title: Effect of 593C>T GPx1 SNP alone and in synergy with 47C>T SOD2 SNP on the outcome of critically ill patients.
abstract: 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 catalase (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. 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. 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% vs. 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% vs. 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 activities, we believe our results may be considered as an important contribution for the understanding of oxidative imbalance during the critical ill.
authors.affiliation: Human and Molecular Genetic Laboratory, Biosciences School, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Brazil; Cell Culture Laboratory, Postgraduate program in Biotechnology, Centro Universitário UNIVATES (UNIVATES), Brazil and Cellular and Molecular Laboratory, Medicine School, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Brazil. Electronic address: fernandamajolo@hotmail.com.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Majolo
authors.affiliation: Department of Biochemistry, Institute of Basic Health Sciences (ICBS), Universidade Federal Do Rio Grande Do Sul (UFRGS), Brazil.
authors.forename: Francis Jackson de
authors.initials: FJ
authors.lastname: Oliveira Paludo
authors.affiliation: Human and Molecular Genetic Laboratory, Biosciences School, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Brazil.
authors.forename: Aline
authors.initials: A
authors.lastname: Ponzoni
authors.affiliation: Human and Molecular Genetic Laboratory, Biosciences School, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Brazil.
authors.forename: Pietra
authors.initials: P
authors.lastname: Graebin
authors.affiliation: Intensive Care Unit of São Lucas Hospital, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Brazil.
authors.forename: Fernando Suparregui
authors.initials: FS
authors.lastname: Dias
authors.affiliation: Human and Molecular Genetic Laboratory, Biosciences School, Pontifícia Universidade Católica Do Rio Grande Do Sul (PUCRS), Brazil.
authors.forename: Clarice Sampaio
authors.initials: CS
authors.lastname: Alho
mesh_terms: D000483:Alleles; D002374:Catalase / Q000378:metabolism; D003422:Critical Care; D016638:Critical Illness; D005609:Free Radicals; D023281:Genomics; D005838:Genotype; D005979:Glutathione Peroxidase / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D010100:Oxygen / Q000737:chemistry; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D018805:Sepsis; D012772:Shock, Septic / Q000235:genetics*; D013482:Superoxide Dismutase / Q000235:genetics*; D016896:Treatment Outcome; D000094765:Glutathione Peroxidase GPX1; D000099156:Superoxide Dismutase 2
chemical_list: D002374:Catalase; D005609:Free Radicals; D005979:Glutathione Peroxidase; D010100:Oxygen; D013482:Superoxide Dismutase; D000094765:Glutathione Peroxidase GPX1; D000099156:Superoxide Dismutase 2; C000722067:GPX1 protein, human
keywords: Critical illness; GPx1; SOD2; Sepsis; Septic shock