The relationship of mutations in the MTHFR, prothrombin, and PAI-1 genes to plasma levels of homocysteine, prothrombin, and PAI-1 in children and adults

Studies in adults have demonstrated that the genetic mutations C677T methyl enetetrahydrofolate reductase (MTHFR), prothrombin 20210A, and the 4G polym orphism of the plasminogen activator inhibitor-1 (PAI-1) gene are associate d with elevated plasma levels of homocysteine, prothrombin and PAI-1, respe ctively and with an increased risk of thrombosis. No similar data is availa ble in children. Therefore, we assessed the relationship of plasma levels o f homocysteine, prothrombin and PAI-1 with their respective mutations in 19 7 normal children, compared to 40 adults. By stepwise multiple regression, homocysteine was positively associated with age, PAI-1 activity was negativ ely associated with age, while PAI-1 antigen and prothrombin levels were as sociated with gender, being higher in girls than boys. When the genotypes w ere added to the regression model as additional explanatory variables, the MTHFR genotype accounted for 2.9% of the variance of homocysteine (p = 0.02 4), and the PAI-1 gene accounted for 2.7% of the variance of PAI-1 antigen levels (p = 0.023). Of children homozygous for the MTHFR mutation, 35% had homocysteine levels greater than or equal to the age-specific 95th percenti le, compared to 2% heterozygotes and 5% wild type normals (p = 0.0001). The mean homocysteine level was higher in children homozygous for the MTHFR ge ne (8.4 mu mol/l) than in heterozygotes (5.5 mu mol/l), p <0.05. Of childre n homozygous for the 4G polymorphism of the PAI-1 gene, 19% had PAI-1 activ ity levels greater than or equal to the age-specific 95th percentile, compa red to 2% of heterozygotes and 3% of wild type normals (p = 0.003). Studies of the incidence of the MTHFR, prothrombin, and PAI-1 4G/5G genotypes in c hildren with thrombosis, when compared to these healthy normals, will provi de evidence as to which of these genes are associated with thrombophilia.