SLE is a disease characterized by the production of pathogenic autoantibodies against nucleoprotein antigens, such as Anti-dsDNA, and is linked to decreased DNase activity (Lauková et al. 2020). Anti-dsDNA antibodies are one of the most common types of autoantibodies, implying that a failure to break down DNA is a contributing factor in the disease (Keyel 2017). DNase I could be a crucial nuclease for removing DNA from nuclear antigens at high-turnover sites and therefore may impede SLE (Shin et al. 2004). The deficiency of this nuclease causes DNA to persist in the serum, resulting in the formation of autoantibodies, a hallmark of many autoimmune disorders, particularly SLE (Keyel 2017). It has been shown that a non-synonymous SNP in DNase I is linked to SLE susceptibility (Bodan´o et al. 2006). This study aimed to identify DNase I level and a genetic variant of DNase I (rs1053874 A/G) contributing to the SLE susceptibility among Egyptian children and adolescents. We found evidence of a potential association between SLE and the DNase I gene SNP rs1053874 A/G.
DNase I is an endonuclease enzyme that is released into the bloodstream and most bodily fluids and is accountable for the digestion of extracellular nucleoproteins, which could be important in the prevention of autoimmune reactions (Malíčková et al. 2011). Physiological effects of DNase I within the digestive tract are thought to be breaking the DNA of dietary products (to provide oligonucleotides to an organism) and thus dissolving chromatin produced by dying cells reduces anti-DNA autoimmunity (Napirei et al. 2004; Napirei et al. 2000). A defect in DNase I production or inhibition may result in inefficient extracellular DNA degradation and may play a role in the formation of anti-nuclear autoantibodies (ANA), suggesting that it may be a prerequisite for the development of an SLE-like disease (Lauková et al. 2020). DNase I activity has been seen in several autoimmune disorders, including systemic and organ-specific SLE (Kim et al. 2008).
Our cohort SLE showed lower levels of serum DNase I than controls. Our findings also showed that serum DNase I concentrations were unrelated to age, other SLE clinical laboratory tests, or demographic characteristics, and that DNase I levels had no meaningful link to disease activity (SLEDAI). These observations corroborate the findings of Martinea-Valle et al. (2009) who reported that the level of DNase I in the serum was lower in patients with SLE and were unable to find a correlation with any epidemiological, clinical, or immunological aspects of SLE. Similarly, circulating DNase I was discovered to be decreased in SLE individuals and did not relate to disease activity (Sallai et al. 2005). Other researchers have suggested that lower DNase I activity in SLE patients may be linked to the disease's progression (Martínez Valle et al. 2008; Leffler et al. 2015).
The etiopathogenesis of SLE is unexplained, however, it is thought to be caused by a mix of genetic, environmental, and hormonal factors (Tsao 2003). Genetic variables are considered to influence disease susceptibility and the patient's autoantibody profile (Camicia et al. 2016). In humans, DNase I gene is polymorphic and is regulated by six codominant alleles (Yasuda et al. 2010). In SLE patients, a genetic variant in the DNase I gene has been discovered (Yasutomo et al. 2001). There have been no reports of this polymorphism in SLE Egyptian patients yet.
Several types of research in experimental sepsis models validated the protective role of DNase I. DNase I protected the gut from injury by lowering the systemic acute inflammatory response (Gao et al. 2015). In our investigation, rs1053874 A/G polymorphism of DNase I gene suggested that the GA, AA, combined GA + AA genotypes, and A allele frequencies were significantly raised in healthy controls than in SLE patients. This means individuals caring for these genotypes and alleles had decreased risk for SLE (P = 0.042, P = 0.001, P = 0.003, and P < 0.001, respectively). To the best of our knowledge, this is the first study in Egypt to show that these variant genotypes and alleles are associated with a decreased risk of SLE. Other studies have investigated the DNase I (rs1053874 /Q222R) variant in SLE patients and found contradictory evidence. In Spanish populations, Bodan´o et al. (2006) found that the mutant genotype GG was significantly inextricably connected to SLE risk (P = 0.002). The DNase I SNP may potentially be a potential risk for SLE in South Indian Tamils (Panneer et al. 2013). In a recent investigation, Camicia et al. (2016) discovered no link between the DNase I rs1053874 A/G polymorphism and SLE susceptibility in Argentinean patients. Although this SNP was linked to the generation of anti-dsDNA antibodies, a Korean investigation showed no such link (Shin et al. 2004). While in our study, we did not detect any link between the DNase I rs1053874 A/G SNP and anti-dsDNA production, active SLEDAI, or any clinical/laboratory features. Both genetic and environmental factors, such as ethnic heterogeneity, disease duration, sample size, and study age, could impact the disparities between our genetic results and previous research.
Mutations in DNase I have been found in several SLE patients.; however, they are uncommon, and only a tiny minority of SLE patients with impaired DNase activity appear to have them (Bodan´o et al. 2006). In the coding sequence, the most common SNP, rs1053874 A/G in DNase I gene, appeared to have very little effect on DNase I function, based on the previous studies (Yasuda et al. 1999; Kishi et al. 2001). Although our study has shown an association between the GA, AA, GA + AA genotypes and A allele of the DNase I rs1053874 A/G SNP and SLE susceptibility, not linked with any clinical/laboratory SLE features and has no relation with DNase I levels. However, DNase I rs1053874 polymorphism was related to the generation of anti-ribonucleoprotein (RNP) and anti-dsDNA antibodies, this is not the case with SLE susceptibility (Bodan´o et al. 2006). The Korean study, on the other hand, discovered a link with autoantibodies but not with a predisposition (Shin et al. 2004). Furthermore, according to a study done by Camicia et al. (2016) in the DNase I gene, the existence of the A allele of the rs1053874 SNP was identified to confer a potential risk for the development of nephropathy and a poorer disease course. This discrepancy may be due to demographic variability, ethnic groups, or technological disparities in antibody detection. Inconsistencies in genetic research are frequently caused by differences in population genetic profiles. The lack of a link between the rs1053874 A/G polymorphism and serum DNase I level was discovered in our investigations. Our findings corroborate the findings of Bodano et al. (2006) who found no link between this variation and serum DNase I levels in the Spanish population.
SLE prediction using univariate and multivariate regression techniques showed genotype “GA + AA” in DNase I rs1053874 A/G SNP and lowered serum DNase I levels were significantly related to SLE susceptibility. Furthermore, we confirmed SNP rs1053874 “GA + AA” and declined DNase I levels were suggested to be independent predictors for SLE susceptibility.
Our current research seems to have some limitations. Because the number of patients studied was so little, large sample studies were required. Furthermore, most of the patients in this study came from Egypt's Delta region. We were unable to gather cases from additional regions to include in our research on how people's place of residence affects their outcomes. Moreover, searching for other SNPs in the DNase I gene will help researchers better comprehend complicated genetic connections and uncover haplotypes.