No abstract

Recent studies associated certain type of cardiovascular disease (CVD) with specific mitochondrial DnA (mtDnA) defects, mainly driven by the central role of mitochondria in cellular metabolism. considering the importance of the control region (cR) on the regulation of the mtDnA gene expression, the aim of the present study was to investigate the role of mtDnA cR mutations in two CVDs: stroke and myocardial infarction (MI). MtDNA CR mutations (both fixed and in heteroplasmy) were analysed in two demographically-matched case-control samples, using 154 stroke cases, 211 MI cases and their corresponding control individuals. Significant differences were found, reporting mutations m.16145 G > A and m.16311 T > c as potential genetic risk factors for stroke (conditional logistic regression: p = 0.038 and p = 0.018, respectively), whereas the m.72 T > C, m.73 A > G and m.16356 T > C mutations could act as possible beneficial genetic factors for MI (conditional logistic regression: p = 0.001, p = 0.009 and p = 0.016, respectively). Furthermore, our findings also showed a high percentage of point heteroplasmy in Mi controls (logistic regression: p = 0.046; OR = 0.209, 95% CI [0.045-0.972]). These results demonstrate the possible role of mtDNA mutations in the CR on the pathogenesis of stroke and Mi, and show the importance of including this regulatory region in genetic association studies. Cardiovascular disease (CVD) is one of the most widespread and common causes of death in the world. The onset and severity of these diseases are influenced by both genetic and environmental factors. Recent evidences associate mitochondrial dysfunction with several cardiovascular manifestations, mainly driven by the central role of mitochondria in cellular metabolism, particularly in energetically demanding tissues such as brain and heart 1,2. Human mitochondrial DNA (mtDNA) is 16.6-kb double-stranded circular DNA molecule that encodes for 13 electron transport chain (ETC) proteins, 2 ribosomal RNAs (rRNAs) and 22 transports RNAs (tRNAs). The control region (CR) encompasses the light and heavy strand promoters, the heavy strand origin of replication (O H), three conserved sequence blocks and the termination associated sequences (TAS) 3. MtDNA is more susceptible than nuclear DNA to oxidative damage, probably due to the lack histone complex and an inefficient DNA repair mechanisms, which may serve as a protective barrier against external and internal noxious agents as reactive oxygen species (ROS) 4. However, the hypothesis of direct damage by ROS is increasingly criticized and it is suggested that errors in mtDNA replication and repair may be the main cause of its high mutation rate (~10-fold greater than in nDNA) 5. Recent evidence have linked certain CVDs with specific mtDNA mutations including base substitutions 6-11 , deletions 12 , duplications 13 and point or length heteroplasmy 14-17 both in coding 6,9,10,12,14,15 and noncoding reg ion 6-9,11,13,16,17 of mtDNA. In particular, mtDNA mutations located in CR have a potential importanc...

2Recent studies associated certain type of cardiovascular disease (CVD) with 3 specific mitochondrial DNA (mtDNA) defects, mainly driven by the central role of 4 mitochondria in cellular metabolism. Considering the importance of the control region 5 (CR) on the regulation of the mtDNA gene expression, the aim of the present study was 6 to investigate the role of the mtDNA CR mutations in two CVDs: stroke and myocardial 7 infarction (MI). Both, fixed and heteroplasmy mutations of the mtDNA CR in two 8 population samples of demographically-matched case and controls, were analysed 9 using 154 stroke cases, 211 MI cases and their corresponding control individuals. 10 Significant differences were found between cases and controls, reporting the 11 m.16145G>A and m.16311T>C as a potential genetic risk factors for stroke (conditional 12 logistic regression: p=0.038 and p=0.018, respectively), whereas the m.72T>C, 13 m.73A>G and m.16356T>C could act as possible beneficial genetic factors for MI 14 (conditional logistic regression: p=0.001, p=0.009 and p=0.016, respectively). 15 Furthermore, our findings also showed a high percentage of point heteroplasmy in MI 16 controls (logistic regression: p=0.046; OR= 0.209, 95% CI [0.045-0.972]). These results 17 demonstrate the possible role of mtDNA mutations in the CR on the pathogenesis of 18 stroke and MI, and show the importance of including this regulatory region in genetic 19 association studies.Given the association between cardiovascular disease and specific mitochondrial 23 DNA (mtDNA) defects and considering the importance of the control region of this 24 genome on the regulation of mtDNA gene expression, here, we investigate the role of 25 mutations in mitochondrial DNA control region in two cardiovascular diseases: stroke 3 26 and myocardial infarction. In this study we found five mitochondrial genetic variants 27 related to cardiovascular disease, based on single nucleotide polymorphisms (SNPs), 28 which are located in the control region of mtDNA. Despite the abundance of work on 29 the role of mitochondrial DNA in relation to cardiovascular disease, little literature has 30 been published on the variation that this genome expresses in relation to this disease. 31For this reason, our study provides significant insight of the genetic variability that 32 determines normality or pathology in relation to the genetic risk of cardiovascular 33 disease. The results obtained demonstrate the possible role of mtDNA mutations in the 34 control region on the pathogenesis of stroke and myocardial infarction, and show the 35 importance of including this regulatory region in genetic association studies. 36 37 48(O H ), three conserved sequence blocks and the termination associated sequences (TAS) 49[3]. MtDNA is more susceptible than nuclear DNA to oxidative damage, probably due 50 to the lack histone complex and an inefficient DNA repair mechanisms, which may 4 51 serve as a protective barrier against external and internal noxious agents as reactive 52 oxygen species (ROS) [4]. ...

The results obtained contribute to the knowledge of the molecular European ABO map, and are discussed in regard to the allelic frequency reported by other Caucasian and Asian populations.