Estudo associativo entre variantes genéticas no gene GPX1, participante da via de controle oxidativo, e o desfecho de pacientes críticos

Abstract

Background: During critical illness and sepsis there is severe antioxidant depletion, and this scenario raises the critical ill patient s mortality risk. Glutathione peroxidase (GPx) is one of the first endogenous antioxidant defense enzymes, and it works cooperatively with superoxide dismutase (SOD) and cathalase (CAT) to detoxify free radicals from the cellular environment. Genetic studies are important to understand the complexity of human oxidative stress and how the organism responds to an extreme situation such as critically care conditions. Previous studies with a GPx1 single nucleotide polymorphism (593C>T SNP; rs1050450; protein variant in GPx1: Pro198Leu) showed 593T carriers and 593TT homozygotes present higher risk to develop different diseases. Objective: We assessed the relationship of the genotype distribution of GPx1 SNP in critically ill patients with their conditions (organ dysfunction, sepsis, and septic shock) and their outcome. Results: We monitored 626 critically ill patients daily from the ICU (intensive care unit) admission to their discharge from hospital, or death. Our study revealed a significant association between 593TT GPx1 genotype and mortality; the mortality rate was higher in homozygous 593TT GPx1 (N = 94) when compared with the group of subjects with genotypes 593CT or 593CC GPx1 (N = 532) (52% versus 38%, P = 0.009; OR = 1.79; 95% CI = 1.13-2.85). Evaluating the subgroup of 293 ICU patients with sepsis, a pooled analysis including two genetic variants GPx1 and SOD2 (47C> T SNP, rs4880; protein variant in MnSOD: Ala-9Val) showed a significant difference in relation to progression to septic shock. The frequency of septic shock among septic patients with 593T GPx1 and 47C SOD2 alleles (N = 122) was higher when compared with septic patients carrying other settings of genotypes (N = 174) (78% versus 66%; P = 0.028; OR = 1.81; 95% CI = 1.03-3.18). Accepting the previously reported functional effects of these two SNPs on GPx1 and SOD2 gene expressions and, consequently, on GPx1 and MnSOD enzyme actvities, we believe our results may be considered as an important contribution for the understanding of oxidative imbalance during the critical ill.