Genetic defects as important factors for moderate hyperhomocysteinemia

The genes for the enzymes methylenetetrahydrofolate reductase (MTHFR), meth ionine synthase (MS), methionine synthase reductase (MSR) and cytathionine- beta -synthase (CBS) play an important role in homocysteine metabolism. Rar e mutations in these genes cause severe hyperhomocysteinemia and clinical s ymptoms. Growing interest has focused on common mutations with moderate eff ects on homocysteine levels. We studied 280 subjects of different age group s for the following mutations: MTHFR677C -->T and 1298A -->C, MS2756A -->G, MSR66A -->G and the 68 bp insertion in the CBS gene. The median value for homocysteine increased significantly with age (median homocysteine levels: 7.5,12.4 and 16.5 mu mol/l in the age groups 20-43, 65-75 and 85-96 years, respectively). The genotypes of the MTHFR677C -->T mutation were associated with differences in plasma homocysteine levels, but without reaching signi ficance. Individuals homozygous for the MTHFR677C -->T mutation had a 2.3 m u mol/l higher median homocysteine level compared to individuals with the w ild-type allele. This effect was pronounced in combination with low folate levels and abolished with higher folate in plasma. For the other three muta tions no association with homocysteine values could be determined. The anal ysis of homocysteine metabolite cystathionine by backward regression analys is revealed a significant correlation of the MS2756A -->G mutation with cys tathionine level. This increase could indicate a disturbed remethylation. I n summary, larger and homogeneous study populations are necessary to quanti fy the small effects of common mutations on homocysteine levels. This may a lso be the reason that no effects of genetic interactions between two genot ypes were observed.