title: Non-homologous end-joining pathway associated with occurrence of myocardial infarction: gene set analysis of genome-wide association study data.
abstract: OBJECTIVE
  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 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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  This 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.
authors: Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
authors: Jeffrey J W
authors: JJ
authors: Verschuren
authors: Stella
authors: S
authors: Trompet
authors: Joris
authors: J
authors: Deelen
authors: David J
authors: DJ
authors: Stott
authors: Naveed
authors: N
authors: Sattar
authors: Brendan M
authors: BM
authors: Buckley
authors: Ian
authors: I
authors: Ford
authors: Bastiaan T
authors: BT
authors: Heijmans
authors: Henk-Jan
authors: HJ
authors: Guchelaar
authors: Jeanine J
authors: JJ
authors: Houwing-Duistermaat
authors: P Eline
authors: PE
authors: Slagboom
authors: J Wouter
authors: JW
authors: Jukema
mesh_terms: D000368:Aged; D002874:Chromosome Mapping; D004249:DNA Damage / Q000235:genetics; D059766:DNA End-Joining Repair / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics