Role of genes GSTM1, GSTT1, and MnSOD in the development of late-onset Alzheimer disease and their relationship with APOE*4

Abstract

IntroductionSeveral studies have reported increased oxidation of lipids, proteins and DNA in the brains of patients with Alzheimer disease (AD). Moreover, these patients display differences in the activity and polymorphisms of the genes encoding the enzymes GST (T1, M1) and MnSOD. For these reasons, we designed a study of the variability in GSTT1, GSTM1, and MnSOD genes in healthy and AD groups from a Venezuelan population. MethodsWe included 179 unrelated Venezuelan subjects classified as either AD patients (n=79) or healthy individuals (n=100). Presence or absence of the GSTT1/GSTM1 genes was determined using PCR-SSP, and polymorphisms of MnSOD and APOE genes were identified with PCR-RFLP. ResultsThe genotype GSTT1+/GSTM1− seems to favour development of AD (OR=2.06, P=.01). The risk level is higher when it is combined with the ɛ4 allele of the APOE gene: GSTT1+/GSTM1−/ɛ3ɛ4 (OR=3.07, P=.05), GSTT1+/GSTM1−/ɛ4ɛ4 (OR=5.52, P=.02). The Ala-9Val polymorphism does not appear to be related to AD. However, the presence of the Ala/Ala genotype increases the risk provided by the ɛ4 allele of the APOE gene: AlaAla/ɛ3ɛ4 (OR=3.47, P=.03), AlaAla/ɛ4ɛ4 (OR=6.3, P=.01). ConclusionsThe results support the hypothesis that impaired mitochondrial function and increased oxidative damage are involved in the pathogenesis of AD. It is important to study other genes related to oxidative stress and antioxidant pathways which could be involved in susceptibility to AD.