Genetic Coronary Risk Factors in Conventionally Low-Risk Patients

Development of coronary artery disease (CAD) is greatly affected by the presence of risk factors such as dyslipidemia, hypertension, smoking and diabetes mellitus. Accumulating epidemiological studies have shown that risk factor reduction is the indispensable approach to the prevention of CAD morbidity and mortality. However, we often encounter patients with few coronary risk factors suffering from severe CAD. Unveiling concealed risk factors in such low-risk patients may provide us with a novel strategy for the prevention of CAD. Recently, several gene polymorphisms have been identified as coronary risk factors. The I/D polymorphism of angiotensin-converting enzyme (ACE) gene has been shown to be associated with CAD (1). Some reports suggest higher association between the D allele and CAD in low-risk patients, but this evidence was not confirmed by other studies. The A/V polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR), one of the key enzymes catalyzing remethylation of homocysteine, may be another genetic risk factor of CAD (2-5), although it remains controversial (6, 7). The VV genotype could increase a risk for CAD through a mild increase in plasma homocyst(e)ine levels caused by impaired enzyme activity. The present analysis was designed to investigate how these genetic risk factors could contribute to the onset of CAD in conventionally lowrisk patients in Japanese population. We examined the genotypes of ACE and MTHFR in patients with myocardial infarction and compared the association between the genotypes and myocardial infarction among subgroups according to the presence or absence of conventional coronary risk factors. We examined 203 Japanese male patients with myocardial infarction. The diagnosis of myocardial infarction was made by coronary angiography, electrocardiography and measurements of serum cardiac markers. We devided patients into two subgroups; low-risk group having 0 to 2 conventional coronary risk factors and high-risk group having 3 to 6 ones. Conventional coronary risk factors in the present analysis included Age >60 years old, body mass index >26.0 kg/m, current smoking, hypertension, diabetes mellitus, total cholesterol >220mg/dL and HDL-cholesterol < 40mg/dL. The genotypes of MTHFR and ACE were analyzed as previously described (1, 2). As shown in (Table 1), both MTHFR VV genotype and ACE DD genotype were significantly more frequent in conventionally low-risk group than in high-risk group (p = 0.017 and p = 0.023, respectively). These data suggest that the risk for the onset of myocardial infarction would consist of genetic and environmental factors. We should never regard conventionally low-risk group as resistant to myocardial infarction and have to take account of genetic risk factors. Whether these factors may be independent of or influence the susceptibility to environmental disadvantage, the consideration of the genetic risk factors would provide us with the more profound understanding of pathophysiology of CAD. In the present study, the objects were limited to the patients because they were well-characterized and welldefined, however, a larger scale analysis on the general population, if possible a cohort study, shoud be promoted. Although the extent to which respective risk factor is associated with the onset of CAD is different, such a viewpoint would improve clinical decision-making as to diagnosis, prevention and treatment.