Studies On Association And Meta-Analysis Of Genetic Variations Of Paraoxonase Gene In Coronary Heart Disease

Objective: The anti-atherogenic effect of HDL has been suggested to be partly due to the action of HDL-associated paraoxonase 1(PON1). Previous research suggested that PON acitivity was substantially influenced by polymorphism among PON gene. Hence, PON gene was a good candidate for CHD susceptibility. Besides, PON2 was also wildly studied for its genetic effect on CHD risk for similary function as PON1. To investigate the relationship between variation in PON gene and risk of coronary heart disease.Methods: Using TaqMan and sequencing method, we genotyped 4 wildly studied polymorphisms [Q192R, L55M, and T(?107)C in the PON1 and the S311C in the PON2] among PON gene in 473 patients with CHD and in 616 healthy controls. Besides, paraoxonase activity was measured spectrophotometrically using paraoxon as a substrate. In addition, we investigate the relationship between plasm lipid level and different genotype distribution among cases and controls.Result: Marginal association was detected between Q192R polymorphism in PON1 gene and CHD risk with a per-allele OR of 1.21 (95%CI: 1.01-1.44) and 1.41 (95%CI: 1.09-1.83) for homozygote. Howevery, such resules was not found among myocardial infarction patients. In addition, no significant association between was found between L55M, T(?107)C, S311C variations and coronary heart disease or myocardial infarction risk which is supported by haplotype analysis. Unfortunately, we failed to found any association between CAD servity and theses polymorphisms mentioned above. We also found a decreased PON activity in CHD patients compared to the control group (P <0.001). In addition, we also didn't find these polymorphisms on lipid levels significantly influenced.Conclusions: Our results suggest that there is marginal significant association between Q192R variation on PON1 gene and coronary heart disease risk. However, we failed to found any association between L55M, T(?107)C, S311C polymorphisms and CHD susceptibility. Objective: The human paraoxonase (PON) is calcium dependent HDL associated ester hydrolase which has attracted considerable attention as a candidate gene for coronary heart disease based on its enzyme function as a key factor in lipoprotein catabolism pathways. Many studies have examined the association between polymorphisms in the PON gene and risk of coronary heart disease (CHD), but the results have been inconsistent. The purpose of this study try to find these inconsistent reason and get a comprehensive conclusion.Methods: Through searching public data base, we conducted a meta-analysis of 88 studies on 4 PON polymorphisms [Q192R, L55M, and T(?107)C in the PON1 and the S311C in the PON2] published before August 2010, including a total of 24,702 CHD cases and 38,232 controls. We also systematically explored potential sources of heterogeneity.Result: In a combined analysis, using random effects model, the summary per-allele odds ratio for CHD of the 192R was 1.11 (95% CI: 1.05–1.17). However, when the analyses were restricted to 10 larger studies (n > 500 cases), the summary per-allele odds ratio was 0.96 (95% CI: 0.90–1.02). Our analyses detected a possibility of publication bias with an overestimate of the true association by smaller studies. In the subgroup analysis by ethnicity, significant associations were found among other population, while such positive results were not found among East Asians or Caucasians. Further stratified according to endpoint, significant results were identified for stenosis subgroup. However, no associations were detected in MI subgroup. Haplotype analysis suggested that there is interaction Q192R and L55M polymorphism which could modify CHD susceptibility. A meta-analysis of studies on the 55M, (?107)T, and 311C variant showed no significant overall association with CHD, yielding a per-allele odds ratio of 0.94 (95% CI: 0.88–1.00), 1.02 (95% CI: 0.91–1.15) and 1.02 (95% CI: 0.90–1.16) respectively. Sensitivity analysis and cumulative analysis suggested that the pooled result is robust.Conclusions: This meta-analysis suggested an overall weak association between the R192 polymorphism and CHD risk. For future study, larger studies of different ethnic populations, especially with detailed individual information, are needed to confirm our findings.