HDL-Associated Protein Gene Linked to Heart Disease Risk

The gene for the HDL-associated protein paraoxonase 1 (PON1) appears to be associated with coronary artery disease and with the risk of developing adverse cardiac events, and variations in both the PON1 gene and its related enzyme activity may increase the risk for cardiovascular disease events, according to a study in the March 19 issue of JAMA, a theme issue on Genetics and Genomics.

Stanley L. Hazen, M.D., Ph.D., of the Cleveland Clinic, presented the findings of the study at a JAMA media briefing at the National Press Club in Washington, D.C.

Despite evidence that PON1 prevents atherosclerosis in animals, a cardio-protective role in humans has not been established. Several studies have suggested that PON1 may have antioxidant and cardio-protective properties, according to background information in the article.

Dr. Hazen and colleagues conducted a study to examine the association between PON1 activity (such as anti-inflammatory and antioxidant activities) and if a PON1 gene variation (polymorphism) Q192R were associated with a higher rate of cardiovascular disease and major adverse cardiac events (heart attack, stroke or death). The study included 1,399 patients undergoing elective diagnostic coronary angiography between September 2002 and November 2003, and were followed-up until December 2006.

The researchers found that the incidence of major adverse cardiac events was significantly lower in participants in the highest PON1 activity quartile (7.3 percent for paraoxonase) compared with those in the lowest activity quartile (25.1 percent for paraoxonase).

The results also indicated that variations of the PON1 gene demonstrated significant dose-dependent associations with decreased levels of serum PON1 activity and increased levels of measures of oxidative stress (damage to cells and tissues from an imbalance between excess free radicals and not enough antioxidants), and that the PON1 Q192R polymorphism and serum PON1 activity were associated with both coronary artery disease and adverse cardiovascular events over the ensuing three year period after enrollment in the study.

“The current findings provide direct prospective evidence of an important mechanistic link between the PON1 gene and PON1 systemic activity measures with both multiple quantitative indices of oxidative stress and atherosclerotic heart disease development in humans. Paraoxonase 1 is [strongly] associated with HDL particles within the circulation and has been argued to promote some of the anti-inflammatory and antioxidant effects attributed to HDL. Thus, the present studies also provide further support for the concept that functional properties beyond the ability of HDL and its associated proteins to promote reverse cholesterol transport contribute to the overall ability of this lipoprotein to reduce or prevent development of atherosclerosis,” the authors conclude.
(JAMA. 2008;299[11]:1265-1276. Available pre-embargo to the media at jamamedia.org)