RESULTS

None of the Sicilian subjects carried the M694I or V726A mutations. The proinflammatory M694V mutation, however, was present in all three cohorts of study. It was most frequent in AMI patients (12%), intermediate in healthy young controls (6%), and less frequent in centenarians (4%; Table 2, P<0.0033). All genotypes were in HWE. As expected from the HWE of M694V genotypes, all subjects with the M694V mutation were heterozygous. The heterozygous genotype was also significantly overexpressed in AMI patients (30/121) and underexpressed in centenarians (5/68) compared with young controls (121/196; Table 3, P<0.0019).

By performing a series of 2x2 separate comparisons, high significance for the different frequencies of M694V genotypes and alleles was obtained between AMI patients and age-matched and centenarian controls. The frequency of M694V proinflammatory genotype and allele in centenarians was lower (but not significantly) than that observed in young healthy controls. Finally, we performed a logistic regression analysis to test the association of genotypes with AMI after adjusting for smoking habits, family history of CHD, and the presence of Type 2 diabetes, obesity, hypertension, hypercholesterolemia, and hypertriglyceridemia. As a result of the different number of women in the groups under study, logistic regression was performed only in men. Taking into account the risk factors, significant differences in genotype frequency persisted between male AMI patients and male young controls and between male AMI patients and male centenarians (Table 4). These results indicate that the M694V genotype is an independent risk factor for developing AMI in the Sicilian population.

DISCUSSION

The role of inflammatory responses in mediating all stages of atherosclerosis and CHD has been well established. Atherosclerosis begins as a focal process at specific regions of the vasculature, so-called lesion-prone areas, where hemodynamic flow is altered. The arterial endothelium expresses numerous adhesion molecules. The specific up-regulation of adhesion molecules suggests that they may regulate leukocyte adhesion in early atherogenesis. Moreover, adhesion molecules on the leukocyte membrane are increased in patients with AMI with respect to control subjects, causing the recruitment of neutrophils and monocytes to the involved myocardial region [28-30].

From literature, several case-control studies show that MEFV mutations do not seem to predispose toward inflammatory diseases such as Crohn's disease, multiple sclerosis, or rheumatoid arthritis. However, patients having that inflammatory burden and at the same time carrying one MEFV mutation appear to be highly susceptible to developing a more severe disease [17, 32, 33]. Therefore, it may be possible that MEFV mutations are not increasing the susceptibility to developing atherosclerosis, but they might affect its severity and complications, enhancing AMI occurrence.