Effect of MTHFR677C > T on plasma total homocysteine levels in renal graftrecipients

Background. Hyperhomocysteinemia is an established, independent risk factor for vascular disease morbidity and mortality. The 5,10-methylenetetrahydro folate reductase (MTHFR) gene polymorphism C677T has been shown to result i n increased total homocysteine concentrations on the basis of low folate le vels caused by a decreased enzyme activity. The effect of this polymorphism on total homocysteine and folate plasma levels in renal transplant patient s is unknown. Methods. We screened 636 kidney graft recipients for the presence of the MT HFR C677T gene polymorphism. The major determinants of total homocysteine a nd folate plasma concentrations of 63 patients, who were identified to be h omozygous for this gene polymorphism compared with heterozygotes (N = 63), and patients with wild-type alleles (N = 63), who were matched for sex, age , glomerular filtration rate (GFR), and body mass index, were identified by analysis of covariance. The variables included sex, age, GFR, body mass in dex, time since transplantation, folate and vitamin B-12 levels, the use of azathioprine, and the MTHFR genotype. To investigate the impact of the kid ney donor MTHFR genotype on total homocysteine and folate plasma concentrat ions, a similar model was applied in 111 kidney graft recipients with stabl e graft function, in whom the kidney donor C677T MTHFR gene polymorphism wa s determined. Results. The allele frequency of the C677T polymorphism in the MTHFR gene w as 0.313 in the whole study population [wild-type (CC), 301; heterozygous ( CT), 272; and homozygous mutant (TT), 63 patients, respectively] and showed no difference in the patient subgroups with various renal diseases. The MT HFR C677T gene polymorphism significantly influenced total homocysteine and folate plasma concentrations in renal transplant recipients (P = 0.0009 an d P = 0.0002, respectively). Furthermore, a significant influence of the GF R (P = 0.0001), folate levels (P = 0.0001), age (P = 0.0001), body mass ind ex (P = 0.0001), gender (P = 0.0005), and vitamin B-12 levels (P = 0.004) o n total homocysteine concentrations was observed. The donor MTHFR gene poly morphism had no influence on total homocysteine and folate levels. Geometri c mean total homocysteine levels in patients homozygous for the mutant MTHF R allele were 18.6 mu mol/liter compared with 14.6 mu mol/liter and 14.9 mu mol/liter in patients heterozygous for the MTHFR gene polymorphism and tho se with wild-type alleles (P < 0.05 for TT vs. CT and CC). Geometric mean f olate levels were lower in CT and TT patients (11.2 and 10.2 nmol/liter) co mpared with CC patients (13.6 nmol/liter, P < 0.05 vs. CT and TT). Conclusions. This study demonstrates that homozygosity for the C677T polymo rphism in the MTHFR gene significantly increases total homocysteine concent rations and lowers folate levels in kidney graft recipients, even in patien ts with excellent renal function (GFR more than median). These findings hav e important implications for risk evaluation and vitamin intervention thera py in these patients who carry an increased risk for the development of car diovascular disease.