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Thromb Haemost 2000; 83(04): 554-558
DOI: 10.1055/s-0037-1613862
Commentary
Schattauer GmbH

Intermediate and Severe Hyperhomocysteinemia with Thrombosis: A Study of Genetic Determinants

Mette Gaustadnes
1   From the Department of Clinical Biochemistry, Aarhus, Denmark
,
Niels Rüdiger
1   From the Department of Clinical Biochemistry, Aarhus, Denmark
,
Karsten Rasmussen
1   From the Department of Clinical Biochemistry, Aarhus, Denmark
,
Jørgen Ingerslev
2   Centre for Haemophilia and Thrombosis, Department of Clinical Immunology, Skejby University Hospital, Aarhus, Denmark
› Author AffiliationsThis work was supported by grants from the Danish Heart Foundation (98-1-5-74A-22579) and the Institute for Experimental Clinical Research, University of Aarhus. The excellent technical assistance of Mie Madsen, Jette Jensen, and the staff of the Coagulation Laboratory is gratefully acknowledged.
Further Information

Publication History

Received 14 September 1999

Accepted after resubmission 14 December 1999

Publication Date:
08 December 2017 (online)

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Summary

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 µmol/l<tHcy ≤100 µmol/l, and tHcy >100 µmol/l, respectively). The methylenetetrahydrofolate reductase (MTHFR) 677C→T genotype, and the complete cystathionine β-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.

Abbreviations: MTHFR, methylenetetrahydrofolate reductase; CBS, cystathionine β-synthase; tHcy, total homocysteine in plasma.

Keywords

Homocysteine - hyperhomocysteinemia - intermediate- - severe- - cystathionine β-synthase deficiency - MTHFR 677C→T polymorphism - venous thrombosis - stroke
 

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