1. ¹Laboratory of Pediatrics and Neurology, University Medical Center Nijmegen, The Netherlands
2. ²Department of Endocrinology, University Medical Center Nijmegen, The Netherlands
3. ³Department of Epidemiology and Biostatistics, University Medical Center Nijmegen, The Netherlands

Correspondence: Dr HJ Blom, Laboratory of Pediatrics and Neurology (424), University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: +31 24 3613469; Fax: +31 24 3618900; E-mail: h.blom@cukz.umcn.nl

Received 21 January 2004; Revised 25 March 2004; Accepted 5 May 2004; Published online 7 July 2004.

Abstract

Hyperhomocysteinemia is an independent and graded risk factor for arterial vascular disease and venous thrombosis. It is still debated via which mechanism homocysteine (Hcy) causes vascular disease. S-adenosylhomocysteine hydrolase (AHCY) catalyses the reversible hydrolysis of S-adenosylhomocysteine (AdoHcy) to Hcy. As an increase in AdoHcy, a strong inhibitor of many methyltransferases, is observed in hyperhomocysteinemic individuals, AdoHcy may play a role in the development of cardiovascular diseases by inhibiting transmethylation reactions. We sequenced the entire coding region and parts of the untranslated regions (UTRs) of the AHCY gene of 20 patients with recurrent venous thrombosis in order to identify genetic variation within this gene. We identified three sequence variants in the AHCY gene: a C>T transition in the 5' UTR (-34 bp C>T), a missense mutation in exon 2, which mandates an amino-acid conversion at codon 38 (112 C>T; Arg38Trp) and a silent mutation in exon 4 (390 C>T; Asp130Asp). We studied the effect of the first two variants on total plasma Hcy and venous thrombosis risk in a case–control study on recurrent venous thrombosis. The two polymorphisms under study seem to have no evident effect on tHcy. The adjusted relative risk of venous thrombosis associated with the 112CT genotype compared with 112CC individuals was 1.27 (95% CI 0.55–2.94), whereas the -34CT genotype confers a risk of 1.25 (95% CI 0.44–3.52) compared with the wild-type genotype at this locus. However, the wide confidence intervals do not allow firm conclusions to be drawn.