Thrombophilic Gene Mutations/Polymorphisms in Young Patients with Myocardial Infarction, MANAL NIAZI and KHALED KASHAB
Abstract
Background: The pathogenesis of myocardial infarction (MI) involves an interaction between environmental influences and genetic predisposition. Although the role of environmental factors in the development of acute myocardial infarction has been clearly established, the role of genetic factors; particularly those related to thrombogenesis; is still undefined. Inherited thrombophilias are well recognized to increase the risk of venous thromboembolism but the relationship between inher-ited thrombophilias and arterial thrombosis is more contro-versial. The predisposition imparted by individual genes may act independently or interact with other genes to result in an additive effect or a synergistic co-effect.
Aim: The aim of this work was to investigate a panel of thrombophilic gene mutations/polymorphisms in young pa-tients with myocardial infarction in a trial to clarify their role in disease pathogenesis and progression as well as their potential value in identifying subjects at risk of myocardial infarction at a young age.
Subjects and Methods: The study included a total of 30 myocardial infarction patients who presented before the age of 45 years and 30 age and sex matched normal subjects as a control group. Polymerase chain reaction (PCR) amplification and reverse hyperdization of the PCR products were used to identify a total of 12 thrombophilic gene mutations and polymorphisms: Factor V R506Q, Factor V H1299R, pro-thrombin G20210A, Factor XIII V34L, beta-Fibrinogen -455 G-A, PAI-1 4G/5G, platelet GPIIIa L33P, MTHFR C677T, MTHFR A1298C, ACE I/D, Apo B R3500Q and Apo E2/E3/ E4, respectively.
Results: The allele frequency of the PAI-1 4G/5G poly-morphism and the allele frequency of the HPA-1 a/b polymor-phisms were significantly higher in MI patients than in controls. PAI-1 4G allele frequency was 63.3% compared to 41.7% in controls (p<0.05, OR: 2.4, 95% CL 1.1 to 5). HPA-1 1b allele frequency was 33.4% compared to 18.3% in controls (p<0.05, OR: 2.2, 95% CL 1 to 5.2). They were both associated with increased risk to MI. None of the other 10 mutations/ poly-morphisms [ G1691A factor V: OR 1.2 ; CI: 0.3 to 4.2; H1299R factor V: OR 1.2; CI: 0.3 to 4.9; G20210 Prothrombin: OR 2; CL: 0.17 to 23; G-455A ß-fibrinogen: OR 1.1; CI: 0.48 to 2.4; G185T factor XIII: OR 0.65; CI: 0.26 to 1.6; C677T methylenetetrahydrofolate reductase: OR 1; CI: 0.45 to 2.35; A1298C methylenetetrahydrofolate reductase: OR 1.1; CI:
0.55 to 2.4; R3500Q Apo-B: 0%; E4 Apo-E; OR 1; CL: 0.2 to 4 and ACE I/D deletion polymorphism: OR 1.07; CL: 0.5 to 2.2] were associated with an increased or decreased risk of myocardial infarction. In this study the presence of more than 7 combined unfavorable alleles was significantly higher in MI patients (66.7%) than in controls (13.3%) and was associated with higher risk of MI (p<0.05 OR 13; 95% CL: 3.5 to 47). 26.6% of patients had 3-7 combined unfavorable alleles, significantly higher than that in controls (16.6%) [p<0.05, OR 1.8; CL: 0.5 to 6]. While 6.7% of patients had less than 3 unfavorable alleles significantly lower than that of controls [p<0.05 OR 0.3 95% CL: 0.06 to 0.5].
Conclusion: In this study PAI-1 4G/5G and HPA-1 a/b polymorphisms were the only genetic thrombophilic factors associated with the risk of developing myocardial infarction under the age of 45 years. A panel of thrombophilic gene mutations/polymorphisms consisting of [FV R506Q (Leiden), FV H1299R (R2), prothrombin G20210A, factor XIII V34L, ß-fibrinogen -455 G-A, PAI-1 4G/5G, GPIIIa L33P (HPA-1), MTHFR C677T, MTHFR A1298C, ACE I/D, Apo B R3500Q, Apo E2/E3/E4] could identify individuals at risk of myocardial infarction as the association between myocardial infarction and thrombophilic mutations/polymorphisms is evident by combined number of mutations/polymorphisms rather than specific gene involvement. Further studies involving simulta-neous analysis of multiple genes in a large sample size are needed to confirm these results.