Glutathione S-transferase, catalase, and mitochondrial superoxide dismutase gene polymorphisms modulate redox potential in systemic lupus erythematosus patients from Manaus, Amazonas, Brazil

Objective: To investigate the frequency of glutathione S-transferase (GST), catalase, and SOD2 genetic polymorphisms and their correlation with SLE.

Methods: A total of 290 females (patients = 151; controls= 139) were recruited. Multiplex PCR was performed for genotyping GSTM1 and GSTT1 genes, whereas real-time qPCR was used for determination of SNPs: CAT C262T, SOD2 C47T, GSTP1 A313G and GSTP1 IVS6 -C16T.

Results: Thiol levels are decreased in SLE patients (p<0.001), while MDA levels were significantly higher (p<0.001) and those carrying the polymorphisms had higher rates of oxidative stress. Patients with double null deletion GSTT1^null/GSTM1^null had a frequency almost five times higher than the controls (p<0.001, OR 4.81, CI 1.98-12.11). SLE patients had a lower wild-type frequency of SOD2^CC allele compared to controls (12.4% vs 27.3%). Statistical significances were observed on the association between the GSTT1^null and GSTM1^null with SOD2^mut (p<0.001, OR 0.15, CI 0.05-0.47), with GSTP1 A303G (p=0.012, OR 0.19, CI 0.05-0.69), and with GSTP1 IVS6 (p=0.008, OR 0.14, CI 0.03-0.63). The same was observed between SOD2 C47T with GSTP1 A303G (p=0.09, OR 0.27, CI 0.09-0.74) and GSTP1 IVS6 (p=0.036, OR 0.41, CI 0.18-0.92).

Conclusions: The deletion GSTT1^null/GSTM1^null may contribute to the increased of the oxidative stress in SLE patients. Isolated GSTP1 and CAT polymorphisms do not seem to influence the increased oxidative stress, neither SLE clinical manifestations. SOD2 47^CT/TT allele may have greater oxidative stress due to structural change in the protein and decreased H₂O₂ production. The combination of polymorphic genes may be involved in the pathogenesis of the disease. Key points • Major question of our paper: Many studies have shown that the antioxidant status levels are decreased in patients with SLE, especially in severe stages of disease. We believe that this paper will be of interest to the readership of your journal had the involvement of polymorphisms and mutations in several genes that contribute to the genetic etiology of SLE, suggesting that these may influence the mechanisms of disease. • Our results. Thiol level was significantly (p<.001) lower and MDA level significantly increased (p<.001) among SLE patients. Those carrying the polymorphisms had higher rates of oxidative stress. SLE Patients had a frequency almost five times higher of double null deletion GSTT1null/GSTM1null than the controls. SLE Patients had a lower wild type frequency of SOD2CC allele compared to controls (12.4% vs 27.3%). We believed the deletion GSTT1null/GSTM1null may contribute to the increased of the oxidative stress in SLE patients while carriers of the mutant SOD2 47CT/TT allele may have greater oxidative stress due to structural change in the protein and decreased H2O2 production. The combination of polymorphic genes may be involved in the pathogenesis of the disease. • Implications of our results: Evidence for the involvement of genetic factors in severe clinical to lupus is compelling. This manuscript shows genetic insights in pathogenic pathways that may lead to severe clinical implications to LES. Therefore, it is necessary to understand their impact on overall disease pathogenesis and prognosis in these patients. We understand from general consensus about environmental factors can modify disease, however, maybe just in individuals who have a permissive genetic background. Even that no single gene predisposes some individuals to LES, we believe the genetic factors described in this manuscript are important elements in susceptibility to severe clinical to LES.