Estudo de associação do polimorfismo R577X do gene ACTN3 com variações da região promotora do gene DPP3 em pacientes em hemodiálise

Abstract

Chronic Kidney Disease (CKD) is a serious public health problem with a worrying prognosis. Although diabetes and hypertension are central factors, genetic predisposition has emerged as a key element in disease risk and progression. Previous studies conducted in our laboratory identified a higher frequency of the "X" allele of the R577X polymorphism of the ACTN3 gene (Alpha-Actinin-3) in hemodialysis patients. Given that the ACTN3 gene has limited expression in renal tissue, we hypothesized that this association could result from linkage disequilibrium with variants in neighboring genes, such as DPP3, located approximately 37,000 base pairs away and involved in oxidative stress pathways and blood pressure regulation. Therefore, this study aimed to investigate possible associations between genetic variations in the promoter region of the DPP3 gene and the R577X polymorphism of the ACTN3 gene in CKD patients on hemodialysis. Twenty DNA samples from patients homozygous for the polymorphism (10 RR and 10 XX) were analyzed by genotyping and sequencing. The coverage region chosen for analysis was the proximal promoter region, the first exon, and the beginning of the first intron of the DPP3 gene. This region was selected to encompass essential functional elements, such as the TATA box and open reading frame. Seven variations were identified, five of which are new to public databases. Variations at positions -209 (rs2279863) and -61 (rs2279864) and their respective known polymorphisms presented sufficient frequency to assess their association with the genotypes of the polymorphism under study. Although the rs2279864 (-61 G>A) variant was observed exclusively in individuals with the RR genotype for ACTN3, statistical analysis (Fisher's exact test) did not indicate a significant association (p = 0.2105), despite the observed trend. The rs2279863 (-209 G>T) polymorphism showed a symmetrical distribution between the RR and XX genotypes, with no indication of association (p > 0.9999). Despite the absence of statistically significant associations, the results indicate high local genetic variability, suggesting the need for further investigations in larger samples.