Prothrombotic gene variants as risk factors of acute myocardial infarction in young women

Given its high incidence, morbidity and mortality, acute myocardial infarction (AMI) is a relevant clinical and social problem making heart disease a leading killer particularly in young women [1, 2]. Importantly, registries and cohort studies revealed an excess mortality risk following AMI in young women compared with similarly aged men [3]. The higher risk may be due to a higher prevalence of various traditional and emerging risk factors in this group compared with men. Data on risk factors for young AMI may help to improve strategies for its prevention. In a relevant percentage of cases, young AMI occurs independently of the presence of typical risk factors such as dyslipidemia, smoking, hypertension, diabetes. In such cases, familiarity for AMI is frequently observed suggesting that genetic predisposition plays a relevant role [4].

Prothrombotic gene variants were found in genes involved in haemostasis and its inhibition, leading to a procoagulant effect. The most common prothrombotic variants are: Factor V (FV) Leiden, which causes resistance to protein C; prothrombin (FII) G20210A variant, that causes a higher plasma level of FII; the C677T variant of methylene-tetrahydrofolate reductase (MTHFR) enzyme which impairs the homocysteine pathway thereby causing higher serum levels of homocysteine that acts as a trigger for coagulation at endothelial level; and the -455G>A variant of beta-fibrinogen which causes increased levels of fibrinogen [5]. Prothrombotic gene variants are already known to be risk factors for recurrent venous thrombosis [6], particularly in patients with other predisposing disease [7] whereas there is no consensus regarding the role of such variants as risk factors for arterial disorders, including AMI and young AMI [8‐12]. The discordant results reported so far may reflect heterogeneous selection criteria and the different number of AMI patients and controls analyzed in different studies [13], and the fact that most studies pooled male and female patients thereby obscuring eventual gender differences. The different results may also depend on the variable incidence of prothrombotic variants in subjects of different ethnic background, and on the fact that some studies compared the frequency of prothrombotic gene variants obtained in AMI patients with that of control populations of other geographical areas.

The aim of the present study was to evaluate the potential role of the four prothrombotic gene variants as risk factors of either young AMI and AMI in female and male subjects in comparison to a large group of individuals from the general population of the same geographic area, whose sex and age distribution corresponded to the anagraphic distribution of the population of southern Italy.

The three populations of our study resulted in the Hardy-Weinberg equilibrium for all tested gene variants.

To our knowledge, this is the first study investigating the possible involvement of the prothrombotic gene variants as risk factors of AMI in different gender and age subjects. Our data indicate that the FV Leiden and FII G20201A variants in females represent a risk factors for young AMI, namely, patients who developed the first episode of AMI before reach the age of 45 years. The FV Leiden is associated to a resistance to the inhibitory effect of protein C that enhances a procoagulant activity, while the FII G20210A variant causes higher levels and more pronounced procoagulant activity of FII, both of which may predispose to ischemic diseases [5]. We observed a higher frequency of such variants only in young AMI females and not in young AMI males or in AMI females, confirming that young AMI females are a well-defined group of subjects with peculiar risk factors [1‐3]. On the other hand, risk factors for young AMI are different from those observed in AMI, e.g., the atherosclerosis burden is less relevant in young AMI, particularly in women [4]. While, genetic factors seem to be more relevant [4, 17, 18]. Our data are in accordance with the results of a large study by Mannucci et al. [9] in which there was a higher (albeit not significantly different) allelic frequency of the FII G20210A variant in young AMI than in controls; however the authors did not analyze the data in terms of gender, and the group they studied contained more men than women (1680 men and 210 female). In the same study, the FV Leiden mutation was significantly more frequent in young AMI patients.

Furthermore, our data indicate that the C677T MTHFR variant confers a higher risk for AMI to males. Such variant is a known risk factor for coronary heart disease [19], but our study revealed that only male homozygous subjects for this variant have a higher odds ratio for AMI. The MTHFR C677T variant causes higher homocysteine and lower folate levels in serum, and this is particularly true in homozygous subjects. In this context, it is noteworthy that the mechanism by which high levels of circulating homocysteine or low levels of folate may contribute to AMI pathogenesis it is still obscure [20]. Interestingly, we observed a higher frequency of MTHFR C677T only in AMI males and not in young AMI patients. It is conceivable that this variant acts as a risk factor in older but not in young subjects because the latter have a better folate intake [21]. The other three prothrombotic variants we investigated (FV Leiden, FII G20201A and -455 G>A in the gene encoding the beta-fibrinogen) do not seem to contribute to AMI risk. These data are in partial discordance with previous studies that implicated these gene variants in AMI, but in most cases the sample size and the differences between patients and controls were small. Another study, in agreement with ours, excluded a major role of these variants as risk factors for AMI [17] and a large meta-analysis concluded that prothrombotic gene variants are only moderately associated with the risk of coronary diseases [9].

AMI is a multifactorial disease due to the combination of many genetic and environmental risk factors; this is the first study reporting on a significant association between some prothrombotic gene variants and the occurrence of young AMI in females, confirming the peculiarity of such phenotype. These data (once confirmed in other populations) may contribute to a better stratification of the genetic AMI risk in different age and gender subjects and may have implications for the use of therapies to reverse the prothrombotic phenotype in high risk patients.