Cleveland, OH - A new study published this week provides evidence of a mechanistic link between a variant of the paraoxonase 1 (PON1) gene and cardiovascular disease events [1]. Investigators showed that functional PON1 gene polymorphisms promote pronounced systemic antioxidant effects in humans, and these effects translate into reductions in coronary artery disease prevalence and risks of major adverse cardiac events.

"The whole study paints a unified picture that there is a genetic variant in the PON1 gene that encodes for a change that actually determines whether you have a high or low activity of the gene, and we see that this strongly correlates with high or low levels of oxidative stress," said senior investigator Dr Stanley Hazen (Cleveland Clinic, OH). "So, high activity levels of the gene translate into low amounts of oxidative stress, and all of this goes hand in hand with cardiovascular protection."

The results of the study, with lead author Dr Tamali Bhattacharyya (Cleveland Clinic), are published in the March 19, 2008 issue of the Journal of the American Medical Association, a special issue devoted to genetics and genomics.

Speaking with heartwire, Hazen explained that PON1 is an HDL-associated protein that "piggybacks" on the HDL particle in the blood and that the PON1 gene has been linked to atherosclerosis protection for more than 10 years. In animals and cell culture, PON1 mediates many of the beneficial effects of HDL cholesterol, such as reducing inflammation and improving reverse transport of cholesterol from the peripheral tissues to the liver. It is also believed to have antioxidative capabilities, but data on atheroprotective effects of the protein in humans, said Hazen, are mixed.

"It's a very interesting protein," said Hazen. "PON1 was first identified as a gene that protects against atherosclerosis in mice models, and it has been linked to atherosclerosis protection for over a decade, but we've been in search of its function. . . . No study has looked at the gene polymorphisms and functional activity and connected this to outcomes data. None has linked all of it together."

One recent meta-analysis of 43 studies examining various single-nucleotide polymorphisms (SNPs) for PON1 identified Q192R as the most promising, although the SNP had only a weak overall association with coronary heart disease. It remained to be established whether the genetic and biochemical determinants of PON1 are linked to oxidative stress and cardiovascular disease risk, said Hazen.

To examine the association between PON1 functional activity, such as the anti-inflammatory and antioxidant effects, and to determine if the PON1 variant Q192R was associated with a higher rate of cardiovascular disease and major adverse cardiac events, such as MI, stroke, or death, investigators obtained DNA samples from 1399 patients undergoing elective diagnostic coronary angiography between September 2002 and November 2003. Patients were followed until December 2006.

There were significant dose-dependent associations between the PON1 genotype and decreased levels of serum PON1 activity, as well as significant associations between the PON1 variants and increased levels of systemic oxidative stress. Following this, the risk of major adverse cardiac events was significantly lower in participants with the highest amount of PON1 functional activity compared with those in the lowest activity quartile. Investigators also report that the PON1 Q192R polymorphism and serum PON1 activity were associated with coronary artery disease and adverse cardiovascular events over the ensuing three-year follow-up period.

"If you have the genotype that encodes a high amount of PON1 activity, you have low oxidative stress, and you have low cardiovascular risk," said Hazen. "Alternatively, if you have the genotype that has very low amounts of activity, you have a high degree of oxidative stress, and you have a substantial increase in risk for experiencing a heart attack or stroke or dying."

Hazen told heartwire that the group also looked at whether knowing the genotype or the biochemical activity, on top of traditional risk factors, added prognostic value. In terms of the ability to predict a major adverse cardiac event, such as heart attack, stroke, or death, the PON1 variants and activity levels both predicted adverse events above and beyond traditional risk factors, he said. Even among those with no known history of cardiovascular disease, high levels of PON1 activity translated into an increased risk of cardiovascular events, he added.