EDITORIAL COMMENT
Cardiovascular Event RiskHigh-Density Lipoprotein and Paraoxonase*
H. Robert Superko, MD*
Celera Inc. Genetics, Alameda, California
* Reprint requests and correspondence: Dr. H. Robert Superko, Celera Inc. Genetics, 1401 Harbor Bay Parkway, Alameda, California 94502 (Email: robert.superko{at}celera.com).
Key Words: ischemic heart disease • prognosis • lipoproteins • genes • epidemiology
 |
Low High-Density Lipoprotein Cholesterol (HDL-C)
|
|---|
Low HDL-C has been established as a cardiovascular risk factor at least since the Framingham study observation of a significant inverse relationship between HDL-C and coronary heart disease (CHD) in 1977 (1). Since then, multiple prospective epidemiological studies have demonstrated this inverse relationship (1–9). The mechanism of this increased risk has been attributed to multiple factors including impaired reverse cholesterol transport, adenosine triphosphatase–binding cassette transporter, and reduced oxidative protection.
This inverse relationship between low HDL-C and increased risk has also been attributed to a specific high-density lipoprotein (HDL) subclass, described by various laboratory techniques as HDL2, HDL2b, alpha1 HDL, and LpAI (10). Differences in HDL subclass distributions in blood were first described by Gofman et al. (11,12) in 1954 using analytic ultracentrifugation (11,12). They noted that the concentrations of the more buoyant particles (HDL2) were 50% higher in women than in men. Later, in 1966, they reported that baseline HDL mass concentrations were 32% lower for HDL2 and 8% lower for HDL3 (the less buoyant particles) in patients who had CHD develop during 10 years of follow-up compared with patients who did not (13). The HDL subclasses appear to have a differential effect on lipoprotein oxidative protection (14).
|
Oxidation, Paraoxonase, and CHD Risk
|
|---|
Modification, or oxidation, of apoproteins may contribute to atherosclerosis in humans. Oxidation of apoprotein B has been shown to result in a modified low-density lipoprotein (m-LDL) particle that is taken up rapidly by a scavenger receptor on tissue macrophages, resulting in atherogenic foam cell formation, inhibition of macrophage egress from tissue, and damage to the endothelial border that results in atherosclerosis in animal models (15). Incubation of LDL with cultured endothelial cells results in a modified low-density lipoprotein (m-LDL) that is taken up by macrophages 3 to 10 times more rapidly than native LDL, resulting in atherogenic foam cell formation (16,17). This m-LDL undergoes many structural changes, most of which depend on peroxidation of polyunsaturated fatty acids in the LDL lipids that can be inhibited by vitamin E (18,19). In plasma, aldehydes (namely, malondialdehyde or 4-hydroxynonenal) are generated by peroxidation of polyunsaturated fatty acids, which are part of LDL phospholipids. These aldehydes may alter lysine residues of apoprotein B and result in m-LDL (19,20). Once the LDL contains fatty acid lipid peroxides, a propagation follows that amplifies the number of free radicals and leads to extensive fragmentation of the fatty acid chains (21).
Paraoxonase (PON) is an enzyme initially of interest in the field of toxicology because it is an "A" esterase and hydrolyzes organophosphate compounds used as insecticides and nerve gases (22). PON is associated with HDL particles, and in sheep, most of the PON activity is associated with the apolipoproteinAI-only particle (23). Thus, part of the protective effect of some, but perhaps not all, HDL particles may be the association of PON and its putative role in decreasing lipid peroxide accumulation on LDL particles (24). The HDL from transgenic mice lacking PON-1 fails to protect LDL against oxidative modification. Thus, PON-1 may be a determinant of resistance to the development of atherosclerosis by protecting lipoproteins against oxidative modification, perhaps by hydrolyzing phospholipid and cholesteryl-ester hydroperoxides.
|
PON and HDL Link
|
|---|
Both PON-1 and PON-3 reside on HDL particles (25). All 3 are associated with oxidative protection. The PON-1 activity is associated with HDL2 and may be a contributing factor to the cardioprotection attributed to elevated HDL2 levels (26).
|
PON Polymorphisms and Atherosclerosis
|
|---|
The PON family is made up of 3 related genes termed PON-1, PON-2, and PON-3 that reside on chromosome 7q21.3 (27). The PON-1 is bound to HDL and appears to hydrolyze inflammatory phospholipids in both LDL and HDL particles, and plays a role in physiologic anti-inflammatory activity (28,29). There are 3 common PON-1 polymorphisms: L55M, Q192R, and the promoter polymorphism T(–107)C (30).
PON polymorphisms have been associated with CHD risk in some, but not all, investigations. Serrato and Marian (31) described an association between HUMPONA and CHD in 1995. Subsequently, a plethora of investigations and associations have been reported (32). In the Nurses' Health and Health Professionals Follow-up Study, the PON-1 polymorphisms Q192R and L55M were not associated with increased CHD risk (33).
The lack of clarity in the association of PON-1 polymorphisms and CHD risk may, in part, be due to the physiologic role of PON, which may be to play a minor role in the early pathogenesis of CHD but a more powerful role in the interaction with lipid and glucose metabolism and the later macrovascular aspects of atherosclerosis (34). The likelihood of severe stenosis has been reported to be greater in CHD patients with hyperglycemia and serum PON-1 activity (35). Differences in genotype distribution may be related to severity of CHD in patients with established CHD (36). Smoking may be a contributing factor, because the Northwick Park Heart Study II reported that the L55M and Q192R genotype did not differ between cases and control subjects but CHD risk associated with smoking was significantly modified by the L55M genotype (37). Ethnic differences may also play a role, as it has been reported that in a Turkish patient population PON-1 L55M was associated with CHD but not PON-1 Q192R (38). The PON-1 Gln192Arg SNP has been associated with a significantly increased risk of stroke (39).
Some uncertainty exists in the relationship between PON polymorphisms and PON concentration or activity. In case-control studies, serum PON-1 concentration and activity were found to be decreased in CHD independent of the PON-1 polymorphism, and in diabetes mellitus, serum PON-1 specific activity decrease is also independent of the PON-1 genetic polymorphism (40).
|
Comments on the Current Article
|
|---|
Within the context of this lack of clarity in regard to PON polymorphisms and CHD risk, the article by Regieli et al. (41) in this issue of the Journal addresses a clinically important issue, which is the importance of HDL and reverse cholesterol transport and the physiologic and genetic attributes that may confer risk reduction benefit. The REGRESS (REgression GRowth Evaluation Statin Study) study population is well described and has been utilized to address other medically relevant questions. The role of oxidative protection attributed to PON residing on HDL particles has been explored by other investigators. What is new is the relationship of PON-1 genetic variants and prospective long-term clinical outcome in well-characterized male Caucasian CHD patients. Their data indicate a significant increase in CHD death in the 14% of the population with the MM L55M genotype. Furthermore, there was an allele-dose effect in that the 10-year risk of CHD death was 4.6% in L55 homozygotes, 7.1% in heterozygotes, and 10.9% in 55M homozygotes. Importantly, this relationship was unchanged when corrected for HDL-C, LDL cholesterol, triglycerides, and current smoking status, suggesting that the PON-1 genotype may be an independent risk factor for CHD death. Some conflict may exist with other case-control studies but is adequately addressed by Regieli et al. (41). This study contributes new knowledge regarding the risk of CHD death in male CHD patients and the relationship of common PON polymorphisms.
|
Footnotes
|
|---|
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
|
References
|
|---|
1. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977;62:707-714.[CrossRef][Web of Science][Medline]2. Rhoads GG, Gulbrandsen CL, Kagan A. Serum lipoproteins and coronary heart disease in a population study of Hawaii Japanese men N Engl J Med 1976;294:293-298.[Web of Science][Medline] 3. Enger SC, Hjermann I, Foss OP, et al. High density lipoprotein cholesterol and myocardial infarction or sudden coronary death: a prospective case-control study in middle-aged men of the Oslo study Artery 1979;5:170-181.[Web of Science][Medline] 4. Goldbourt U, Holtzman E, Neufeld HN. Total and high density lipoprotein cholesterol in the serum and risk of mortality: evidence of a threshold effect Br Med J (Clin Res Ed) 1985;290:1239-1243.[CrossRef][Medline] 5. Multiple Risk Factor Intervention Trial Research Group Relationship between baseline risk factors and coronary heart disease and total mortality in the Multiple Risk Factor Intervention Trial Prev Med 1986;15:254-273.[CrossRef][Web of Science][Medline] 6. Gordon DJ, Knoke J, Probstfield JL, Superko R, Tyroler HA. High-density lipoprotein cholesterol and coronary heart disease in hypercholesterolemic men: the Lipid Research Clinics Coronary Primary Prevention Trial Circulation 1986;74:1217-1225.[Abstract/Free Full Text] 7. Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989;79:8-15.[Abstract/Free Full Text] 8. Manninen V, Huttunen JK, Heinonen OP, Tenkanen L, Frick MH. Relation between baseline lipid and lipoprotein values and the incidence of coronary heart disease in the Helsinki Heart Study Am J Cardiol 1989;63:42H-47H.[CrossRef][Medline] 9. Pocock SJ, Shaper AG, Phillips AN. Concentrations of high density lipoprotein cholesterol, triglycerides, and total cholesterol in ischaemic heart disease Br Med J 1989;298:998-1002.[Abstract/Free Full Text] 10. Superko HR. Advanced lipoprotein testing and subfractionation are clinically useful Circulation 2009;119:2383-2395.[Free Full Text] 11. Lindgren FT, Elliott HA, Gofman JW. The ultracentrifugal characterization and isolation of human blood lipids and lipoproteins, with applications to the study of atherosclerosis J Phys Colloid Chem 1951;55:80-93.[CrossRef][Web of Science][Medline] 12. DeLalla OF, Gofman JW. Ultracentrifugal analysis of serum lipoproteins Meth Biochem Anal 1954;1:459-478.[Web of Science][Medline] 13. Gofman JW, Young W, Tandy R. Ischemic heart disease, atherosclerosis, and longevity Circulation 1966;34:679-697.[Free Full Text] 14. Davidson WS, Silva RA, Chantepie S, Lagor WR, Chapman MJ, Kontush A. Proteomic analysis of defined HDL subpopulations reveals particle-specific protein clusters: relevance to antioxidative function Arterioscler Thromb Vasc Biol 2009;29:870-876.[Abstract/Free Full Text] 15. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 1989;320:915-924.[Web of Science][Medline] 16. Henriksen T, Mahoney EM, Steinberg D. Enhanced macrophage degradation of low density lipoprotein previously incubated with cultured endothelial cells: recognition by receptors for acetylated low density lipoproteins Proc Natl Acad Sci U S A 1981;78:6499-6503.[Abstract/Free Full Text] 17. Henriksen T, Mahoney EM, Steinberg D. Enhanced macrophage degradation of biologically modified low density lipoprotein Arteriosclerosis 1983;3:149-159.[Abstract/Free Full Text] 18. Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D. Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids Proc Natl Acad Sci U S A 1984;81:3883-3887.[Abstract/Free Full Text] 19. Fogelman AM, Shechter I, Seager J, Hokom M, Child JS, Edwards PA. Malondialdehyde alteration of low density lipoproteins leads to cholesteryl ester accumulation in human monocyte-macrophages Proc Natl Acad Sci U S A 1980;77:2214-2218.[Abstract/Free Full Text] 20. Jurgens G, Lang J, Esterbauer H. Modification of human low-density lipoprotein by the lipid peroxidation product 4-hydroxynonenal Biochim Biophys Acta 1986;875:103-114.[Medline] 21. Esterbauer H, Jurgens G, Quehenberger O, Koller E. Autoxidation of human low density lipoprotein: loss of polyunsaturated fatty acids and vitamin E and generation of aldehydes J Lipid Res 1987;28:495-509.[Abstract] 22. Mackness MI, Mackness B, Durrington PN, Connelly PW, Hegele RA. Paraoxonase: biochemistry, genetics and relationship to plasma lipoproteins Curr Opin Lipidol 1996;7:69-76.[Web of Science][Medline] 23. Mackness MI, Walker CH. Multiple forms of sheep serum A-esterase activity associated with the high-density lipoprotein Biochem J 1988;250:539-545.[Web of Science][Medline] 24. Mackness MI, Arrol S, Abbott C, Durrington PN. Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase Atherosclerosis 1993;104:129-135.[CrossRef][Web of Science][Medline] 25. Reddy ST, Devarajan A, Bourquard N, Shih D, Fogelman AM. Is it just paraoxonase 1 or are other members of the paraoxonase gene family implicated in atherosclerosis? Curr Opin Lipidol 2008;19:405-408.[CrossRef][Web of Science][Medline] 26. Proudfoot JM, Barden AE, Loke WM, Croft KD, Puddey IB, Mori TA. HDL is the major lipoprotein carrier of plasma F2-isoprostanes J Lipid Res 2009;50:716-722.[Abstract/Free Full Text] 27. Primo-Parmo SL, Sorenson RC, Teiber J, La Du BN. The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family Genomics 1996;33:498-507.[CrossRef][Web of Science][Medline] 28. Shih DM, Xia YR, Wang XP, et al. Combined serum paraoxonase knockout/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis J Biol Chem 2000;275:17527-17535.[Abstract/Free Full Text] 29. Getz GS, Reardon CA. Paraoxonase, a cardioprotective enzyme: continuing issues Curr Opin Lipidol 2004;15:261-267.[CrossRef][Web of Science][Medline] 30. Deakin SP, James RW. Genetic and environmental factors modulating serum concentrations and activities of the antioxidant enzyme paraoxonase-1 Clin Sci (Lond) 2004;107:435-447.[Medline] 31. Serrato M, Marian AJ. A variant of human paraoxonase/arylesterase (HUMPONA) gene is a risk factor for coronary artery disease J Clin Invest 1995;96:3005-3008.[Web of Science][Medline] 32. Wheeler JG, Keavney BD, Watkins H, Collins R, Danesh J. Four paraoxonase gene polymorphisms in 11212 cases of coronary heart disease and 12786 controls: meta-analysis of 43 studies Lancet 2004;363:689-695.[CrossRef][Web of Science][Medline] 33. Mukamal KJ, Pai JK, Jensen MK, Rimm EB. Paraoxonase 1 polymorphisms and risk of myocardial infarction in women and men Circ J 2009;73:1302-1307.[CrossRef][Web of Science][Medline] 34. Thyagarajan B, Jacobs Jr. DR, Carr JJ, et al. Factors associated with paraoxonase genotypes and activity in a diverse, young, healthy population: the Coronary Artery Risk Development in Young Adults (CARDIA) study Clin Chem 2008;54:738-746.[Abstract/Free Full Text] 35. Lu C, Gao Y, Zhou H, Tian H. The relationships between PON1 activity as well as oxLDL levels and coronary artery lesions in CHD patients with diabetes mellitus or impaired fasting glucose Cor Artery Dis 2008;19:565-573.[CrossRef][Web of Science][Medline] 36. Najafi M, Gohari LH, Firoozrai M. Paraoxonase 1 gene promoter polymorphisms are associated with the extent of stenosis in coronary arteries Thromb Res 2009;123:503-510.[CrossRef][Web of Science][Medline] 37. Robertson KS, Hawe E, Miller GJ, Talmud PJ, Humphries SE. Human paraoxonase gene cluster polymorphisms as predictors of coronary heart disease risk in the prospective Northwick Park Heart Study II Biochim Biophys Acta 2003;1639:203-212.[Medline] 38. Kaman D, Ilhan N, Metin K, Akbulut M, Ustundag B. A preliminary study of human paraoxonase and PON 1 L/M55-PON 1 Q/R 192 polymorphisms in Turkish patients with coronary artery disease Cell Biochem Funct 2009;27:88-92.[CrossRef][Web of Science][Medline] 39. Ranade K, Kirchgessner TG, Iakoubova OA, et al. Evaluation of the paraoxonases as candidate genes for stroke: Gln192Arg polymorphism in the paraoxonase 1 gene is associated with increased risk of stroke Stroke 2005;36:2346-2350.[Abstract/Free Full Text] 40. Mackness MI, Mackness B, Durrington PN, et al. Paraoxonase and coronary heart disease Curr Opin Lipidol 1998;9:319-324.[CrossRef][Web of Science][Medline] 41. Regieli JJ, Jukema JW, Doevendans PA, et al. Paraoxonase variants relate to 10-year risk in coronary artery disease: impact of a high-density lipoprotein–bound antioxidant in secondary prevention J Am Coll Cardiol 2009;54:1238-1245.[Abstract/Free Full Text]
Related Articles
-
Paraoxonase Variants Relate to 10-Year Risk in Coronary Artery Disease: Impact of a High-Density Lipoprotein–Bound Antioxidant in Secondary Prevention
- Jakub J. Regieli, J. Wouter Jukema, Pieter A. Doevendans, Aeilko H. Zwinderman, John J. Kastelein, Diederick E. Grobbee, and Yolanda van der Graaf
J. Am. Coll. Cardiol. 2009 54: 1238-1245.
[Abstract]
[Full Text]
[PDF]
-
Inside This Issue
J. Am. Coll. Cardiol. 2009 54: A26.
[Full Text]
[PDF]
|
Top
Low High-Density Lipoprotein...
Oxidation, Paraoxonase, and CHD...