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Polymorphism

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Description

A common polymorphism at codon 192 in the PON1 gene (168820.0001) has been shown to be associated with increased risk of coronary heart disease (CHD) in Caucasian populations. However, the failure to find the association consistently in all Caucasian and non-Caucasian populations suggests that it is not a functional mutation but may mark a functional mutation present in either PON1 or a nearby gene. Sanghera et al. (1998) described a common polymorphism at codon 311 of the PON2 gene: cys311 to ser (PON2*S; 602447.0001).(1) They found that this polymorphism, alone or in combination with the gln192-to-arg (Q192R) polymorphism of the PON1 gene, is associated with CHD in Asian Indians. They presented data indicating that the PON1*B and PON2*S alleles contribute synergistically to the CHD risk in this sample and that this genetic risk is independent of the conventional plasma lipid profile. Heinecke and Lusis (1998) reviewed the results of previous studies of the PON1 Q92R polymorphism in CHD and raised the question of whether these PON polymorphisms support the oxidative damage hypothesis of atherosclerosis. (2)

In genomewide scanning to identify noninsulin-dependent diabetes mellitus (NIDDM; 125853) susceptibility genes in Pima Indians, Prochazka et al. (1995) found linkages of DNA markers at 7q21.3-q22.1 with both quantitative traits related to glucose uptake and storage and possibly with NIDDM itself.

Abstracts

References

Dietary antioxidants and paraoxonases against LDL oxidation and atherosclerosis development

Handb Exp Pharmacol. 2005;(170):263-300. Aviram M, Kaplan M, Rosenblat M, Fuhrman B.

  • Oxidative modification of low-density lipoprotein (LDL) in the arterial wall plays a key role in the pathogenesis of atherosclerosis. Under oxidative stress LDL is exposed to oxidative modifications by arterial wall cells including macrophages. Oxidative stress also induces cellular-lipid peroxidation, resulting in the formation of 'oxidized macrophages', which demonstrate increased capacity to oxidize LDL and increased uptake of oxidized LDL. Macrophage-mediated oxidation of LDL depends on the balance between pro-oxidants and antioxidants in the lipoprotein and in the cells. LDL is protected from oxidation by antioxidants, as well as by a second line of defense--paraoxonase 1 (PON1), which is a high-density lipoprotein-associated esterase that can hydrolyze and reduce lipid peroxides in lipoproteins and in arterial cells. Cellular paraoxonases (PON2 and PON3) may also play an important protective role against oxidative stress at the cellular level. Many epidemiological studies have indicated a protective role for a diet rich in fruits and vegetables against the development and progression of cardiovascular disease. A large number of studies provide data suggesting that consumption of dietary antioxidants is associated with reduced risk for cardiovascular diseases. Basic research provides plausible mechanisms by which dietary antioxidants might reduce the development of atherosclerosis. These mechanisms include inhibition of LDL oxidation, inhibition of cellular lipid peroxidation and consequently attenuation of cell-mediated oxidation of LDL. An additional possible mechanism is preservation/increment of paraoxonases activity by dietary antioxidants. This review chapter presents recent data on the anti-atherosclerotic effects and mechanism of action of three major groups of dietary antioxidants-vitamin E, carotenoids and polyphenolic flavonoids.

1. Sanghera, D. K.; Aston, C. E.; Saha, N.; Kamboh, M. I. DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease. Am. J. Hum. Genet. 62: 36-44, 1998.

2. Heinecke, J. W.; Lusis, A. J. Paraoxonase-gene polymorphisms associated with coronary heart disease: support for the oxidative damage hypothesis? (Letter) Am. J. Hum. Genet. 62: 20-24, 1998.

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