title: Gene-gene interaction affects coronary artery disease risk.
abstract: BACKGROUND
  Various studies have compared coronary artery disease (CAD) patients with controls in order to determine which polymorphisms are associated with a higher risk of disease. The results have often been contradictory. Moreover, these studies evaluated polymorphisms in isolation and not in association, which is the way they occur in nature.
  
  
  OBJECTIVE
  Our purpose was to evaluate the risk of CAD in patients with associated polymorphisms in the same gene or in differen genes.
  
  
  METHODS
  We evaluated the risk associated with ACE DD, ACE 8 CC, ACT 174MM, AGT 235TT, MTHFR 677TT, MTHFR 1298AA, PON1 192RR and PON1 55MM in 298 CAD patients and 298 healthy individuals. We then evaluated the risk of associated polymorphisms in the same gene (ACE DD + ACE 8GG; AGT 174MM + AGT 235TT; MTHFR 677TT + MTHFR 1298AA). Finally, for the isolated polymorphisms which were significant, we evaluated the risk of polymorphism associations at different functional levels (ACE + AGT; ACE + MTHFR; ACE + PON1). Multiple logistic regression was used to identify independent risk factors for CAD.
  
  
  RESULTS
  Isolated polymorphisms including ACE DD(p < 0.0001), ACE 8 gg (p=0.023), and MTHFR 1298AA (p = 0.049) presented with a significantly higher frequency in the CAD group. An association of polymorphisms in the same gene did not have an additive or synergistic effect, nor did it increase the risk of CAD. Polymorphic associations in different genes increased the risk of CAD, compared with the isolated polymorphisms. The association of ACE DD or ACE 8 GG with PON1 192RR increased the risk of CA fourfold (1.8 to 4.2). After logistic regression analysis, current smoking, family history, fibrinogen, diabetes, and the ACE DD or ACE 8 GG + MTHFR 1298AA and ACE DD or ACE 8 GG + PON1 192RR associations remained in the, model and proved to be independent predictors of CAD.
  
  
  CONCLUSIONS
  The association of polymorphisms in the same gene did not increase the risk of the isolated polymorphism. The association of polymorphisms in genes belonging to different enzyme systems was always linked to increased risk compared to the isolated polymorphisms. This study may contribute to a better understanding of overall genetic risk for CAD rather than that associated with each polymorphism in isolation.
authors.affiliation: Unidade de Investigção, Hospital Central do Funchal, Funchal, Portugal. dep.card@srs.pt
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Mendonça
authors.forename: R Palma
authors.initials: RP
authors.lastname: Dos Reis
authors.forename: A Isabel
authors.initials: AI
authors.lastname: Freitas
authors.forename: Ana Célia
authors.initials: AC
authors.lastname: Sousa
authors.forename: Andreia
authors.initials: A
authors.lastname: Pereira
authors.forename: Paula
authors.initials: P
authors.lastname: Faria
authors.forename: Susana
authors.initials: S
authors.lastname: Gomes
authors.forename: Bruno
authors.initials: B
authors.lastname: Silva
authors.forename: Nuno
authors.initials: N
authors.lastname: Santos
authors.forename: Marco
authors.initials: M
authors.lastname: Serrao
authors.forename: Ilídio
authors.initials: I
authors.lastname: Ornelas
authors.forename: Sónia
authors.initials: S
authors.lastname: Freitas
authors.forename: C
authors.initials: C
authors.lastname: Freitas
authors.forename: José Jorge
authors.initials: JJ
authors.lastname: Araújo
authors.forename: António
authors.initials: A
authors.lastname: Brehm
authors.forename: A Almada
authors.initials: AA
authors.lastname: Cardoso
mesh_terms: D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000453:epidemiology* / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors