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Paraoxonase activity in two healthy populations with differing rates of coronary heart disease
B MacKness1, M I Mackness, P N Durrington
1Manchester Royal Infirmary, University Department of Medicine, Oxford Road, Manchester, UK.
Insights
Populations with higher coronary heart disease risk show lower serum paraoxonase-1 (PON1) concentrations and more frequent R alleles. This suggests PON1
Area of Science:
- Cardiovascular Genetics
- Biochemistry
- Epidemiology
Background:
- Coronary heart disease (CHD) rates are significantly higher in Belfast compared to Toulouse.
- Classical risk factors do not fully explain this disparity in CHD risk.
Purpose of the Study:
- To investigate the association between the human serum paraoxonase (PON1) 192-genetic polymorphism and lipid/lipoprotein profiles.
- To compare PON1 activity and concentration in healthy subjects from Belfast and Toulouse.
Main Methods:
- Examined 186 healthy subjects from Toulouse and 165 from Belfast.
- Assessed the PON1 192-genetic polymorphism, plasma lipid and lipoprotein concentrations, and PON1 activity and concentration.
Main Results:
- The PON1 R allele frequency was higher in Belfast (0.33) than Toulouse (0.24).
- Belfast subjects had higher cholesterol, triglycerides, LDL-C, and ApoB, and lower HDL-C and ApoA1, independent of PON1 genotype.
- PON1 activity was higher in Belfast, but serum PON1 concentration was lower compared to Toulouse.
Conclusions:
- Increased CHD risk is linked to diminished serum PON1 concentration and higher PON1 R allele prevalence.
- These findings support PON1's role in atherogenesis, with potential inverse relationship between paraoxon hydrolysis and lipid-peroxide hydrolysis.
Background:
The rate of coronary heart disease is over three-fold greater in Belfast than in Toulouse and the excess risk cannot be totally explained by 'classical' risk factors such as total cholesterol, LDL-cholesterol, smoking, etc.
Design:
The effect of the human serum paraoxonase (PON1) 192-genetic polymorphism on plasma lipid and lipoprotein concentrations and on PON1 activity and concentration was investigated in 186 randomly selected healthy subjects from Toulouse and 165 from Belfast.
Results:
The frequency of the R allele of PON1, which has been related to the risk of coronary heart disease, was significantly higher in Belfast (0.33) than in Toulouse (0.24; chi2 = 7.229, P = 0.0072). Subjects from Belfast also had significantly higher serum cholesterol, triglycerides, LDL-cholesterol, and apolipoprotein B, and significantly lower HDL-cholesterol and apolipoprotein A1, but these lipoprotein parameters were independent of the PON1 192-polymorphisms. PON1 activity towards paraoxon was significantly higher in the Belfast population than in Toulouse (median values: 179.7 vs. 129.4 nmol min-1 mL-1 serum, respectively; P < 0.05), which is consistent with our finding of a greater prevalence of the R allele. The median serum concentration of PON1 was 56.3 microgram mL-1 in Belfast, which was significantly lower (P < 0.005) than the level of 71 microgram mL-1 in Toulouse.
Conclusions:
Our results thus provide further support for the hypothesis that populations at increased CHD risk have diminished serum PON1 concentration and an increased prevalence of the R allele of PON1. They are also consistent with reports that the ability of PON1 to hydrolyse paraoxon is inversely related to its capacity to hydrolyse lipid-peroxides, and thus to its antiatherogenic action.