Allele frequency in population:
According to the 1000 Genomes database, the A allele has a frequency of 46% in the general population.
Gene and SNP Summary
PON1 encodes the glycoprotein enzyme paraoxonase, which has broad substrate specificity and is able to catalyse the hydrolysis of lipid peroxides, lactones, and organophosphate pesticides. Paraoxonase is partly responsible for the inhibitory and cardioprotective effect of HDL cholesterol on lipid peroxidation by attaching to HDL particles in serum, and inhibiting LDL oxidation, thus protecting against atherogenesis. The G allele, specifically the GG genotype, is associated with lower concentrations of PON1 and decreased PON1 hydrolytic activity. This SNP has been linked to increased risk for atherosclerosis, ischaemic stroke, metabolic syndrome, and certain cancers.
PON1 Gene Detail
PON1 encodes the enzyme, paraoxanase 1. This enzyme is synthesised in the kidney and the liver and is then secreted into circulation, exhibiting broad substrate specificity, including lactonase and ester hydrolase activity, where it binds to HDL cholesterol and is responsible for the hydrolysis of thiolactones and xenobiotics including organophosphate pesticides. PON1 is important in mediating the enzymatic protection of low density lipoproteins and polyunsaturated fatty acids (PUFAs) against oxidative modification, thus protecting against atherosclerosis.
PON1 and SNPs on the gene has been linked with several inflammatory diseases including atherosclerosis, diabetes, liver and kidney diseases, rheumatic diseases, macular degeneration, and certain cancers.
Modification of PON1 expression can occur through several factors, including environmental and genetic factors. The PON1 gene is activated by PPAR-γ, which increases synthesis and release of paraoxonase 1 enzyme from the liver, thus reducing atherosclerosis burden. Components of the Mediterranean diet have also been found to have a nutrigenomic effect on the gene, leading to increased expression of PON1.
The PON1 G>A, or Gln192Arg, SNP has been associated with having an abnormal lipogram and an increased risk for CVD, as well as raised homocysteine levels, and predisposition to some cancers. The G allele leads to a decrease in the PON1 catalytic activity, and PON1 GG genotype individuals seem to be particularly at risk.
In individuals with the GG genotype it was found that smoking increased the atherogenic index of the plasma from (estimated mean ± SEM) -0.038 ± 0.039 to 0.224 ± 0.094. Smoking by GG genotype carriers significantly increased the Framingham risk score (17.23 ± 2.04) as compared to smoking (13.00 ± 1.06) and non-smoking (7.79 ± 0.70) by AA and AG genotype carriers. GG genotype carriers who were also smokers had a significantly increased risk for raised triglycerides and lowered HDL cholesterol. It is thus imperative for PON1 GG individuals to stop smoking.
Adherence to the Mediterranean diet, and incorporating components of the diet into the intervention plan; including focusing on decreasing saturated fat intake, increasing dietary intake of monounsaturated fats (MUFAs) such as olives and avocado, and including a variety of phytonutrient rich, plant-based foods, will lead to increased expression of the gene. Individuals of the GG genotype should consider adapting their lifestyle accordingly.
It has also been shown that regular physical activity is associated with improved HDL levels, especially in G allele carriers, and so regular exercise should also be encouraged.
Associations of PON1 rs662 polymorphism with circulating oxidized low-density lipoprotein and lipid levels: a systematic review and meta- analysis.
Luo et al, 2019