Laura Stocchi1, Emanuela Polidori2, Lucia Potenza3, Marco Bruno Luigi Rocchi2, Cinzia Calcabrini2, Paolo Busacca4, Maria Capalbo5, Domenico Potenza6, Francesca Amati1, Ruggiero Mango7, Francesco Romeo8, Giuseppe Novelli9, Vilberto Stocchi2. 1. Department of Biomedicine and Prevention, University of Tor Vergata, Rome, Italy. 2. Department of Biomolecular Sciences, University of Urbino Carlo Bo, Italy. 3. Department of Biomolecular Sciences, University of Urbino Carlo Bo, Italy. Electronic address: lucia.potenza@uniurb.it. 4. Complex Operative Unit of Cardiology (UOC),Santa Maria della Misericordia Hospital, Urbino, Italy. 5. ASUR Marche-Area Vasta 1, Italy. 6. Complex Operative Unit of Cardiology (UOC), IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy. 7. Complex Operative Unit of Cardiology (UOC), Polyclinic Tor Vergata, Rome, Italy. 8. Complex Operative Unit of Cardiology (UOC), Polyclinic Tor Vergata, Rome, Italy; Department of System Medicine, University of Tor Vergata, Rome, Italy. 9. Department of Biomedicine and Prevention, University of Tor Vergata, Rome, Italy; St. Peter Fatebenefratelli Hospital, Rome, Italy; Department of Internal Medicine, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
Abstract
BACKGROUND: Brugada syndrome (BrS) is a primary electrical disease associated with an increased risk of sudden cardiac death due to ventricular fibrillation. This pathology has nuclear heterogeneous genetic origins, and at present, molecular diagnostic tests on nuclear DNA cover only 30% of BrS patients. The aim of this study was to assess the possible involvement of mitochondrial (mt) DNA variants in BrS since their etiological role in several cardiomyopathies has already been described. METHODS AND RESULTS: The whole mt genome of BrS patients was sequenced and analyzed. A specific mtDNA mutation responsible for BrS can be excluded, but BrS patient d-loop was found to be more polymorphic than that of control cases (P=0.003). Moreover, there appears to be an association between patients with the highest number of variants (n>20) and four mt Single Nucleotide Polymorphism (SNPs) (T4216C, A11251G, C15452A, T16126C) and the most severe BrS phenotype (P=0.002). CONCLUSIONS: The high substitution rate found in BrS patient mtDNA is unlikely to be the primary cause of the disease, but it could represent an important cofactor in the manifestation of the BrS phenotype. Evidence suggesting that a specific mtDNA allelic combination and a high number of mtDNA SNPs may be associated with more severe cases of BrS represents the starting point for further cohort studies aiming to test whether this mt genetic condition could be a genetic modulator of the BrS clinical phenotype.
BACKGROUND:Brugada syndrome (BrS) is a primary electrical disease associated with an increased risk of sudden cardiac death due to ventricular fibrillation. This pathology has nuclear heterogeneous genetic origins, and at present, molecular diagnostic tests on nuclear DNA cover only 30% of BrS patients. The aim of this study was to assess the possible involvement of mitochondrial (mt) DNA variants in BrS since their etiological role in several cardiomyopathies has already been described. METHODS AND RESULTS: The whole mt genome of BrS patients was sequenced and analyzed. A specific mtDNA mutation responsible for BrS can be excluded, but BrS patient d-loop was found to be more polymorphic than that of control cases (P=0.003). Moreover, there appears to be an association between patients with the highest number of variants (n>20) and four mt Single Nucleotide Polymorphism (SNPs) (T4216C, A11251G, C15452A, T16126C) and the most severe BrS phenotype (P=0.002). CONCLUSIONS: The high substitution rate found in BrS patient mtDNA is unlikely to be the primary cause of the disease, but it could represent an important cofactor in the manifestation of the BrS phenotype. Evidence suggesting that a specific mtDNA allelic combination and a high number of mtDNA SNPs may be associated with more severe cases of BrS represents the starting point for further cohort studies aiming to test whether this mt genetic condition could be a genetic modulator of the BrS clinical phenotype.
Authors: Siarhei A Dabravolski; Victoria A Khotina; Vasily N Sukhorukov; Vladislav A Kalmykov; Liudmila M Mikhaleva; Alexander N Orekhov Journal: Int J Mol Sci Date: 2022-01-16 Impact factor: 5.923