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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 the mtDNA CR mutations in two CVDs: stroke and myocardial infarction (MI). Both, fixed and heteroplasmy mutations of the mtDNA CR in two population samples of demographically-matched case and controls, were analysed using 154 stroke cases, 211 MI cases and their corresponding control individuals. Significant differences were found between cases and controls, reporting the m.16145G>A and m.16311T>C as a potential genetic risk factors for stroke (conditional logistic regression: p=0.038 and p=0.018, respectively), whereas the m.72T>C, m.73A>G and m.16356T>C 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.Author SummaryGiven the association between cardiovascular disease and specific mitochondrial DNA (mtDNA) defects and considering the importance of the control region of this genome on the regulation of mtDNA gene expression, here, we investigate the role of mutations in mitochondrial DNA control region in two cardiovascular diseases: stroke and myocardial infarction. In this study we found five mitochondrial genetic variants related to cardiovascular disease, based on single nucleotide polymorphisms (SNPs), which are located in the control region of mtDNA. Despite the abundance of work on the role of mitochondrial DNA in relation to cardiovascular disease, little literature has been published on the variation that this genome expresses in relation to this disease. For this reason, our study provides significant insight of the genetic variability that determines normality or pathology in relation to the genetic risk of cardiovascular disease. The results obtained demonstrate the possible role of mtDNA mutations in the control region on the pathogenesis of stroke and myocardial infarction, and show the importance of including this regulatory region in genetic association studies.

Aim To assess the role of human platelet antigens (HPA), P-selectin gene (SELP) polymorphisms, and HPA and SELP haplotypes with factor V (FV) R506Q in ischemic pediat - ric stroke (IPS) subtypes: cerebral sinovenous thrombosis (CSVT), perinatal (PAIS), and childhood (CAIS) arterial isch - emic stroke. Methods This case-control study enrolled 150 children with confirmed IPS and 150 age- and sex-matched con - trols. FV R506Q and HPA-1 were genotyped with CVD Stri - pAssay®, HPA-2 and HPA-3 with real-time polymerase chain reaction, SELP S290N, V599L, and T715P with high resolu - tion melting analysis, and SELP N562D with sequence-spe - cific polymerase chain reaction. Results HPA-1b allele (odds ratio [OR] 2.75, 95% confidence interval [CI] 1.02-7.42, P =0.048) and HPA-1a2a3b (OR 5.46, 95% CI 1.51-19.76, P =0.011), HPA-1b2a3a (OR 7.00, 95% CI 1.25-39.13, P =0.028), and HPA-1b2b3a (OR 11.39, 95% CI 1.39-92.95, P =0.024) haplotypes increased the risk for CSVT. HPA-3b allele was significantly associated with 2-fold lower risk for PAIS (OR 0.49, 95% CI 0.26-0.89, P =0.020) and CAIS (OR 0.47, 95% CI 0.26-0.86, P =0.014) and non-signifi - cantly associated with increased risk for CSVT (OR 6.43, 95% CI 0.83-50.00, P =0.022). HPA-1a2b3a haplotype was significantly associated with CAIS (OR 6.76, 95% CI 2.13-21.44, P=0.001). The inclusion of FV R506Q in SELP haplotype analysis increased the risk for PAIS 4-fold in QNDVT carri - ers (OR 8.14, 95% CI 0.93-71.33, P =0.060) compared with NDVT haplotype (OR 2.45, 95% CI 0.98-6.18, P =0.058), but the result was not significant. Conclusion Individual HPAs, and particularly HPA haplo - types, are involved in IPS subtypes pathogenesis. A possi - ble risk-inducing synergistic effect of SELP haplotypes with FV R506Q is restricted to PAIS only.