Role of methylenetetrahydrofolate reductase 677C->T polymorphism in the development of premature myocardial infarction
Introduction
Young adults are a relatively small proportion of patients who sustain acute myocardial infarction (MI) [1]. It is estimated that young patients make up between 5% and 10% of all MIs [1], [2]. Young patients with MI have a different risk factor profile compared to older patients. In particular, young survivors of MI are characterized by a higher proportion of heavy smoking and family history of coronary heart disease (CHD) and a lower proportion of hypertension and diabetes mellitus [3], [4].
Another distinct characteristic of patients with MI at young age is the relatively high proportion of angiographically “normal” or near “normal” coronary arteries [3]. The exact pathogenetic mechanism of MI in young patients with “normal” coronary arteries remains unknown. It is likely to result from multiple pathogenetic mechanisms [5]. It has been proposed that thrombus formation due to rupture of a vulnerable non-obstructive plaque or due to erosion of endothelial layer is the main mechanism. In addition, hypercoagulable states, coronary artery spasm, coronary embolism and inflammation, per se or in combination may play a role in the pathogenesis of MI in young individuals [6], [7], [8].
Several studies [9], [10], [11] have shown an association of raised homocysteine levels with CHD. However, this association was weaker in prospective studies [10] and randomized controlled trials of homocysteine-lowering therapy failed to prove a causal relationship between homocysteine and cardiovascular risk [12]. There are only few studies regarding the role of hyperhomocysteinemia in the development of premature MI [13], [14], [15].
Plasma homocysteine levels are modulated by nutritional and genetic factors among which the methyleletetrahydrofolate reductase (MTHFR) gene has attracted special attention. In particular, the 677C->T mutation in the gene coding for MTHFR, characterized by the replacement of cytosine with thymidine, leads to reduced MTHFR activity and is associated with moderately elevated homocysteine levels. There are conflicting data regarding the association between the MTHFR 677C->T polymorphism and the risk of CHD [11], [16], [17], [18]. A meta-analysis [19] of case-control observational studies reported a higher risk of CHD of individuals with the MTHFR 677TT genotype, while another meta-analysis later [20] did not support this association in Europe, North America or Australia. Assuming that factors associated with increased thrombotic tendency, such as homocysteine, are more likely to have a greater impact in patients with premature MI, we explored the role of homocysteine and its main genetic modulator MTHFR 677C->T polymorphism in patients who sustained MI ≤35 years of age.
Section snippets
Subjects
This case-control study included 147 consecutive patients who had survived their first MI occurring ≤35 years of age. They had been admitted to the Coronary Care Unit of the General Hospital of Nikea and the University General Hospital “Attikon” between January 2000 and December 2006. The diagnosis of acute MI was based on the presence of ≥2 of the following three criteria: (1) characteristic chest pain lasting >30 min, (2) ST elevation >0.1 mV on at least 2 adjacent electrocardiographic leads
Traditional risk factors and homocysteine
The vast majority of patients were men (85.4%). One patient had chronic renal failure and two were current multivitamin users. All these three patients were excluded from further analysis. Table 1 shows the prevalence of traditional risk factors and biochemical measurements. There was a significantly higher prevalence of smoking and hypertension in patients than in controls. Body mass index was significantly higher in patients than in controls. Total cholesterol, triglycerides, low density
Discussion
We found a high frequency (almost 1 out of 2) of homozygosity for the 677C->T mutation of MTHFR in individuals who develop premature MI (≤35 years) in the setting of angiographically “normal” coronary arteries. Particularly, individuals with TT genotype had an approximately 5-fold increased risk to develop premature MINCA. Furthermore, this association was independent of traditional risk factors and was more marked when associated with low folate plasma levels.
To the best of our knowledge this
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