Resumen de Adn mitocondrial i risc cardiovascular
In recent years, several studies have focused on understanding the role of nuclear and, to a lesser extent, mitochondrial genetic determinants, in cardiovascular diseases to prevent clinical events. Although most studies have tried to predict cardiovascular risk using a genetic risk scores based on nuclear variants, so far no risk score was developed using the mitochondrial genome.
The main goals of this thesis are summarized in the following three points: 1) to analyse the state of mortality and hospital morbidity from the most relevant cardiovascular diseases in Spain; 2) to determine the possible association of control region variants of the mitochondrial genome with the susceptibility to develop a myocardial infarction and stroke; and 3) to assess whether the incorporation of mitochondrial variants in a genetic risk score, based in nuclear SNPs, improves the ability to discriminate and predict cardiovascular risk.
The methods as well as the presentation of the results and the discussion were organized in 4 chapters aimed to answer the defined objectives. In chapter 1, a descriptive epidemiological study that responds to the need to update the mortality and morbidity data of the main subtypes of cardiovascular disease, by age and sex, in all the Spanish autonomous communities over the last 15 years has been carried out. The results obtained show that cardiovascular diseases continue to be one of the main causes of mortality and morbidity in Spain. However, there is also a decrease in standardized mortality rates by age.
Bearing this in mind, mitochondrial DNA has been considered for analysis in individuals residing in in the Spanish autonomous community of Castile and Leon who come from cross-sectional, observational and descriptive study. For this reason, in chapter 2 of this thesis the link between mitochondrial haplogroups and two cardiovascular diseases, myocardial infarction and stroke, and the classic cardiovascular risk factors, was investigated. The data obtained showed suggestive evidence that haplogroup H can act as a genetic risk factor for myocardial infarction. Additionally, in relation to classic risk factors, the results also suggested a beneficial role of haplogroup J against hypertension.
In chapter 3, for the same Castile and Leon population, the role of fixed and heteroplasmy mutations of the mitochondrial DNA control region, which act as independent risk factors from haplogroups, was analysed. In this case, significant differences were also observed, reporting that the variants m.16.145G> A and m.16.311T> C could act as possible risk factors in the development of stroke, while variants m.72T>C, m.73A>G and m.16.356T>C could act as possible beneficial genetic factors for myocardial infarction.
Taking into account the results obtained, a final analysis (chapter 4) was carried out in order to evaluate the magnitude of the mitochondrial genetic information in improving the ability to discriminate cardiovascular diseases. A risk score was created based on the additive model that adds the susceptibility alleles from the 11 nuclear SNPs and the 5 mitochondrial positions described above. The addition of mitochondrial variants improves, in this population, the ability to discriminate cardiovascular diseases beyond the set of classic risk factors and nuclear SNPs.
In summary, the results presented in this thesis show the influence of mitochondrial variants on cardiovascular diseases. This is the first work to evaluate the use of a risk score that incorporates the mitochondrial genome and that significantly improves the ability to discriminate cardiovascular events.
