Numerous studies have extensively documented that variations in enzymes involved in DNA repair mechanisms impact enzyme activity, and these genetic variations serve as risk factors for a wide range of diseases. STEMI represents the most severe manifestation of coronary artery disease, and a wealth of literature indicates the involvement of DNA damage in the development of this condition. Hence, in our study, we investigated the association between STEMI and four enzyme polymorphisms that are involved in distinct types of DNA repair mechanisms. Our study revealed a correlation between genotypes linked to XPA and LIG4 polymorphisms and STEMI.
Gu et al. conducted a study examining alterations in gene expression linked to oxidative stress in STEMI patients [12]. Their findings revealed notable disparities in three specific genes (GADD45A, RAD50, and ATM) that are involved in the DNA repair mechanism. Among the two genes that were up-regulated, GADD45A is a protein that participates in the response to DNA damage, whereas RAD50 is a protein involved in the process of repairing DSBs in DNA. In contrast, the down-regulation of ATM gene expression, as detected by the researchers, may initiate a process that facilitates the appropriate repair of damaged DNA. According to the authors, the observed gene expression changes in this process indicate the involvement of oxidative stress, DNA repair, cell cycle, and apoptosis in the pathogenesis of STEMI disease.
In our study, we established a correlation between STEMI disease and a polymorphism in the LIG4 enzyme, which is involved in the repair of DSBs. This indicates a potential association between STEMI and compromised mending of double-chain fractures. Specifically, our findings revealed that individuals harboring the mutant T allele (Ile) have a higher susceptibility to STEMI disease. In a study examining the correlation between glioma risk and the LIG4 Thr9Ile polymorphism, it was discovered that individuals who carried the T allele either homozygously or heterozygously were at an increased risk of developing glioma, which aligns with our own findings [13]. Likewise, consistent findings were observed in multiple studies investigating the association between infertility and this particular polymorphism. These studies revealed that individuals who carried the T allele either homozygously or heterozygously exhibited a correlation with male infertility, characterized by elevated levels of DNA fragmentation and a decreased sperm count (14, 15). In another study investigating the impact of the LIG4 Thr9Ile polymorphism on chemotherapy responses in patients with non-small cell lung cancer, it was determined that individuals carrying the T allele as homozygotes or heterozygotes exhibited poorer treatment response compared to patients carrying the CC genotype [16]. A study examining the correlation between cytogenetic damage and this polymorphism in patients with human granulocytic anaplasmosis demonstrated that individuals carrying the Ile/Ile genotype exhibited a higher degree of damage [17]. All of these findings demonstrate that carrying the T allele in the LIG4 Thr9 polymorphism is effective in predisposing individuals to diseases by inducing greater DNA damage. Similarly, our results indicate that carrying the T allele is associated with STEMI disease.
We have demonstrated that the XPA − 4A/G polymorphism is another genetic variation linked to susceptibility to STEMI disease, and we have established a significant association between individuals carrying the G allele and STEMI. Despite the significant involvement of the BER mechanism in repairing oxidative damage, which is believed to contribute to the pathogenesis of STEMI, multiple studies have presented evidence indicating that specific proteins from both NER and BER pathways work together synergistically to efficiently eliminate oxidative lesions [18, 19]. Lawania et al. conducted a study demonstrating that individuals carrying the G allele in the XPA − 4A/G polymorphism exhibited an increased risk of developing lung cancer [20]. Numerous studies have aimed to elucidate the association between this polymorphism and other types of cancer; however, a definitive consensus has not yet been reached [21]. The XPA − 4A/G polymorphism, located in the 5' untranslated region (UTR), could potentially affect the transcription of XPA, which plays a crucial role in the NER pathway. It has been reported that this polymorphism has an impact on the levels of XPA [9]. As a result, it is likely to contribute to the susceptibility to certain diseases.
Our study found no association between the XRCC6 promoter C-57G and OGG1 Ser326Cys polymorphisms and STEMI. The XRCC6 promoter C-57G polymorphism resides within the promoter region of the XRCC6 gene, which has been associated with the regulation of transcription and mRNA stability. Several studies have extensively investigated the association between the XRCC6 promoter C-57G polymorphism and susceptibility to various diseases, including cancer [22, 23]. However, the results of these studies have been contradictory, presenting inconsistent findings. In a study conducted by Mumbrekar et al., the presence of XRCC6 promoter C-57G polymorphism was found to be linked to an increase in double-strand DNA breaks [24]. A study exploring the connection between myelodysplastic syndrome and the XRCC6 promoter C-57G polymorphism revealed that individuals carrying the G allele exhibited a normal karyotype [23]. In studies examining the association between nasopharyngeal carcinoma, breast cancer, colorectal cancer, and the XRCC6 promoter C-57G polymorphism, no similar relationship was observed, consistent with our study findings [25–27]. The variation in frequencies of polymorphisms across different ethnic groups is a significant factor contributing to the disparities in results.
According to reports, the OGG1 Ser326Cys polymorphism's amino acid alteration plays a role in disease susceptibility by influencing DNA repair activity. However, the results of epidemiological studies have been inconclusive, with some studies suggesting an increased risk of cancer associated with this polymorphism, while others found no significant association. Studies conducted on diseases other than cancer have yielded conflicting results. In studies involving patients diagnosed with rheumatoid arthritis, Parkinson's disease, infertility, diabetes, and hypertension, no association was found between OGG1 Ser326Cys polymorphism and the risk of these diseases [28–32]. However, a correlation was identified between cataract disease, chronic obstructive pulmonary disease, and OGG1 Ser326Cys polymorphism [33, 34]. In a study investigating the association between genotypes and the tendency for DNA damage, it was reported that the genotypes had no impact on the level of DNA damage observed in both the control group and radiotherapy workers [35]. In a study examining the impact of the OGG1 Ser326Cys polymorphism on DNA damage levels induced by welding fume exposure in welding workers, it was concluded that this polymorphism had no significant effect [36]. These findings were consistent with the results observed in the control group. Conversely, a notable correlation was discovered between DNA damage and pesticide exposure among agricultural workers [37]. These discrepancies could potentially be attributed to relatively small sample sizes and variations in genetic backgrounds among the studies.
Our study's findings contribute to one of the initial investigations in this field, examining the association between STEMI and DNA repair polymorphisms. These findings emphasize the significance of the LIG4 and XPA genes in preserving the integrity of the genome and contribute to a better comprehension of the origin of STEMI. The NHEJ and NER mechanisms play crucial roles in maintaining chromosomal stability and offer a fresh avenue of investigation for understanding the development of STEMI.