Associações entre variantes nos genes SERPINA1, SLC6A14 e SLC26A9 e a fibrose cística.

Abstract

Introduction: Cystic fibrosis (CF) is an autosomal recessive, multisystemic and potentially lethal disease, which incidence is higher in Caucasian population. CF aetiology is characterized by the presence of pathogenic variants in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which encodes a homonymous protein. CF heterogeneity is high in frequency and complexity of its clinical manifestations and modifier genes are described as one of the factors that regulates the phenomenon. Objective: To establish the frequency of allelic variants in SERPINA1, SLC6A14 and SLC26A9 genes and to analyze their influence on the heterogeneity of clinical manifestations in individuals with CF. Materials and Methods: The study is cross-sectional. Genomic DNA samples from 56 individuals were subjected to real-time PCR (qPCR) technique in order to identify the genotypes of rs28929474 (SERPINA1), rs3788766 (SLC6A14) and rs7512462 (SLC26A9) variants. The Gene-Calc, dbSNP (NCBI), RegulomeDB 2.0.3 and HaploReg 4.1 platforms were consulted for determining the Hardy-Weinberg Equilibrium and obtaining genetic and functional data on the analyzed variants. The association between variants and CF-related clinical variables was determined by binomial logistic regression which was performed in RStudio 2022.07.0 software, in which four genetic models were considered: allelic, dominant, recessive and additive. Results: The minor alleles frequencies (MAF) for the rs3788766 and rs7512462 variants were A (0.41) and C (0.4), respectively. All of the alleles in rs28929474 variant were represented by nucleotide C. The rs3788766 variant was significantly associated with dornase alfa use in the recessive (OR = 0.23; p = 0.04) and additive (OR = 0.23; p = 0.04) models, occurrence of pulmonary exacerbations in dominant model (OR = 9.09; p = 0.04), nutritional risk of overweight in the allelic (OR = 4.48; p = 0.03), recessive (OR = 16.03; p = 0.02), and additive (OR = 19.73; p = 0.03) models, and nutritional risk of malnutrition in the allelic (OR = 0.22; p = 0.03), recessive (OR = 0.06; p = 0.02), and additive (OR = 0.05; p = 0.03) models. No significant associations were observed for the rs7512462 variant. Conclusions: The A and C alleles related to rs3788766 and rs7512462 variants, respectively, were frequent among the people in the study. The rs3788766 variant was associated with markers of lung disease (use of dornase alfa and episodes of lung exacerbations) and, especially, nutritional risk of overweight and malnutrition.