Intermediate and severe hyperhomocysteinemia with thrombosis: A study of genetic determinants

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. In search of genetic factors causing elevated levels of total homocysteine in plasma (tHcy), we investigated a cohort of consecutively identified, unrelated thrombosis patients (n = 28) having intermediate or severe hyperhomocysteinemia (30 mu mol/l<tHcy less than or equal to 100 mu mol/l, and tHcy >100 mu mol/l, respectively). The methylenetetrahydrofolate reductase (MTHFR) 677C-->T genotype. and the complete cystathionine beta-synthase (CBS) genotype was determined in all patients. We found that the MTHFR TIT genotype was strongly correlated with intermediate hyperhomocysteinemia being present in 73.9% of those cases (17 of 23). In three of five patients with severe hyperhomocysteinemia, compound heterozygosity for CBS mutations was detected. Among the mutations, two novel missense mutations: 1265C-->T (S422L) and 1397C-->T (S466L) were detected. The phenotype in those patients was quite mild, thromboembolism apart. This indicates that a search for CBS mutations in patients with seven hyperhomocysteinemia is important to ensure the detection of a possible CBS deficiency, thus enabling treatment. Go-existence of the MTHFR T/T genotype and the common CBS 844ins68 variant was significantly higher among patients (10.7%) as compared to controls (1.2%), indicating that this genotype combination is a thrombotic risk factor (P < 0.05). In a few patients, hyperhomocysteinemia could not be explained by this genetic approach, suggesting that other genetic risk factors were implicated.