Interaction of paraoxonase-192 polymorphism with low HDL-cholesterol in coronary artery disease risk.
BACKGROUND
Coronary artery disease (CAD) is the main cause of mortality in developed countries. Increased lipid peroxidation is associated with accelerated progression of atherosclerosis. Paraoxonase (PON1) is an antioxidant enzyme bound to high-density lipoprotein (HDL), which protects against lipid peroxidation and coronary artery disease. PON1 activity is under genetic control and its molecular basis is a polymorphism in the PON1 gene that shows two common isoforms: the wild Q form (192 Gln) with high ability to protect LDL from lipid peroxidation in vitro, and the mutated R (Arg) form with lower ability.


OBJECTIVE
To explore the interaction of the R allele of the paraoxonase gene and low HDL-cholesterol concentrations in CAD risk.


METHODS
The study population consisted of 818 individuals, 298 coronary patients, aged 55.0 +/- 10.3 years, 78.9% male, and 520 age and gender matched healthy controls, aged 53.3 +/- 11.7 years, 72.5% male. Low HDL-cholesterol was defined as < 0.90 mmol/l in men and < 1.11 mmol/l in women. Comparisons of genotypes between cases and controls were performed by a chi-square test. Statistical significance was accepted at p < 0.05. Odds ratios and 95% confidence intervals for the RR genotypes and HDL-deficient subjects were computed using univariate analysis (2 x 2 tables). To determine the interaction between the RR paraoxonase genotype and HDL-deficient subjects, we used 4 x 2 epidemiologic tables and synergy measures: the additive model (Rothman's synergy index, SI) and multiplicative model (Khoury's synergy index, SIM). The relative excess risk due to interaction (RERI) and the attributable proportion (AP) due to interaction (Rothman) were calculated.


RESULTS
The PON1 RR192 polymorphism was associated with coronary heart disease (OR = 1.61; p = 0.043) in the whole population. HDL-deficient subjects with the RR192 genotype showed increased risk for CAD (OR = 17.38; p < 0.0001) compared to those with normal HDL and RR192 (OR = 1.39; p = 0.348) and HDL-deficient subjects not carrying the RR genotype (OR = 7.79; p < 0.0001). Synergy measures were SI = 2.3, SIM = 1.6; RERI = 9.2.


CONCLUSIONS
These data suggest the existence of a synergistic effect of the PON1 RR192 genotype (with lower antioxidant ability) and HDL-deficient subjects in risk for development of CAD. The AP due to this interaction was 0.53, meaning that 53% of CAD was explained by this interaction.
Mendonça
Maria Isabel
MI
Unidade de Investigação e Serviço de Cardiologia do Hospital Dr. Nélio Mendonça (Hospital Central do Funchal), Funchal, Madeira, Portugal. dep.card@srs.pt
Dos Reis
Roberto Palma
RP
Freitas
Ana Isabel
AI
Pereira
Andreia
A
Sousa
Ana Célia
AC
Freitas
Sónia
S
Ornelas
Ilídio
I
Freitas
Carolina
C
Brehm
António
A
Araújo
José Jorge
JJ
D043303:Aryldialkylphosphatase / Q000097:blood* / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors
D008076:Cholesterol, HDL; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human