Evidence for Sub-Haplogroup H5 of Mitochondrial DNA as a Risk Factor for Late Onset Alzheimer's Disease

PLoS One

Luisa Benussi¹  Valentina Balbi¹  Fabiola Olivieri¹  Francesca Marchegiani¹  Nadia Minicuci²  Elisa Balducci³  Chiara Pirazzini³  Aurelia Santoro³  Stefano Salvioli³  Andrea Maria Chiamenti³  Maurizio Cardelli³  Francesca Tavano³  Francesca Rosini³  Alessandro Achilli³  Paola Siviero⁴  Giuliano Binetti⁵  Sandro Sorbi⁶  Benedetta Nacmias⁷  Roberta Ghidoni⁸  Carlo Gabelli⁸  Giuseppina Rose⁸  Michele Mishto⁹  Elena Bellavista⁹  Giuseppe Passarino^1,10  Antonio Torroni^1,10  Claudio Franceschi^1,11  Gaetano Crepaldi^1,12 

[1] CIG-Interdepartmental Center for Biophysics and Biocomplexity Studies, University of Bologna, Bologna, Italy;Department of Cell and Environmental Biology, University of Perugia, Perugia, Italy;Department of Experimental Pathology, University of Bologna, Bologna, Italy;Department of Genetics and Microbiology, University of Pavia, Pavia, Italy;Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona, Italy;Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy;Institute of Biochemistry, Medical Faculty Charité, Berlin, Germany;Italian National Research Center for Aging (I.N.R.C.A.), Ancona, Italy;National Council Research, Institute of Neuroscience, Padova, Italy;NeuroBioGen Lab-Memory Clinic, “Centro S.Giovanni di Dio-Fatebenefratelli”, Brescia, Italy;Proteomics Unit, “Centro S.Giovanni di Dio-Fatebenefratelli”, Brescia, Italy;Regional Center for Cerebral Aging, Valdagno, Vicenza, Italy

关键词: Alzheimer's disease;    Mitochondrial DNA;    Haplogroups;    Mitochondria;    Transfer RNA;    Ribosomal RNA;    Mutation detection;    Sequence motif analysis;   

DOI  :  10.1371/journal.pone.0012037

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

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. Methodology/Principal Findings 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.

【 授权许可】

CC BY