twenty-one reports, one study was performed on Arabs [ 45 ], two reports on Russians [ 42 , 43 ], one report on Caucasian Americans [ 36 ], one report on South Americans [ 24 ], five reports on Asians, Han Chinese population [ 22 , 23 , 38 , 39 , 46 ], and the other eleven reports on Europeans [ 16 , 17 , 19 , 20 , 25 , 26 , 35 , 37 , 40 , 41 , 44 ]. Genotyping was carried out by different methods, two reports using real-time PCR [ 19 ], one KASPar [ 35 ...…”

“…Regarding demographics, from the twenty-one reports, one study was performed on Arabs [ 45 ], two reports on Russians [ 42 , 43 ], one report on Caucasian Americans [ 36 ], one report on South Americans [ 24 ], five reports on Asians, Han Chinese population [ 22 , 23 , 38 , 39 , 46 ], and the other eleven reports on Europeans [ 16 , 17 , 19 , 20 , 25 , 26 , 35 , 37 , 40 , 41 , 44 ]. Genotyping was carried out by different methods, two reports using real-time PCR [ 19 ], one KASPar [ 35 ], two reports MassArray [ 23 , 37 ], four reports PCR-RFPL [ 42 , 43 , 44 , 46 ] and the remaining twelve reports using TaqMan assay [ 16 , 17 , 20 , 22 , 24 , 25 , 26 , 36 , 38 , 39 , 40 , 41 , 45 ]. The characteristics, genotyping methods, sample size and genotype frequency of the twenty one reports are presented in Table 1 .…”

“…Wigner et al (2022) assessed the association between GPX4 (rs713041) SNP and the development of multiple sclerosis (MS) in a Polish population [ 26 ]. They detected that the C/C and C allele of rs713041 decreased the risk of MS, whereas the T/T genotype and T allele increased the risk suggesting some links between polymorphic variability in oxidative-stress-related genes and the risk of MS development in the Polish population [ 26 ].…”

“…Du et al (2012) investigated the association between GPX4 (rs713041) SNP in Kashin-Beck disease, an endemic joint disease mainly distributed in areas with low selenium intake, and stated that no significant differences were observed in either genotype or allele frequency between healthy and Kashin-Beck disease subjects [46]. Wigner et al (2022) assessed the association between GPX4 (rs713041) SNP and the development of multiple sclerosis (MS) in a Polish population [26]. They detected that the C/C and C allele of rs713041 decreased the risk of MS, whereas the T/T genotype and T allele increased the risk suggesting some links between polymorphic variability in oxidative-stress-related genes and the risk of MS development in the Polish population [26].…”

“…Substitution of the major C allele into the minor T allele has been reported to be linked to different types of cancer, such as breast cancer [ 15 , 16 , 17 ], colorectal cancer [ 18 ], lung and laryngeal cancer [ 19 ] and prostate cancer [ 20 ]. Moreover, other diseases have been reported to be linked with GPX4 (rs713041) SNP, such as obesity [ 21 ], endometriosis [ 22 ], autoimmune thyroid diseases [ 23 ], Alzheimer’s disease [ 24 ], depression [ 25 ] and multiple sclerosis [ 26 ]. The C allele of GPX4 (rs713041) SNP was shown to have a protective role against oxidative DNA damage when selenium levels are adequate in in-vitro studies [ 13 ]; in addition, to maintain GPX4 concentrations in lymphocytes from individuals with CC genotype better than in individual with TT genotype when selenium intake falls [ 12 ].…”