IS is a complex neurological disease caused by many factors, which is related to environmental factors and genetic factors, and gene variation has become one of the important factors of ischemic stroke. This cerebrovascular disease is related to age, sex, and genetic factors, and is directly related to hypertension, smoking, diabetes, hyperlipidemia, coronary heart disease, hyperhomocysteine, and other factors[21]. Recent epidemiological studies suggested that IS was closely related to genetic factors. Single nucleotide polymorphisms (SNPs) are the most common types of deoxyribonucleic acid (DNA) variants in humans, caused by the stable substitution of a single nucleotide from a point mutation in the genome. Today, the latest advances in molecular genetics have allowed people to realize that a single nucleotide polymorphism was closely related to the pathogenesis of a stroke[22]. Ischemic stroke results in increased levels of reactive oxygen species (ROS) such as superoxide anions (O2-), hydroxyl radical (OH- ), and hydrogen peroxide (H2O2) in the blood. Increased ROS levels are associated with reperfusion injury[23]. ROS damaged cellular proteins, lipids, and DNA, and disrupted normal cellular signaling and gene regulation[24].
In the case-control study, six SNPs of SOD genes (rs17880487, rs80265967, rs4880, rs284296, rs2695232, and rs7655372) were investigated to determine their association with the risk of IS in the Chinese Han population. SNP rs7655372 was found to be associated with an increased risk of IS; however, no significant relationship was found between IS and the other investigated SNPs. Six sites were included: rs17880487 and rs80265967 in the SOD1 gene, rs4880 and rs2842960 in the SOD2 gene, and rs2695232 and rs7655372 in the SOD3 gene.
Rs17880487 is located on chromosome 21:31668917, presenting a 3 prime UTR variant and a downstream transcript variant. Rs80265967 is located on chromosome 21:31667290, presenting a missense variant and a coding sequence variant. Otaki16 reported that rsl7880487 was associated with cardiovascular mortality, but the present study showed no correlation between the rsl7880487 and IS risk in the Chinese Han population of Dali City. Furthermore, rs80265967 did not exhibit polymorphisms in this study.
Rs4880 is located on chromosome 6:159692840, presenting a coding sequence variant, missense variant, and 5 prime UTR variant. rs2842960 is located on chromosome 6:159692289, presenting an intron variant and a 3 prime UTR variant. rs4880 and rs2842960 loci are located in the promoter region of the SOD2 gene. Promoter region SNPs could alter gene expression, leading to the development of various diseases. The spatial conformation of a signal peptide could be changed by the rs4880 mutation of the SOD2 gene, thus reducing the rate of transport to the mitochondria and the entry of SOD2 into the mitochondria, where it plays an antioxidant role. This disruption of SOD2 transport increases oxidative stress, leading to cardiovascular disease. The mutation of this site is C→T could change alanine (Ala) to valine (Val) in the position of the signal peptide, at this point, the signal peptide space transformed from α helix to β fold, α helix is amphiphilic, which induced SOD2 from the cytoplasm to the mitochondria, and β folding affected the proper identification of the signal peptides and related receptors on the mitochondrial inner membrane, and exhibited reduced the transcriptional activity of SOD2 to the mitochondria by 30-40% affect the entry of SOD2 into mitochondria to play an antioxidant role, which increased the risk of coronary artery disease[25].Mutations in the SOD2 gene increase the risk of developing cancer, SOD2 SNP rs4880 (T > C) resulted in conformational changes of the protein helix structure, an increased risk of oral cancer, and has been linked to a variety of others cancers[26]. Studies have shown that rs4880 SNP (T > C changes at the nucleotide level) at codon 16 causes alanine (GCT) to replace valine (GTT)[27]. The C allele of SOD2 rs4880 has been reported to retain the protein helix structure of many diseases, and maintained the normal activity of the enzymes, related to Alzheimer's disease[28], however, the polymorphism of rs2842960 (C > T) has been rarely studied, and therefore the association with disease is unclear. In the present study, our results showed that there was not a significant association between rs4880, rs2842960 polymorphism, and IS in the Chinese Han population of Dali City.
Rs2695232 is located on chromosome 4:24800327, presenting a non-coding transcript variant and a 3 prime UTR variant. rs7655372 is located on chromosome 4:24797264, presenting an intron variant. Currently, there are no reports of these two SNPs being associated with diseases. However, studies have shown that the polymorphism of the other SOD3 locus was correlated with disease. The SOD3 Ala40Thr missense mutation (GCG-ACG) was associated with susceptibility to type 2 diabetes by increasing the risk of type 2 diabetes[29]. Takahiro studied the correlation between the polymorphism of SOD3 and cerebral infarction. The frequency of C-C-C haplotype in the female SOD3 polymorphisms (rs13306703, rs699473, and rs1799895) was significantly higher in patients with cerebral infarction than in the control group. Therefore, SOD3 haploid C-C-C might be a marker of female cerebral infarction[30]. In this study, the rs7655372 A allele and GA genotype increased the risk of IS, whereas A and GA were risk factors for IS. Polymorphisms of the other loci had no correlation with the risk of IS. We analyzed the genotype of rs7655372 (G>A) locus and found that there was no homozygous AA; therefore, allele (A/G) and additive (GA/GG) were selected for analysis. The allele testing and the additive model indicated rs7655372 increased the risk of IS 2.722-fold. After adjusting the risk factors, A and GA of rs7655372 were still found to be risk factors for IS. In addition to traditional stroke risk factors such as hypertension, hyperlipidemia, and diabetes, this SNP might be an independent risk factors for stroke. However, no data about the relationship between rs7655372 and the risk of IS has been reported.
Our results indicate that polymorphisms of rs7655372 increase the risk of IS in the Chinese Han population. However, this study has some limitations. First, our samples were generated from the Han Chinese population of Dali City, and hence the findings are cannot be applicable to other ethnicities. In addition, regional disparity could lead to possible inconsistencies in the role of the SNPs of the same locus in similar diseases of different ethnic groups and different diseases of the same ethnic group.