Effect of Common Methylenetetrahydrofolate Reductase Gene Mutation on Coronary Artery Disease in Familial Hypercholesterolemia Running Head: MTHFR mutation accelerates CAD in FH

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 inter-individual variations. An elevated level of plasma homocysteine (tHcy) has been recognized as an independent risk factor for CAD, and a MTHFR gene mutation, valine (V) was substituted for alanine (A), has been reported to be associated with elevated levels of tHcy in mutant homozygotes, i.e. VV. We studied 199 consecutive male heterozygous FH patients, 99 with CAD and 100 without CAD. In CAD group, genotype VV and V allele were significantly more frequent than in non-CAD group, 15% vs 7% in genotype (p=0.035) and 0.41 vs 0.30 in allele (p=0.017). The mean ages of onset in the CAD group were 50, 51, and 43 years, for genotypes AA, AV, and VV, respectively (p<0.05); the age of onset of CAD in genotype VV was significantly lower than in other two 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 VV was shown to be an independent predictor of the early onset of CAD in the stepwise multiple regression analysis. The mean plasma tHcy level of genotype VV was significantly higher than those of other two genotypes. Thus, the MTHFR mutation appears to accelerate the onset of CAD through elevation of plasma tHcy levels in male heterozygous FH patients.