title: Evidence for sub-haplogroup h5 of mitochondrial DNA as a risk factor for late onset Alzheimer's disease.
abstract: BACKGROUND
  Alzheimer's Disease (AD) is the most common neurodegenerative disease and the leading cause of dementia among senile subjects. It has been proposed that AD can be caused by defects in mitochondrial oxidative phosphorylation. Given the fundamental contribution of the mitochondrial genome (mtDNA) for the respiratory chain, there have been a number of studies investigating the association between mtDNA inherited variants and multifactorial diseases, however no general consensus has been reached yet on the correlation between mtDNA haplogroups and AD.
  
  
  RESULTS
  We applied for the first time a high resolution analysis (sequencing of displacement loop and restriction analysis of specific markers in the coding region of mtDNA) to investigate the possible association between mtDNA-inherited sequence variation and AD in 936 AD patients and 776 cognitively assessed normal controls from central and northern Italy. Among over 40 mtDNA sub-haplogroups analysed, we found that sub-haplogroup H5 is a risk factor for AD (OR=1.85, 95% CI:1.04-3.23) in particular for females (OR=2.19, 95% CI:1.06-4.51) and independently from the APOE genotype. Multivariate logistic regression revealed an interaction between H5 and age. When the whole sample is considered, the H5a subgroup of molecules, harboring the 4336 transition in the tRNAGln gene, already associated to AD in early studies, was about threefold more represented in AD patients than in controls (2.0% vs 0.8%; p=0.031), and it might account for the increased frequency of H5 in AD patients (4.2% vs 2.3%). The complete re-sequencing of the 56 mtDNAs belonging to H5 revealed that AD patients showed a trend towards a higher number (p=0.052) of sporadic mutations in tRNA and rRNA genes when compared with controls.
  
  
  CONCLUSIONS
  Our results indicate that high resolution analysis of inherited mtDNA sequence variation can help in identifying both ancient polymorphisms defining sub-haplogroups and the accumulation of sporadic mutations associated with complex traits such as AD.
authors.affiliation: Department of Experimental Pathology, University of Bologna, Bologna, Italy. aurelia.santoro@unibo.it
authors.forename: Aurelia
authors.initials: A
authors.lastname: Santoro
authors.forename: Valentina
authors.initials: V
authors.lastname: Balbi
authors.forename: Elisa
authors.initials: E
authors.lastname: Balducci
authors.forename: Chiara
authors.initials: C
authors.lastname: Pirazzini
authors.forename: Francesca
authors.initials: F
authors.lastname: Rosini
authors.forename: Francesca
authors.initials: F
authors.lastname: Tavano
authors.forename: Alessandro
authors.initials: A
authors.lastname: Achilli
authors.forename: Paola
authors.initials: P
authors.lastname: Siviero
authors.forename: Nadia
authors.initials: N
authors.lastname: Minicuci
authors.forename: Elena
authors.initials: E
authors.lastname: Bellavista
authors.forename: Michele
authors.initials: M
authors.lastname: Mishto
authors.forename: Stefano
authors.initials: S
authors.lastname: Salvioli
authors.forename: Francesca
authors.initials: F
authors.lastname: Marchegiani
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cardelli
authors.forename: Fabiola
authors.initials: F
authors.lastname: Olivieri
authors.forename: Benedetta
authors.initials: B
authors.lastname: Nacmias
authors.forename: Andrea Maria
authors.initials: AM
authors.lastname: Chiamenti
authors.forename: Luisa
authors.initials: L
authors.lastname: Benussi
authors.forename: Roberta
authors.initials: R
authors.lastname: Ghidoni
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Rose
authors.forename: Carlo
authors.initials: C
authors.lastname: Gabelli
authors.forename: Giuliano
authors.initials: G
authors.lastname: Binetti
authors.forename: Sandro
authors.initials: S
authors.lastname: Sorbi
authors.forename: Gaetano
authors.initials: G
authors.lastname: Crepaldi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Passarino
authors.forename: Antonio
authors.initials: A
authors.lastname: Torroni
authors.forename: Claudio
authors.initials: C
authors.lastname: Franceschi
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D016022:Case-Control Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010802:Phylogeny; D011110:Polymorphism, Genetic
chemical_list: D004272:DNA, Mitochondrial