Synergistic Effect of Thrombomodulin Promoter -33G/A Polymorphism and Smoking on the Onset of Acute Myocardial Infarction

Summary

Thrombomodulin is an endothelial cell surface receptor for thrombin. It plays an important role in the regulation of blood coagulation by decreasing thrombin activity and activating protein C. This study examined the possible association between the thrombomodulin -33G/A polymorphism and acute myocardial infarction. We recruited 278 patients (mean age 57.5 years, 241 men) with documented myocardial infarction and 450 age-and sex-matched control subjects. Polymerase chain reaction and single-strand conformation polymorphism was used to define the thrombomodulin -33G/A polymorphism. The frequency of the thrombomodulin GA+AA genotype among patients with myocardial infarction was higher than that in control subjects (22.7% vs. 16.2%, odds ratio [OR] 1.5, 95% confidence interval [CI] 1.0 to 2.2). The -33G/A polymorphism (GA+AA genotype) was significantly associated with myocardial infarction (OR 1.6, 95% CI 1.1 to 2.5) as was hypertension, diabetes mellitus and smoking. Among young myocardial infarction patients (age ≤45 years, n = 72), the frequency of -33G/A polymorphism was more significantly higher than that in control subjects (29.2% vs. 16.2%, OR 2.1, 95% CI 1.2 to 3.8). The -33G/A polymorphism (OR 2.3, 95% CI 1.3 to 4.1) and smoking (OR 4.5, 95% CI 2.5 to 7.9) were the only independent risk factors for young myocardial infarction. Furthermore, among patients who did not smoke, the polymorphism was associated with a nonsignificant increase in the risk of young myocardial infarction (OR 1.9, 95% CI 0.6 to 5.6); whereas, in the presence of smoking, the increase was statistically significant (OR 2.3, 95% CI 1.2 to 4.7). Smoking carriers of the thrombomodulin -33G/A polymorphism had a nearly 10-fold increased risk of young myocardial infarction (OR 9.8, 95% CI 4.3 to 22.4) when compared with nonsmoking non-carriers. We concluded that there was a significant association between the thrombomodulin -33G/A polymorphism and myocardial infarction in our population, especially in young patients. The clinical effect of this genetic factor was enhanced by smoking.

Keywords

Myocardial infarction - polymorphism - smoking

• References

• 1 DeWood MA, Spores J, Notske RN. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980; 303: 897-902.
• 2 Ridolfi RL, Hutchins GM. The relationship between coronary arterial lesions and myocardial infarcts: ulceration of atherosclerotic plaques precipitating coronary thrombosis. Am Heart J 1977; 93: 468-86.
• 3 Fuster V, Badimon L, Badimon JJ, Chesebro JH. Mechanisms of disease: The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992; 326: 242-50.
• 4 Miletich JP, Prescott SM, White R, Majerus PW, Bovill EG. Inherited predisposition of thrombosis. Cell 1993; 72: 477-80.
• 5 Siscovick DS, Schwartz SM, Rosendaal FR, Psaty BM. Thrombosis in the young: effect of atherosclerotic risk factors on the risk of myocardial infarction associated with prothrombotic factors. Thromb Haemost 1997; 78: 7-12.
• 6 Esmon CT. Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. FASEB J 1995; 09: 946-55.
• 7 Esmon CT. The regulation of natural anticoagulant pathways. Science 1987; 235: 1348-52.
• 8 Esmon CT. The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 1989; 264: 4743-6.
• 9 Healy AM, Hancock WW, Christie PD, Rayburn HB, Rosenberg RD. Intravascular coagulation activation in a murine model of thrombomodulin deficiency: effects of lesion size, age, and hypoxia on fibrin deposition. Blood 1998; 92: 4188-97.
• 10 Ireland H, Kunz G, Kyriakoulis K, Stubbs PJ, Lane DA. Thrombomodulin gene mutations associated with myocardial infarction. Circulation 1997; 96: 15-8.
• 11 Yi-Heng Li, Jyh-Hong Chen, Bi-Ing Chang, Jia-Chung Lin, Hua-Lin Wu, Guey-Yueh Shi, Wei-Chuan Tsai, Ting-Hsing Chao, Liang-Miin Tsai, Li-Jen Lin. Functional significance of G-33A promoter mutation of thrombomodulin gene and its influence on plasma soluble thrombomodulin level in patients with coronary artery disease (Abstr). J Am Coll Cardiol 2000; 35: 259A
• 12 Le Flem L, Picard V, Emmerich J, Gandrille S, Fiessinger J, Aiach M, Alhenc-Gelas M. Mutations in promoter region of thrombomodulin and venous thromboembolic disease. Arterioscler Thromb Vasc Biol 1999; 19: 1098-104.
• 13 Park HY, Jang Y, Kim Y, Shim WH, Kwon HM. Common genetic variants of the thrombomodulin gene as a risk factor for myocardial infarction. (Abstr). J Am Coll Cardiol 2000; 35: 327A
• 14 Dahlback B. Resistance to activated protein C, the Arg506 to Gln mutation in the factor V gene, and venous thrombosis. Thromb Haemost 1995; 73: 739-42.
• 15 Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C). Blood 1995; 85: 1504-8.
• 16 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-703.
• 17 Cumming AM, Keeney S, Salden A, Bhavnani M, Shwe KH, Hay CR. The prothrombin gene G20210A variant: prevalence in a UK anticoagulant clinic population. Br J Haematol 1997; 98: 353-5.
• 18 Ko YL, Hsu TS, Wu SM, Chen WJ, Cheng NJ, Kuo CT, Chiang CW, Lee YS. The G1691A mutation of the coagulation factor V gene (factor V Leiden) is rare in Chinese: an analysis of 618 individuals. Hum Genet 1996; 98: 176-7.
• 19 Lin JS, Shen MC, Tsay W. The mutation at position 20210 in the 3’-untranslated region of the prothrombin gene is extremely rare in Taiwanese Chinese patients with venous thrombophilia. Thromb Haemost 1998; 80: 343.
• 20 Yu K, Morioka H, Fritze LMS, Beeler DL, Jackman RW, Rosenberg RD. Transcriptional regulation of the thrombomodulin gene. J Biol Chem 1992; 267: 23237-47.
• 21 Tazawa R, Hirosawa S, Suzuki K, Hirokawa K, Aoki N. Functional characterization of the 5’-regulatory region of the human thrombomodulin gene. J Biochem 1993; 113: 600-6.
• 22 Seigneur M, Dufourcq P, Conri C, Constans J, Mercie P, Pruvost A, Amiral J, Midy D, Baste JC, Boisseau MR. Levels of plasma thrombomodulin are increased in atheromatous arterial disease. Thromb Res 1993; 71: 423-31.
• 23 Blann AD, Amiral J, McCollum CN. Prognostic value of increased soluble thrombomodulin and increased soluble E-selectin in ischaemic heart disease. Eur J Haematol 1997; 59: 115-20.
• 24 Zimmerman FH, Cameron A, Fisher LD, Ng G. Myocardial infarction in young adults: angiographic characterization, risk factors and prognosis (Coronary Artery Surgery Registry). J Am Coll Cardiol 1995; 26: 654-61.
• 25 Glover MU, Kuber MT, Warren SE, Vieweg WVR. Myocardial infarction before age 36: risk factor and arteriographic analysis. Am J Cardiol 1982; 49: 1600-3.
• 26 Doggen CJM, Kunz G, Rosendaal FR, Lane DA, Vos HL, Stubbs PJ, Cats VM, Ireland H. A mutation in the thrombomodulin gene, 127 G to A coding for Ala25Thr, and the risk of myocardial infarction in men. Thromb Haemost 1998; 80: 743-8.
• 27 Teng JK, Lin LJ, Tsai LM, Kwan CM, Chen JH. Acute myocardial infarction in young and very old Chinese adults: clinical and therapeutic implications. Int J Cardiol 1994; 44: 29-36.
• 28 Sharp DS, Benowitz NL, Bath PM, Martin JF, Beswick AD, Elwood PC. Cigarette smoking sensitizes and desensitizes impedance-measured ADP-induced platelet aggregation in whole blood. Thromb Haemost 1995; 74: 730-5.
• 29 Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci 1989; 86: 2766-70.
• 30 Sheffield VC, Beck JS, Kwitek AE, Sandstrom DW, Stone EM. The sensitivity of single-strand conformation polymorphism analysis for the detection of single base substitutions. Genomics 1993; 16: 325-32.