To shifted to QR and RR carriers closer

To further derive support for the role of Q192R in
CAD development, we analyzed the distribution of confounding variables in CAD
patients according to Q192R genotype. We found the QR and RR genotypes to be
significantly associated with cholesterol, triglycerides, LDL, MDA and reduced
levels of HDL and PON1 activity. These all parameters shifted to QR and RR
carriers closer to the impending risk of atherosclerosis suggest that possible
participation of the Q192R polymorphism in CAD etiology. Interestingly, our
data showed that CAD patients carrying the RR and QR genotypes had
significantly high levels of lipids, when compare to QQ genotype. These above
results are agreement with Hassan et al 9 and Saha et al 50, demonstrated
that PON1 polymorphism affects the lipid profile in CAD disease. Moreover,
Ombres et al 51. revealed that the 192QQ genotype is associated to less
atherogenic lipid profile and also he hypothesized that low serum PON1 activity
alleles are associated with a decrease transfer of lipids between HDL and LDL. So
many studies revealed that increase of MDA in CAD patients 6, 52. In our
study, significant increase of lipid peroxidation marker i.e. MDA concentration
was found in CAD patients compare to controls (7.1 ±1.5 vs 3.9 ±0.9)
respectively. We also observed that the individual of RR genotypes had higher
levels of serum MDA than the QR and QQ genotypes (p<0.051). Similar results were seen in North African population study 15. A recent case control study from Chandrasekaran et al 29, observed that RR and QR genotypes having a significant low PON1 activity compare to QQ genotype. In the present study, we also observed the lower PON1 activity was associated with all 3 PON1 genotypes (QQ, QR and RR). There was a significant low PON1 activity among in RR genotypic individuals (68.5 ±11.5) when compared to QR (75.8 ±10.8) and QQ (86.3 ±11.0) genotypes. P value is 0.002 suggesting the fact that RR genotype is associated with low PON1 activity and this low activity makes a person more susceptible to atherosclerosis. The possible mechanism for replacement of glutamine by arginine in 192nd position reduces the affinity of N- terminal amphipathic helix of PON enzyme with HDL thereby the enzyme gets destabilized and the activity is lowered. Recently prospective case- controlled study, observed that RR genotypes having a lower PON1 activity compare to QR and QQ genotypes 53. Finally, we carried out multiple logistic regression analysis of PON1 gene polymorphism and the confounding variables i.e. age, gender; hypertension, obesity and smoking have no such significant association in relation to Q192R with CAD risk. The significant p value for HDL, MDA, PON1 activity and PON1 gene polymorphism (QR and RR genotype) indicate that alteration of these parameters will affect the risk of CAD disease. Whereas interestingly, the odds of developing CAD were increased close to 2.706 - fold in the RR genotypes compared to healthy controls in Saudi populations. Our results were consistent with recent findings of Saudi Arabian, North African and South Indian studies also reported that CAD with RR genotype has more than 2 to 3 fold risk of developing coronary arthrosclerosis 9, 15, 29.      The Q192R polymorphism in the PON1 gene hinders the ability of PON1 to inhibit oxidation of LDL, because the R192 allele is less potent than Q192 allele in preventing LDL oxidation. The ability of recombinant PON1 is decreased due to the presence of arginine in place of glutamine, reflecting the anticipate effect of the Q192R polymorphism. Furthermore, subjects with the RR genotype are more prone to experience coronary spasm, which reflect endothelial dysfunction related to oxidative damage, providing further more support that the R allele could increase the susceptibility to CHD 54.    Human epidemiological and experimental studies provide convincing evidence that PONs play a very important role in protection against atherosclerosis 55. So the measuring of the PON1 activity is a useful informative in predicting future CAD risk, It is very important to suggest that PON1 enzyme activity can be used as cardiovascular disease prediction best marker in diagnostic tool. The present study had several limitations, study cohorts were relatively small for both cases and controls and it was a hospital based study. So we can't represent over the entire population. We believe that it is necessary to conduct large cohort studies on this additional genetic polymorphism, haplotypes, and other genes that might be related to PON1 gene function.   5. Conclusion This will be first report to measure PON1 Q192R polymorphism in CAD disease among the Saudi population in Central province (Al- Quwayiyah region) of Saudi Arabia. The study illustrated that significant association was observed between the RR genotype of the PON1 polymorphism and low serum PON1 activity may be a potent independent risk factor for coronary atherosclerosis in Saudi populations and suggests that it may have prognostic value. We strongly predict that the PON1 is an important enzyme in oxidant - antioxidant status of atherosclerosis with its antioxidant effect. Therefore, assessing of enzyme PON1 activity can be used as prediction marker in diagnostic tool for cardiovascular disease. Future Prospects in Clinical Research Moreover, now 3- D structure of PON1 has been determined. These needs to be a establish in future. Experiments aimed at identifying the strategies to improve PON activity can be performed. The PON1 enzyme activity is considered as a promising target for pharmaceutical intervention. Therefore pharmacological modulations of PON1 activity or PON1 gene expression could constitute a useful approach for the prevention of CAD.