Evidence of major genes effects on serum homocysteine and fibrinogen levels, and premature ischemic heart disease in Italian extended families.

The purpose of the present study was to investigate the effect of novel genetic factors on plasma levels of total homocysteine (tHcy) and fibrinogen (FIB). As tHcy and FIB have been consistently associated to increased risk of ischemic heart disease (IHD) and acute myocardial infarction (MI) also genes-trait-MI mediational effects were tested.A complex segregation analysis, and a mediation analysis of a highly selected group of 44 extended families (302 subjects), each including at least one member with fatal premature (<50 years) IHD were carried out.tHcy and FIB levels turned out to be influenced by at least two major genes. A significant tHcy latent class-MI association (OR = 3.24; 95\% CI, 1.37 to 7.68), and a non-significant tHcy plasma level-MI association (OR = 1.65 per 1 = log 10 mumol/l, 95\% CI, 0.56 to 4.81) were estimated, suggesting a direct influence of the homocysteine major gene as suppressor of plasma tHcy levels effect. In contrast, FIB latent class-MI association (OR = 0.97; 95\% CI, 0.31 to 3.05) and FIB level-MI association (OR = 1.32 per 1 = 70 g/l; 95\% CI, 0.88 to 2.00) were not statistically significant.These data provide evidence for a major latent gene effect influencing variation in tHcy plasma levels, which is independent on C677T MTHFR polymorphism, and significantly affecting the risk of MI.