Abstract 12814: Non-Homologous End-Joining Pathway Associated with Occurrence of Myocardial Infarction: Bioinformatical Pathway Analysis of Genome-Wide Association Study Data
Introduction: DNA repair deficiencies have been postulated to play a role in the development and progression of cardiovascular disease. The hypothesis is that DNA damage may induce cell death that promotes formation of unstable plaques. Defects in DNA repair mechanisms may therefore increase the risk of cardiovascular disease (CVD) events. In the genome-wide association studies (GWAS) on cardiovascular diseases no association was found with genetic markers in DNA repair genes. However, considering the multi-factorial nature of the condition it is likely that more factors, with small individual effect sizes, are involved besides those detected in GWAS. We examined whether the combined effect of common genetic variation in DNA repair pathways may influence the risk of CVD events.
Methods: GWAS data of 866 subjects of the GENetic DEterminants of Restenosis (GENDER) study and of 5,244 subjects of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study were analyzed. Using the PLINK set-based test the relation of the 5 main DNA repair pathways (base excision repair, nucleotide excision repair, mismatch repair, homologous recombination and non-homologous end-joining), as described by the KEGG database, with prevalent and incident myocardial infarction (MI) was examined by selecting all single nucleotide polymorphisms in the genetic region of all genes involved in each pathway and analyzing their joint effect on the endpoint MI.
Results: The non-homologous end-joining pathway was associated with the occurrence of MI in both GENDER (P=0.0083) and PROSPER (P=0.014). The association appears to be mainly driven by genetic variation in het MRE11A gene (PGENDER=0.0001 and PPROSPER=0.0017). The homologous recombination pathway was associated with MI (P=0.011) in GENDER, but not in PROSPER (P=0.14). The other pathways were not associated with MI.
Conclusion: This is the first study to analyze the joint effect of common genetic variation in DNA repair pathways and the risk of CVD events, demonstrating an association between the KEGG non-homologous end-joining pathway and myocardial infarction in 2 different cohorts.
- © 2012 by American Heart Association, Inc.