Synergistic Effects of Prothrombotic Polymorphisms and Atherogenic Factors on the Risk of Myocardial Infarction in Young Males

Abstract

Several recent studies evaluated a possible effect of the prothrombotic polymorphisms such as 5,10 methylenetetrahydrofolate reductase (MTHFR) nt 677C → T, factor V (F V) nt 1691G → A (F V Leiden), and factor II (F II) nt 20210 G → A on the risk of myocardial infarction. In the present study, we analyzed the effect of these prothrombotic polymorphisms, as well as apolipoprotein (Apo) E4, smoking, hypertension, diabetes mellitus, and hypercholesterolemia, on the risk of myocardial infarction in young males. We conducted a case-control study of 112 young males with first acute myocardial infarction (AMI) before the age of 52 and 187 healthy controls of similar age. The prevalences of heterozygotes for F V G1691A and F II G20210A were not significantly different between cases and controls (6.3% v 6.4% and 5.9% v 3.4% among cases and controls, respectively). In contrast, the prevalence of MTHFR 677T homozygosity and the allele frequency of Apo E4 were significantly higher among patients (24.1% v 10.7% and 9.4% v5.3% among cases and controls, respectively). Concomitant presence of hypertension, hypercholesterolemia, or diabetes and one or more of the four examined polymorphisms increased the risk by almost ninefold (odds ratio [OR] = 8.66; 95% confidence interval [CI], 3.49 to 21.5) and concomitant smoking by almost 18-fold (OR = 17.6; 95% CI, 6.30 to 48.9). When all atherogenic risk factors were analyzed simultaneously by a logistic model, the combination of prothrombotic and Apo E4 polymorphisms with current smoking increased the risk 25-fold (OR = 24.7; 95% CI, 7.17 to 84.9).The presented data suggest a synergistic effect between atherogenic and thrombogenic risk factors in the pathogenesis of AMI, as was recently found in a similar cohort of women.

Prothrombin G20210A (rs1799963) polymorphism increases myocardial infarction risk in an age-related manner: A systematic review and meta-analysis

“…There was one prospective study 6 and 33 cross-sectional case–control studies. Twenty-two studies included Caucasian patients 4 , 6 , 11 , 13 , 14 , 16 , 18 , 20 , 21 , 23 – 27 , 29 , 33 – 39 , 9 included non-Caucasians 8 , 10 , 12 , 15 , 17 , 19 , 28 , 30 , 32 , and 3 did not depict ethnicity of subjects 5 , 22 , 31 . As the study population overlapped in two reports 6 , 39 , Maren’s data 39 were evaluated only in the >55-year-old subgroup analysis and not in the overall analysis.…”

Genetic Modulation of Homocysteinemia

“…In some studies in which traditional risk factors were excluded, the MTHFR homozygous mutant genotype (V/V) conferred a higher risk. 39,41 The MTHFR genotype has been shown to interact with other risk factors for cardiovascular disease, such as Factor V Leiden, 25,26 apo E variants, 48 and diabetes, 49 to increase risk.…”

Combination of factor V Leiden and MTHFR mutations in myocardial infarction

“… 11 A synergistic effect between atherogenic risk factors and thrombogenic mutations in the pathogenesis of MI has also been suggested. 6 In particular, the concomitant presence of smoking and factor V Leiden mutation was found to increase the risk of MI in young men. 12 , 13 Therefore, in our patient, MI may have been a consequence of the synergism between inherited thrombophilia and cigarette smoking.…”

“…For example, the association between the homozygous 677TT MTHFR polymorphism and MI have been examined, but the results of studies demonstrated that the role of MTHFR in MI was not well established. 6 Moreover, other studies have failed to establish a definitive role of certain inherited thrombophilias in MI. 7 Recently, however, large-scale multigenic association studies have revealed that the C677T MTHFR polymorphism is a significant risk factor associated with the prevalence of MI.…”