Paraoxonase 1 192 Gln/Arg gene polymorphism and cerebrovascular disease: interaction with type 2 diabetes

Summary:

Paraoxonase 1 (PON1) is an HDL-associated enzyme which protects HDL and LDL particles from lipid peroxidation. Its enzymatic serum activity varies 10-40-fold between individuals, and its biallelic gene polymorphism at codon 192 (glutamine → arginine, Gln/Arg) has been associated with coronary artery disease in diabetic patients. To evaluate the role of this PON1 gene polymorphism in cerebrovascular disease, we determined the PON1 192 genotype in 149 patients with hemodynamically relevant extracranial artery stenosis and in 241 controls. The PON1 192 Gln/Arg genotype was determined using polymerase chain reaction followed by Alw I digestion and polyacrylamide gel electrophoresis. Among all subjects, there was no association between the PON1 192 Gln/Arg genotype and cerebrovascular disease (Odds ratio for Arg/Arg and Gln/Arg vs Gln/Gln 0.99, 95%-CI 0.70-1.39). In contrast, in the subgroup of type 2 diabetic patients the PON1 192 Arg allele conferred about twice the risk of cerebrovascular stenosis compared to those homozygous for the Gln allele (Odds ratio 2.00, 95%-CI 0.92-4.38). Our data indicate that in the general population the PON1 192 Gln/Arg gene polymorphism cannot be regarded as a major risk marker for cerebrovascular disease. The observed interaction with type 2 diabetes, however, is supporting the hypothesis that the effect of the PON1 192 Arg allele on atherosclerosis is modulated by other risk factors like diabetes.

Key words:

Paraoxonase 1 - genetics - atherosclerosis - carotid artery stenosis - stroke

References

• 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.. 52 598-608 1993; 
• 2 Antikainen M, Murtomaki S, Syvanne 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.. 98 883-885 1996; 
• 3 Cao H, Girard-Globa A, Serusclat A, Bernard S, Bondon P, Picard S, Berthezene F, Moulin P. Lack of association between carotid intima-media thickness and paraoxonase gene polymorphism in non-insulin dependent diabetes mellitus.  Atherosclerosis. 138 361-366 1998; 
• 4 Dessi M, Gnasso A, Motti C, Pujia A, Irace C, Casciani S, Staffa F, Federici G, Cortese C. Influence of the human paraoxonase polymorphism (PON1 192) on the carotid-wall thickening in a healthy population.  Coron Artery Dis. 10 595-599 1999; 
• 5 Friedewald W T, Levy R I, Fredrickson D S. Estimation of the concentration of low density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge.  Clin. Chem.. 18 499-502 1972; 
• 6 Hassett C R, Richter J, Humbert R, Chapline C, Crabb J W, Omiecinski C J, Furlong C E. Characterization of cDNA clones encoding rabbit and human serum paraoxonase: the mature protein retains its signal sequence.  Biochemistry. 30 10141-10149 1991; 
• 7 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.. 3 73-76 1993; 
• 8 Hegele R A. Paraoxonase genes and disease.  Ann Med. 31 217-224 1999; 
• 9 Imai Y, Morita H, Kurihara H, Sugiyama T, Kato N, Ebihara A, Hamada C, Kurihara Y, Shindo T, Oh-hashi Y, Vazaki Y. Evidence for association between paraoxonase gene polymorphisms and atherosclerotic diseases.  Atherosclerosis. 149 435-442 2000; 
• 10 James R W, Leviev I, Righetti A. Smoking is associated with reduced serum paraoxonase activity and concentration in patients with coronary artery disease.  Circulation. 101 2252-2257 2000; 
• 11 Kiely D K, Wolf P A, Cupples L A, Beiser A S, Myers R H. Familial aggregation of stroke: the Framingham Study.  Stroke. 24 1366-1371 1993; 
• 12 Mackness B, Mackness M I, Arrol S, Turkie W, Julier K, Abuasha B, Miller J E, Boulton A J, Durrington P N. Serum paraoxonase (PON1) 55 and 192 polymorphism and paraoxonase activity and concentration in non-insulin dependent diabetes mellitus.  Atherosclerosis. 139 341-349 1998; 
• 13 Mackness M I, Arrol S, Durrington P N. Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein.  FEBS Lett.. 286 152-154 1991; 
• 14 Mackness M I, Arrol S, Abbott C A, Durrington P N. Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase.  Atherosclerosis. 104 129-135 1993; 
• 15 Mackness M I, Arrol S, Mackness B, Durrington P N. Alloenzymes of paraoxonase and effectiveness of high-density lipoproteins in protecting low-density lipoprotein against lipid peroxidation.  Lancet. 349 851-852 1997; 
• 16 Mackness M I, Durrington P N. HDL, its enzymes and its potential to influence lipid peroxidation.  Atherosclerosis. 115 243-253 1995; 
• 17 Mackness M I, Mackness B, Durrington P N, Connelly P W, Hegele R A. Paraoxonase: biochemistry, genetics and relationship to plasma lipoproteins.  Curr. Opin. Lipidol.. 7 69-76 1996; 
• 18 Pfohl M, Koch M, Enderle M D, Kuhn R, Füllhase J, Karsch K R, Häring H U. Paraoxonase 192 Gln/Arg gene polymorphism, coronary artery disease, and myocardial infarction in type 2 diabetes.  Diabetes. 48 623-627 1999; 
• 19 Pfohl M, Fetter M, Koch M, Barth C M, Weiss R, Häring H U. Association between angiotensin I-converting enzyme genotypes, extracranial artery stenosis, and stroke.  Atherosclerosis. 140 161-166 1998; 
• 20 Ruiz J, Blanche 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. 346 869-872 1995; 
• 21 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.. 17 1067-1073 1997; 
• 22 Serrato M, Marian A J. A variant of human paraoxonase/arylesterase (HUMPONA) gene is a risk factor for coronary artery disease.  J. Clin. Invest.. 96 3005-3008 1995; 
• 23 Suehiro T, Nakauchi Y, Yamamoto M, Arii K, Itoh H, Hamashige N, Hashimoto K. Paraoxonase gene polymorphism in Japanese subjects with coronary heart disease.  Int. J. Cardiol.. 57 69-73 1996;