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J Clin Invest. Jan 1, 1997; 99(1): 62–66.
PMCID: PMC507768

Paraoxonase polymorphism Met-Leu54 is associated with modified serum concentrations of the enzyme. A possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes.


Paraoxonase was identified as a genetic risk factor for cardiovascular disease (CVD) in recent studies focusing on a polymorphism affecting position 191. A second polymorphism of the paraoxonase gene affects position 54 and involves a methionine (M allele) to leucine (L allele) change. It was investigated in diabetic patients (n = 408) with and without vascular disease. There were highly significant differences in plasma concentrations and activities of paraoxonase between genotypes defined by the 54 polymorphism: MMAA, MLAA, LLAA; protein, 65.3+/-18.0, 77.9+/-18.0, 93.5+/-26.0 microg/ml; P < 0.0001: activity (phenylacetate), 48.6+/-13.5, 64.1+/-14.5, 68.1+/-13.0 U/ml; P < 0.0001. The 191 variant had little impact on paraoxonase concentrations. Homozygosity for the L allele was an independent risk factor for CVD (odds ratio 1.98 (1.07-3.83); P = 0.031). A linkage disequilibrium (P < 0.0001) was apparent between the mutations giving rise to leucine and arginine at positions 54 and 191, respectively. The study underlines that susceptibility to CVD correlates with high activity paraoxonase alleles. The 54 polymorphism would appear to be of central importance to paraoxonase function by virtue of its association with modulated concentrations. The latter could explain the association between both the 54 and 191 polymorphisms and CVD.

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Selected References

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  • Pyörälä K, Laakso M, Uusitupa M. Diabetes and atherosclerosis: an epidemiologic view. Diabetes Metab Rev. 1987 Apr;3(2):463–524. [PubMed]
  • Krolewski AS, Warram JH, Valsania P, Martin BC, Laffel LM, Christlieb AR. Evolving natural history of coronary artery disease in diabetes mellitus. Am J Med. 1991 Feb 21;90(2A):56S–61S. [PubMed]
  • Witztum JL, Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest. 1991 Dec;88(6):1785–1792. [PMC free article] [PubMed]
  • Hunt JV, Smith CC, Wolff SP. Autoxidative glycosylation and possible involvement of peroxides and free radicals in LDL modification by glucose. Diabetes. 1990 Nov;39(11):1420–1424. [PubMed]
  • Bucala R, Makita Z, Koschinsky T, Cerami A, Vlassara H. Lipid advanced glycosylation: pathway for lipid oxidation in vivo. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6434–6438. [PMC free article] [PubMed]
  • Tribble DL. Lipoprotein oxidation in dyslipidemia: insights into general mechanisms affecting lipoprotein oxidative behavior. Curr Opin Lipidol. 1995 Aug;6(4):196–208. [PubMed]
  • Blatter MC, James RW, Messmer S, Barja F, Pometta D. Identification of a distinct human high-density lipoprotein subspecies defined by a lipoprotein-associated protein, K-45. Identity of K-45 with paraoxonase. Eur J Biochem. 1993 Feb 1;211(3):871–879. [PubMed]
  • Mackness MI, Arrol S, Durrington PN. Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein. FEBS Lett. 1991 Jul 29;286(1-2):152–154. [PubMed]
  • Mackness MI, Arrol S, Abbott C, Durrington PN. Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase. Atherosclerosis. 1993 Dec;104(1-2):129–135. [PubMed]
  • Watson AD, Berliner JA, Hama SY, La Du BN, Faull KF, Fogelman AM, Navab M. Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein. J Clin Invest. 1995 Dec;96(6):2882–2891. [PMC free article] [PubMed]
  • Ruiz J, Blanché H, James RW, Garin MC, Vaisse C, Charpentier G, Cohen N, Morabia A, Passa P, Froguel P. Gln-Arg192 polymorphism of paraoxonase and coronary heart disease in type 2 diabetes. Lancet. 1995 Sep 30;346(8979):869–872. [PubMed]
  • Serrato M, Marian AJ. A variant of human paraoxonase/arylesterase (HUMPONA) gene is a risk factor for coronary artery disease. J Clin Invest. 1995 Dec;96(6):3005–3008. [PMC free article] [PubMed]
  • Mackness MI, Durrington PN. HDL, its enzymes and its potential to influence lipid peroxidation. Atherosclerosis. 1995 Jun;115(2):243–253. [PubMed]
  • Sorenson RC, Primo-Parmo SL, Kuo CL, Adkins S, Lockridge O, La Du BN. Reconsideration of the catalytic center and mechanism of mammalian paraoxonase/arylesterase. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7187–7191. [PMC free article] [PubMed]
  • Adkins S, Gan KN, Mody M, La Du BN. Molecular basis for the polymorphic forms of human serum paraoxonase/arylesterase: glutamine or arginine at position 191, for the respective A or B allozymes. Am J Hum Genet. 1993 Mar;52(3):598–608. [PMC free article] [PubMed]
  • Humbert R, Adler DA, Disteche CM, Hassett C, Omiecinski CJ, Furlong CE. The molecular basis of the human serum paraoxonase activity polymorphism. Nat Genet. 1993 Jan;3(1):73–76. [PubMed]
  • Eckerson HW, Wyte CM, La Du BN. The human serum paraoxonase/arylesterase polymorphism. Am J Hum Genet. 1983 Nov;35(6):1126–1138. [PMC free article] [PubMed]
  • Blatter Garin MC, Abbott C, Messmer S, Mackness M, Durrington P, Pometta D, James RW. Quantification of human serum paraoxonase by enzyme-linked immunoassay: population differences in protein concentrations. Biochem J. 1994 Dec 1;304(Pt 2):549–554. [PMC free article] [PubMed]
  • Furlong CE, Richter RJ, Chapline C, Crabb JW. Purification of rabbit and human serum paraoxonase. Biochemistry. 1991 Oct 22;30(42):10133–10140. [PubMed]
  • Mackness MI, Walker CH, Carlson LA. Low A-esterase activity in serum of patients with fish-eye disease. Clin Chem. 1987 Apr;33(4):587–588. [PubMed]
  • Mackness MI, Peuchant E, Dumon MF, Walker CH, Clerc M. Absence of "A"-esterase activity in the serum of a patient with Tangier disease. Clin Biochem. 1989 Dec;22(6):475–478. [PubMed]
  • Saha N, Roy AC, Teo SH, Tay JS, Ratnam SS. Influence of serum paraoxonase polymorphism on serum lipids and apolipoproteins. Clin Genet. 1991 Oct;40(4):277–282. [PubMed]
  • Hegele RA, Brunt JH, Connelly PW. A polymorphism of the paraoxonase gene associated with variation in plasma lipoproteins in a genetic isolate. Arterioscler Thromb Vasc Biol. 1995 Jan;15(1):89–95. [PubMed]
  • Mackness MI, Durrington PN. Paraoxonase: another factor in NIDDM cardiovascular disease. Lancet. 1995 Sep 30;346(8979):856–856. [PubMed]
  • Patsch JR, Prasad S, Gotto AM, Jr, Patsch W. High density lipoprotein2. Relationship of the plasma levels of this lipoprotein species to its composition, to the magnitude of postprandial lipemia, and to the activities of lipoprotein lipase and hepatic lipase. J Clin Invest. 1987 Aug;80(2):341–347. [PMC free article] [PubMed]
  • Demant T, Carlson LA, Holmquist L, Karpe F, Nilsson-Ehle P, Packard CJ, Shepherd J. Lipoprotein metabolism in hepatic lipase deficiency: studies on the turnover of apolipoprotein B and on the effect of hepatic lipase on high density lipoprotein. J Lipid Res. 1988 Dec;29(12):1603–1611. [PubMed]
  • Austin MA, Breslow JL, Hennekens CH, Buring JE, Willett WC, Krauss RM. Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA. 1988 Oct 7;260(13):1917–1921. [PubMed]
  • Cheung MC, Albers JJ. Characterization of lipoprotein particles isolated by immunoaffinity chromatography. Particles containing A-I and A-II and particles containing A-I but no A-II. J Biol Chem. 1984 Oct 10;259(19):12201–12209. [PubMed]
  • Eisenberg S. High density lipoprotein metabolism. J Lipid Res. 1984 Oct;25(10):1017–1058. [PubMed]
  • Kelso GJ, Stuart WD, Richter RJ, Furlong CE, Jordan-Starck TC, Harmony JA. Apolipoprotein J is associated with paraoxonase in human plasma. Biochemistry. 1994 Jan 25;33(3):832–839. [PubMed]

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