Abstract
PurposeDNA repair deficiencies have been postulated to play a role in the development and progression of cardiovascular disease (CVD). The hypothesis is that DNA damage accumulating with age may induce cell death, which promotes formation of unstable plaques. Defects in DNA repair mechanisms may therefore increase the risk of CVD events. We examined whether the joints effect of common genetic variants in 5 DNA repair pathways may influence the risk of CVD events.MethodsThe PLINK set-based test was used to examine the association to myocardial infarction (MI) of the DNA repair pathway in GWAS data of 866 subjects of the GENetic DEterminants of Restenosis (GENDER) study and 5,244 subjects of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. We included the main DNA repair pathways (base excision repair, nucleotide excision repair, mismatch repair, homologous recombination and non-homologous end-joining (NHEJ)) in the analysis.ResultsThe NHEJ pathway was associated with the occurrence of MI in both GENDER (P = 0.0083) and PROSPER (P = 0.014). This association was mainly driven by genetic variation in the MRE11A gene (PGENDER = 0.0001 and PPROSPER = 0.002). The homologous recombination pathway was associated with MI in GENDER only (P = 0.011), for the other pathways no associations were observed.ConclusionThis is the first study analyzing the joint effect of common genetic variation in DNA repair pathways and the risk of CVD events, demonstrating an association between the NHEJ pathway and MI in 2 different cohorts.
Highlights
Cardiovascular disease (CVD) is caused by interplay of environmental factors and multiple predisposing genes
The non-homologous end-joining (NHEJ) pathway was associated with the occurrence of myocardial infarction (MI) in both GENetic DEterminants of Restenosis (GENDER) (P = 0.0083) and PROSPER (P = 0.014)
This association was mainly driven by genetic variation in the meiotic recombination 11 homolog A (MRE11A) gene (PGENDER = 0.0001 and PPROSPER = 0.002)
Summary
Cardiovascular disease (CVD) is caused by interplay of environmental factors and multiple predisposing genes. DNA damage, caused by for instance oxidative stress and cigarette smoking, has been recognized as a significant contributor to the pathogenesis of CVD. [1,2] Mechanistically, in cells where the DNA damage is beyond repair apoptosis is induced. [3] The effect of this damage induced cell death is dependent on the cell type. [5,6] To further complicate matters, apoptosis is not the only response of cells to DNA damage, cellular senescence has been described. [7] So besides cell death, DNA damage could increases the risk of CVD by inducing cell senescence. Adequate DNA repair is crucial for survival of an organism, as the DNA is continuously exposed to various types of external factors, like mutagenic chemicals and radiation, and endogenously generated triggers like reactive oxygen species (ROS) and DNA replication errors, all capable of inducing DNA damage. For the repair of double-strand breaks other repair mechanisms like non-homologous end-joining (NHEJ) or homologous recombination are required. [10]
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