Abstract 12819: Genetic Variation in Dna Repair Genes and Cardiovascular Disease
Purpose: DNA repair deficiencies have been postulated to play a role in the development and progression of cardiovascular disease (CVD). The hypothesis is that DNA damage may induce cell death that promotes formation of unstable plaques. Defects in the DNA repair mechanisms may therefore increase the risk of cardiovascular events. Using a DNA repair pathway approach we systematically examined whether common genetic variation in DNA repair genes influence the risk of cardiovascular disease progression and cardiovascular events.
Methods: DNA repair genes were selected using a systematic pathway approach and a total of 59 single nucleotide polymorphisms (SNPs) within 24 genes were selected using several criteria such as adequate heterogeneity, LD pattern and validation status. Eleven additional SNPs from literature were added. Genotyping was performed using Illumina Human 660-Quad Beadchips in 5244 subject of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. Collected endpoints in PROSPER included several cardio- and cerebro-vascular related endpoints as well as cancer deaths. Associations were tested with trend analysis using PLINK, the threshold for significance was set at p <0.013 after Bonferroni correction.
Results: A polymorphism in the excision repair gene ERCC5 (rs873601) was associated with an increased risk of myocardial infarction, OR 1.21 (95% CI 1.06-1.39), p=0.0062, but a decreased risk of fatal cancer, OR 0.70 (0.54-0.91), p=0.0087. The previously published SNP rs2072671 in the cytidine deaminase gene was associated with CVD mortality, OR 1.36 (1.14-1.63), p=0.00085. In SMARCA2, also involved in the excision repair machinery, the rs6475422 variant allele was associated with an increase in the risk of stroke OR 1.34 (1.08-1.67), p=0.0089.
Conclusion: In this explorative study we found SNPs in several DNA repair genes to be potentially associated with differential CVD endpoints. Especially interesting is the paradoxal association found with the ERCC5 gene. We propose the theory that DNA damage leads to more vulnerable plaques and subsequent plaque rupture whereas it enhances the effects of fatal cancer. These hypotheses-generating findings require extension by replication and functional analysis.
- © 2011 by American Heart Association, Inc.