Direct Link Ties HDL-Related Gene to Cardiovascular Risk

By Charles Bankhead
CLEVELAND, March 18 -- Cardiac events and mortality were significantly associated with genotypic variations in paraoxonase 1 (PON1), which contributes to the anti-inflammatory and antioxidant activities of high-density lipoprotein (HDL), investigators here reported. Patients with the genotype (QQ192) associated with the lowest serum PON1 activity had a significantly increased risk of mortality and major adverse cardiac events compared with two other PON1 genotypes (P=0.01), Stanley L. Hazen, M.D., Ph.D., of the Cleveland Clinic, and colleagues reported in the March 19 issue of the Journal of the American Medical Association.In contrast, patients with the highest PON1 activity had a significantly lower risk of cardiac events compared with individuals with the lowest PON1 activity (P<0.001)."Paraoxonase I is almost exclusively found to be associated with HDL particles within the circulation and has been argued to promote some of the anti-inflammatory and antioxidant effects attributed to HDL," the authors said.
"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," they concluded.
Several lines of evidence suggested that PON1 promotes antioxidant and atheroprotective effects. For example, PON1 inhibits oxidation of LDL in vitro, and deletion of PON1 is associated with increased susceptibility to LDL oxidation ex vivo.
The antiatherogenic effects of PON1 observed in animals had remained unproven in humans, attempts having been confounded by multiple polymorphisms.
A meta-analysis of 43 studies examining single-nucleotide polymorphisms for PON1 revealed the Q192R variant as one of the most promising, the authors noted.
Acting on that information, Dr. Hazen and colleagues conducted a comprehensive in vivo investigation of a mechanistic link between the functional PON1 Q192R polymorphism and serum PON1 activity.
Investigators examined associations between Q192R and PON1 activity in 1,386 patients undergoing diagnostic coronary angiography at the Cleveland Clinic from September 2002 through November 2003. Follow-up continued until December 2006.
Genotyping results showed that 46.3% of the patients had the QQ192 genotype, 43.9% had the Q192R genotype, and 9.8% had the RR192 genotype.
PON1 activity, as reflected by serum levels of paraoxonase and arylesterase, was significantly lower in patients with cardiovascular disease compared with those who did not have CVD (P<0.001).
During a mean follow-up of 44 months, 13.8% of study participants had at least one major adverse cardiac event.
Patients with the QQ192 genotype had a significantly higher event rate compared with patients who had other genotypes:
All cause mortality was 11.1% versus 6.75% (HR 2.05, 95% CI 1.32 to 3.18)
Major adverse cardiac events were 18% versus 13.6% (HR 1.48, 95% CI 1.09 to 2.03)
"Our results demonstrate that both the PON1 Q192R polymorphism and serum PON1 activity are associated with both prevalent coronary artery disease and incident adverse cardiovascular events," the authors concluded.
The authors noted several elements that limited the generalizability of the study, including the fact that most participants were white and all were undergoing elective diagnostic coronary angiography. The latter fact also raises the possibility of selection bias.
They also pointed out that "it also is possible that the reduction in PON1 activity may result from the presence of vascular disease rather than be the direct cause of future CVD events."
The study was supported by grants from the National Institutes of Health, Case Western Reserve University/Cleveland Clinic, and the AHA.
Dr. Hazen has received grant support and/or honoraria and consulting fees from Abbott Diagnostics, ArgiNOx, AstraZeneca, BioPhysical, BioSite, Hawaii Biotech, Merck, Lilly, Pfizer, PrognostiX Inc, sanofi-aventis, Takeda, and Wyeth. He is named as coinventor on pending and approved patents filed by the Cleveland Clinic that refer to the use of biomarkers to inflammatory and cardiovascular diseases and is the scientific founder of PrognostiX.
Primary source: Journal of the American Medical AssociationSource reference:Bhattacharyya T, et al "Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk" JAMA 2008; 299: 1265-1276.