Paraoxonase-Gene Polymorphisms Associated with Coronary Heart Disease: Support for the Oxidative Damage Hypothesis?

The study reported by Sanghera et al. (1998)xDNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease. Sanghera, DK, Aston, CE, Saha, N, and Kamboh, MI. Am J Hum Genet. 1998; 62: 36–44Abstract | Full Text | Full Text PDF | PubMed | Scopus (205)See all ReferencesSanghera et al. (1998) has important mechanistic implications. In vitro studies suggest that paraoxonase inhibits LDL oxidation by decomposing peroxidized lipids, such as the oxygenated phospholipids implicated in monocyte attachment to endothelium. However, the allele most commonly associated with an increased risk of coronary heart disease, PON1 B, elevates paraoxonase activity in plasma. Whether this allele alters the activity of the enzyme toward the natural substrate(s) is not yet established. Moreover, the biochemical mechanisms by which the enzyme degrades oxidized lipids have not been clearly identified. It is intriguing, however, that Sanghera et al.xDNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease. Sanghera, DK, Aston, CE, Saha, N, and Kamboh, MI. Am J Hum Genet. 1998; 62: 36–44Abstract | Full Text | Full Text PDF | PubMed | Scopus (205)See all ReferencesSanghera et al. find that both PON1 B and PON2*S appear to increase the risk of atherosclerosis. This raises the interesting possibility that the two paraoxonase proteins act in concert to influence the formation of atherogenic molecules. Alternatively, this combination of genotypes may be less effective at removing oxidative damage from lipoproteins.Another important implication of the study reported by Sanghera et al. (1998)xDNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease. Sanghera, DK, Aston, CE, Saha, N, and Kamboh, MI. Am J Hum Genet. 1998; 62: 36–44Abstract | Full Text | Full Text PDF | PubMed | Scopus (205)See all ReferencesSanghera et al. (1998) relates to our understanding of the genetic contribution to coronary heart disease. Although a number of Mendelian disorders contributing to atherosclerosis, such as familial hypercholesterolemia, have been characterized and are now relatively well understood, such disorders explain only a small fraction of cases of coronary heart disease, the vast majority of which result from the interactions of multiple genetic and environmental factors. However, epidemiologic studies of candidate genes are slowly adding to our understanding. The PON-locus polymorphisms should now be added to a short list of other genes for which there is significant evidence for contributions to common forms of coronary heart disease (table 2table 2). A number of other genetic variations are very likely to affect risk, since they influence factors such as homocysteine levels (the methylenetetrahydrofolate reductase gene) or HDL cholesterol (the hepatic lipase gene). Several very interesting candidate genes, such as the scavenger receptors that mediate cellular uptake of cholesterol to give rise to foam cells, have yet to be examined. As this list grows, it may be possible to subdivide the different forms of coronary heart disease to tailor treatments to specific genetic defects or even to predict an individual's risk.Table 2Genes Involved in Common Forms of Coronary Heart DiseaseGenePolymorphismApolipoprotein EMissenseApolipoprotein (a)Number of “kringle” repeatsAngiotensin-converting enzymeMissenseParaoxonaseMissenseNote.—Reviewed in Lusis et al. (1998)xGenetics of atherosclerosis. Lusis, AJ, Wainsab, A, and Drake, TA. : 2389–2413See all ReferencesLusis et al. (1998).