Gene-gene interaction affects coronary artery disease risk.
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.
Mendonça
Maria Isabel
MI
Unidade de Investigção, Hospital Central do Funchal, Funchal, Portugal. dep.card@srs.pt
Dos Reis
R Palma
RP
Freitas
A Isabel
AI
Sousa
Ana Célia
AC
Pereira
Andreia
A
Faria
Paula
P
Gomes
Susana
S
Silva
Bruno
B
Santos
Nuno
N
Serrao
Marco
M
Ornelas
Ilídio
I
Freitas
Sónia
S
Freitas
C
C
Araújo
José Jorge
JJ
Brehm
António
A
Cardoso
A Almada
AA
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