title: A 31 bp VNTR in the cystathionine beta-synthase (CBS) gene is associated with reduced CBS activity and elevated post-load homocysteine levels.
abstract: Molecular defects in genes encoding enzymes involved in homocysteine metabolism may account for mild hyperhomocysteinaemia, an independent and graded risk factor for cardiovascular disease (CVD). Although heterozygosity for cystathionine beta-synthase (CBS) deficiency has been excluded as a major genetic cause of mild hyperhomocysteinaemia in vascular disease, mutations in (non-)coding DNA sequences may lead to a mildly decreased CBS expression and, consequently, to elevated plasma homocysteine levels. We assessed the association between a 31 bp VNTR, that spans the exon 13-intron 13 boundary of the CBS gene, and fasting, post-methionine load and increase upon methionine load plasma homocysteine levels in 190 patients with arterial occlusive disease, and in 381 controls. The 31 bp VNTR consists of 16, 17, 18, 19 or 21 repeat units and shows a significant increase in plasma homocysteine concentrations with an increasing number of repeat elements, in particular after methionine loading. In 26 vascular disease patients the relationship between this 31 bp VNTR and CBS enzyme activity in cultured fibroblasts was studied. The CBS enzyme activity decreased with increasing number of repeat units of the 31 bp VNTR. RT-PCR experiments showed evidence of alternative splicing at the exon 13-intron 13 splice junction site. The 31 bp VNTR in the CBS gene is associated with post-methionine load hyperhomocysteinaemia that may predispose individuals to an increased risk of cardiovascular diseases.
authors.affiliation: Department of Pediatrics, University Medical Center Nijmegen, The Netherlands.
authors.forename: K J
authors.initials: KJ
authors.lastname: Lievers
authors.forename: L A
authors.initials: LA
authors.lastname: Kluijtmans
authors.forename: S G
authors.initials: SG
authors.lastname: Heil
authors.forename: G H
authors.initials: GH
authors.lastname: Boers
authors.forename: P
authors.initials: P
authors.lastname: Verhoef
authors.forename: D
authors.initials: D
authors.lastname: van Oppenraay-Emmerzaal
authors.forename: M
authors.initials: M
authors.lastname: den Heijer
authors.forename: F J
authors.initials: FJ
authors.lastname: Trijbels
authors.forename: H J
authors.initials: HJ
authors.lastname: Blom
mesh_terms: D000483:Alleles; D017398:Alternative Splicing / Q000235:genetics; D001157:Arterial Occlusive Diseases / Q000097:blood / Q000201:enzymology / Q000235:genetics; D016384:Consensus Sequence / Q000235:genetics; D003541:Cystathionine beta-Synthase / Q000235:genetics* / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006710:Homocysteine / Q000097:blood* / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D012307:Risk Factors
chemical_list: D006710:Homocysteine; D003541:Cystathionine beta-Synthase