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. 1998 Jan;62(1):36–44. doi: 10.1086/301669

DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease.

D K Sanghera 1, C E Aston 1, N Saha 1, M I Kamboh 1
PMCID: PMC1376796  PMID: 9443862

Abstract

A common polymorphism at codon 192 in the human paraoxonase (PON) 1 gene has been shown to be associated with increased risk for coronary heart disease (CHD) in Caucasian populations. However, these findings have not been reported consistently in all Caucasian and non-Caucasian populations, suggesting that this is not a functional mutation but may mark a functional mutation present in either PON1 or a nearby gene. Recently, two other PON-like genes, designated "PON2" and "PON3," have been identified, and they are linked with the known PON1 gene on chromosome 7. Identification of additional polymorphisms in the PON-gene cluster may help to locate the functional polymorphism. In this report, we describe the existence of a common polymorphism at codon 311 (Cys-->Ser; PON2*S) in the PON2 gene, as well as its association with CHD alone and in combination with the PON1 codon 192 polymorphism in Asian Indians. The frequency of the PON2*S allele was significantly higher in cases than in controls (.71 vs. .61; P=.016). The age- and sex-adjusted odds ratio (OR) was 2.5 (95% confidence interval &sqbl0;95% CI&sqbr0;=1.8-3.1; P=.0090) for the PON2*S allele carriers. Further stratification of the PON2*S association, on the basis of the presence or absence of the PON1*B allele, showed that the CHD risk associated with the PON2*S allele was confined to PON1*B-allele carriers. Likewise, the PON1*B-allele risk was present only among PON2*S carriers. Age- and sex-adjusted ORs for the PON2*S and PON1*B were 3.6 (95% CI=2.6-4.6; P=.011) and 2.9 (95% CI=2.4-3.5; P=.0002) among the PON1*B and PON2*S carriers, respectively. Our data indicate that both polymorphisms synergistically contribute to the CHD risk in this sample and that this genetic risk is independent of the conventional plasma lipid profile.

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Selected References

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  1. Adkins S., Gan K. N., Mody M., La Du B. N. 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] [Google Scholar]
  2. Antikainen M., Murtomäki S., Syvänne M., Pahlman R., Tahvanainen E., Jauhiainen M., Frick M. H., Ehnholm C. The Gln-Arg191 polymorphism of the human paraoxonase gene (HUMPONA) is not associated with the risk of coronary artery disease in Finns. J Clin Invest. 1996 Aug 15;98(4):883–885. doi: 10.1172/JCI118869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Blatter M. C., James R. W., 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. doi: 10.1111/j.1432-1033.1993.tb17620.x. [DOI] [PubMed] [Google Scholar]
  4. Davies H. G., Richter R. J., Keifer M., Broomfield C. A., Sowalla J., Furlong C. E. The effect of the human serum paraoxonase polymorphism is reversed with diazoxon, soman and sarin. Nat Genet. 1996 Nov;14(3):334–336. doi: 10.1038/ng1196-334. [DOI] [PubMed] [Google Scholar]
  5. Diepgen T. L., Geldmacher-von Mallinckrodt M. Interethnic differences in the detoxification of organophosphates: the human serum paraoxonase polymorphism. Arch Toxicol Suppl. 1986;9:154–158. doi: 10.1007/978-3-642-71248-7_18. [DOI] [PubMed] [Google Scholar]
  6. Furlong C. E., Richter R. J., Seidel S. L., Motulsky A. G. Role of genetic polymorphism of human plasma paraoxonase/arylesterase in hydrolysis of the insecticide metabolites chlorpyrifos oxon and paraoxon. Am J Hum Genet. 1988 Sep;43(3):230–238. [PMC free article] [PubMed] [Google Scholar]
  7. Garin M. C., James R. W., Dussoix P., Blanché H., Passa P., Froguel P., Ruiz J. 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. J Clin Invest. 1997 Jan 1;99(1):62–66. doi: 10.1172/JCI119134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Herrmann S. M., Blanc H., Poirier O., Arveiler D., Luc G., Evans A., Marques-Vidal P., Bard J. M., Cambien F. The Gln/Arg polymorphism of human paraoxonase (PON 192) is not related to myocardial infarction in the ECTIM Study. Atherosclerosis. 1996 Oct 25;126(2):299–303. doi: 10.1016/0021-9150(96)05917-5. [DOI] [PubMed] [Google Scholar]
  9. Hill W. G. Estimation of linkage disequilibrium in randomly mating populations. Heredity (Edinb) 1974 Oct;33(2):229–239. doi: 10.1038/hdy.1974.89. [DOI] [PubMed] [Google Scholar]
  10. Humbert R., Adler D. A., Disteche C. M., Hassett C., Omiecinski C. J., Furlong C. E. The molecular basis of the human serum paraoxonase activity polymorphism. Nat Genet. 1993 Jan;3(1):73–76. doi: 10.1038/ng0193-73. [DOI] [PubMed] [Google Scholar]
  11. Kelso G. J., Stuart W. D., Richter R. J., Furlong C. E., Jordan-Starck T. C., Harmony J. A. Apolipoprotein J is associated with paraoxonase in human plasma. Biochemistry. 1994 Jan 25;33(3):832–839. doi: 10.1021/bi00169a026. [DOI] [PubMed] [Google Scholar]
  12. Klimov A. N., Gurevich V. S., Nikiforova A. A., Shatilina L. V., Kuzmin A. A., Plavinsky S. L., Teryukova N. P. Antioxidative activity of high density lipoproteins in vivo. Atherosclerosis. 1993 Apr;100(1):13–18. doi: 10.1016/0021-9150(93)90063-z. [DOI] [PubMed] [Google Scholar]
  13. La Du B. N., Piko J. I., Eckerson H. W., Vincent-Viry M., Siest G. An improved method for phenotyping individuals for the human serum paraoxonase arylesterase polymorphism. Ann Biol Clin (Paris) 1986;44(4):369–372. [PubMed] [Google Scholar]
  14. Mackness M. I., Arrol S., Abbott C., Durrington P. N. Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase. Atherosclerosis. 1993 Dec;104(1-2):129–135. doi: 10.1016/0021-9150(93)90183-u. [DOI] [PubMed] [Google Scholar]
  15. Mackness M. I., Harty D., Bhatnagar D., Winocour P. H., Arrol S., Ishola M., Durrington P. N. Serum paraoxonase activity in familial hypercholesterolaemia and insulin-dependent diabetes mellitus. Atherosclerosis. 1991 Feb;86(2-3):193–199. doi: 10.1016/0021-9150(91)90215-o. [DOI] [PubMed] [Google Scholar]
  16. Mackness M. I., Peuchant E., Dumon M. F., Walker C. H., Clerc M. Absence of "A"-esterase activity in the serum of a patient with Tangier disease. Clin Biochem. 1989 Dec;22(6):475–478. doi: 10.1016/s0009-9120(89)80101-8. [DOI] [PubMed] [Google Scholar]
  17. Mackness M. I., Walker C. H., Carlson L. A. Low A-esterase activity in serum of patients with fish-eye disease. Clin Chem. 1987 Apr;33(4):587–588. [PubMed] [Google Scholar]
  18. McElveen J., Mackness M. I., Colley C. M., Peard T., Warner S., Walker C. H. Distribution of paraoxon hydrolytic activity in the serum of patients after myocardial infarction. Clin Chem. 1986 Apr;32(4):671–673. [PubMed] [Google Scholar]
  19. Navab M., Berliner J. A., Watson A. D., Hama S. Y., Territo M. C., Lusis A. J., Shih D. M., Van Lenten B. J., Frank J. S., Demer L. L. The Yin and Yang of oxidation in the development of the fatty streak. A review based on the 1994 George Lyman Duff Memorial Lecture. Arterioscler Thromb Vasc Biol. 1996 Jul;16(7):831–842. doi: 10.1161/01.atv.16.7.831. [DOI] [PubMed] [Google Scholar]
  20. Parzer S., Mannhalter C. A rapid method for the isolation of genomic DNA from citrated whole blood. Biochem J. 1991 Jan 1;273(Pt 1):229–231. doi: 10.1042/bj2730229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Primo-Parmo S. L., Sorenson R. C., Teiber J., La Du B. N. The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family. Genomics. 1996 May 1;33(3):498–507. doi: 10.1006/geno.1996.0225. [DOI] [PubMed] [Google Scholar]
  22. Roy A. C., Saha N., Tay J. S., Ratnam S. S. Serum paraoxonase polymorphism in three populations of southeast Asia. Hum Hered. 1991;41(4):265–269. doi: 10.1159/000154010. [DOI] [PubMed] [Google Scholar]
  23. Ruiz J., Blanché H., James R. W., Garin M. C., 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. doi: 10.1016/s0140-6736(95)92709-3. [DOI] [PubMed] [Google Scholar]
  24. Sanghera D. K., Saha N., Aston C. E., Kamboh M. I. Genetic polymorphism of paraoxonase and the risk of coronary heart disease. Arterioscler Thromb Vasc Biol. 1997 Jun;17(6):1067–1073. doi: 10.1161/01.atv.17.6.1067. [DOI] [PubMed] [Google Scholar]
  25. Serrato M., Marian A. J. 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. doi: 10.1172/JCI118373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sorenson R. C., Primo-Parmo S. L., Kuo C. L., Adkins S., Lockridge O., La Du B. N. 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. doi: 10.1073/pnas.92.16.7187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Stafforini D. M., Zimmerman G. A., McIntyre T. M., Prescott S. M. The platelet-activating factor acetylhydrolase from human plasma prevents oxidative modification of low-density lipoprotein. Trans Assoc Am Physicians. 1992;105:44–63. [PubMed] [Google Scholar]
  28. Watson A. D., Berliner J. A., Hama S. Y., La Du B. N., Faull K. F., Fogelman A. M., 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. doi: 10.1172/JCI118359. [DOI] [PMC free article] [PubMed] [Google Scholar]

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