title: Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease.
abstract: Allele epsilon4 of the nuclear APOE gene is a leading genetic risk factor for sporadic Alzheimer's disease (AD). Moreover, an allele-specific effect of APOE isoforms on neuronal cell oxidative death is known. Because of the role of the mitochondrial genome (mtDNA) in oxidative phosphorylation and oxidative stress, an interaction between APOE polymorphism and mtDNA inherited variability in the genetic susceptibility to sporadic AD can be hypothesized. We have explored this hypothesis by analyzing mtDNA germline variants (mtDNA haplogroups) in a sample of AD patients (213 subjects) genotyped for APOE and classified as APOE epsilon4 carriers and non-carriers. We found that the frequency distribution of mtDNA haplogroups is different between epsilon4 carriers and non-carriers (P=0.018), thus showing non-random association between APOE and mtDNA polymorphisms. The same analysis, carried out in two samples of healthy subjects (179 age-matched and 210 individuals aged more than 100 years), showed independence between epsilon4 allele and mtDNA haplogroups. Therefore, the APOE/mtDNA interaction is restricted to AD and may affect susceptibility to the disease. In particular, some mtDNA haplogroups (K and U) seem to neutralize the harmful effect of the APOE epsilon4 allele, lowering the epsilon4 odds ratio from statistically significant to non-significant values.
authors.affiliation: Department of Cell Biology, University of Calabria, Rende, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Carrieri
authors.forename: M
authors.initials: M
authors.lastname: Bonafè
authors.forename: M
authors.initials: M
authors.lastname: De Luca
authors.forename: G
authors.initials: G
authors.lastname: Rose
authors.forename: O
authors.initials: O
authors.lastname: Varcasia
authors.forename: A
authors.initials: A
authors.lastname: Bruni
authors.forename: R
authors.initials: R
authors.lastname: Maletta
authors.forename: B
authors.initials: B
authors.lastname: Nacmias
authors.forename: S
authors.initials: S
authors.lastname: Sorbi
authors.forename: F
authors.initials: F
authors.lastname: Corsonello
authors.forename: E
authors.initials: E
authors.lastname: Feraco
authors.forename: K F
authors.initials: KF
authors.lastname: Andreev
authors.forename: A I
authors.initials: AI
authors.lastname: Yashin
authors.forename: C
authors.initials: C
authors.lastname: Franceschi
authors.forename: G
authors.initials: G
authors.lastname: De Benedictis
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics*; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics*; D004247:DNA / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic
chemical_list: D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D004272:DNA, Mitochondrial; D004247:DNA