title: Intermediate and severe hyperhomocysteinemia with thrombosis: a study of genetic determinants.
abstract: 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 micromol/l<tHcy < or =100 micromol/l, and tHcy > 100 micromol/l, respectively). The methylene-tetrahydrofolate reductase (MTHFR) 677C-->T genotype, and the complete cystathionine beta-synthase (CBS) genotype was determined in all patients. We found that the MTHFR T/T 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 severe hyperhomocysteinemia is important to ensure the detection of a possible CBS deficiency, thus enabling treatment. Co-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.
authors.affiliation: Department of Clinical Biochemistry, Skejby University Hospital, Aarhus, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Gaustadnes
authors.forename: N
authors.initials: N
authors.lastname: Rüdiger
authors.forename: K
authors.initials: K
authors.lastname: Rasmussen
authors.forename: J
authors.initials: J
authors.lastname: Ingerslev
mesh_terms: D000328:Adult; D017668:Age of Onset; D019943:Amino Acid Substitution; D015331:Cohort Studies; D003541:Cystathionine beta-Synthase / Q000172:deficiency* / Q000235:genetics; D004252:DNA Mutational Analysis; D003718:Denmark / Q000453:epidemiology; D005260:Female; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D020138:Hyperhomocysteinemia / Q000145:classification / Q000150:complications* / Q000235:genetics; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008875:Middle Aged; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation; D012307:Risk Factors; D012720:Severity of Illness Index; D020521:Stroke / Q000453:epidemiology / Q000209:etiology; D013923:Thromboembolism / Q000453:epidemiology / Q000209:etiology; D019851:Thrombophilia / Q000209:etiology* / Q000235:genetics; D013927:Thrombosis / Q000097:blood* / Q000235:genetics
chemical_list: D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D003541:Cystathionine beta-Synthase