P485Variation in DNA repair genes and risk of cardiovascular events

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Abstract

Purpose

DNA repair processes might play a role in cardiovascular disease (CVD) development and progression. DNA damage can induce cell death that promotes unstable plaque formation. Defects in DNA repair mechanisms may therefore increase the risk of CVD events. We systematically examined whether common genetic variation in DNA repair genes may influence the risk of CVD disease progression and events.

Methods

The DNA biobank from 5,244 subjects of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) was studied. PROSPER was a cardiovascular intervention clinical trial in which collected clinical endpoints included cardiovascular and cerebrovascular events. DNA repair genes were chosen using a systematic pathway approach. A total of 77 single nucleotide polymorphisms (SNPs) within 29 genes of three major DNA repair pathways were selected. Genotyping was performed using Illumina Human 660-Quad Beadchips. Associations with clinical endpoints were tested with trend analysis and a correction for multitesting was applied.

Results

A total of 5 SNPs in 5 different genes were significantly associated with a cardiovascular endpoint. Using the GWAS data exploration of the genomic region of these 5 genes resulted in identification of 3 additional independent loci in the SMARCA2 gene associated with fatal/non-fatal stroke. After calculation of a risk score, the increasing number of risk alleles of SMARCA2 showed a strong association with fatal/non-fatal stroke. Per additional risk allele, the risk for stroke increased, HR 1.30 (95% CI 1.17-1.44), p=1.0E-6.

Conclusion

In this explorative study we found an association with cardiovascular endpoints of the genetic variation in 5 genes involved in DNA repair. These associations provide a signal that DNA repair processes indeed may be involved in the development and progression of CVD. These hypotheses-generating findings require extension by replication and functional analysis.

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