Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer´s disease

Carrieri, G., Bonafe, M., De Luca, M., Rose, G., Varcasia, O., Bruni, A., Maletta, R., Nacmias, B., Sorbi, S., Corsonello, F., Feraco, E., Andreev, K. F., Yashin, A. I., Franceschi, C., De Benedictis, G.
Human Genetics, 108:3, 194–198 (2001)


Allele e 4 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 be-tween APOE polymorphism and mtDNA inherited vari-ability in the genetic susceptibility to sporadic AD can be hypothesized. We have explored this hypothesis by analyz-ing mtDNA germline variants (mtDNA haplogroups) in a sample of AD patients (213 subjects) genotyped for APOE and classified as APOE e 4 carriers and non-carriers. We found that the frequency distribution of mtDNA haplo-groups is different between e 4 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 e 4 allele and mtDNA hap-logroups. Therefore, the APOE/mtDNA interaction is re-stricted 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 e 4 allele, lowering the e 4 odds ratio from statistically significant to non-significant values. (SPRINGER-VERLAG)
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