Effect of common methylenetetrahydrofolate Reductase gene mutation on coronary artery disease in familial hypercholesterolemia

Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by primary hypercholesterolemia and premature coronary artery disease (CAD). However, the development of CAD in FH shows considerable interindividual variations. Elevated levels of plasma homacysteine have been recognized as independent risk factors for CAD. A 5,10-methylenetetrahydrofolate reductase (MTHFR) gene mutation (valine [V] was substituted for alanine [A]) has been reported to be associated with elevated levels of plasma homocysteine in mutant homozygotes (i.e., W). We studied 199 consecutive male heterozygous FH patients, 99 with and 100 without CAD. In the CAD group, genotype W and V alleles were significantly more frequent than in the non-CAD group (15% vs 7% in genotypes [p = 0.035] and 0.41 vs 0.30 in alleles [p = 0.017]). The mean ages at onset in the CAD group were 50, 51, and 43 years for genotypes AA, AV, and W, respectively (p < 0.05); the age of onset of CAD in genotype W was significantly lower than in the other 2 genotypes. Kaplan-Meier survivor curves indicated that the development of CAD was significantly accelerated by MTHFR mutation, probably in a gene dose-dependent manner. Furthermore, only MTHFR genotype W was shown to be an independent predictor of the early onset of CAD in a stepwise multiple regression analysis. The mean plasma homacysteine levels of genotype W were significantly higher than those of the other 2 genotypes. Thus, the MTHFR mutation appears to accelerate the onset of CAD through elevation of plasma homocysteine levels in male heterozygous patients with FH. (C) 2000 by Excerpta Medica, Inc.