Linkage disequilibrium at the cystathionine beta synthase (CBS) locus and the association between genetic variation at the CBS locus and plasma levels of homocysteine

Cystathionine beta synthase (CBS) is a key enzyme in homocysteine metabolis m We have examined four apparently non-functional polymorphisms in the CBS gene and have determined their frequency, degree of linkage disequilibrium and association with plasma homocysteine levels. The polymorphisms are a 68 bp insertion in exon 8, C699T in exon 8, C1080T in exon 11 and C1985T in t he 3' untranslated region. 785 individuals participating in the European At herosclerosis Research Study II (EARSII), from 11 countries across Europe w ere genotyped for these polymorphisms. The 68bp insertion had the highest f requency in the UK and in the Middle region, with a lower frequency in the Baltic and the South (p = 0.01), and the exon 11. polymorphism had the high est frequencies of the rare allele in the Baltic (p < 0.05). There was a hi gh degree of linkage disequilibrium between the polymorphisms (p < 0.001 ov erall). except between C699T and the C1985T, with three common haplotypes a ccounting for nearly 80% of chromosomes. Examination of the association bet ween these polymorphisms and plasma homocysteine levels revealed that the c arriers of the rare alleles of the C699T, C1080T and C1985T polymorphisms h ad lower plasma homocysteine concentrations than those homozygous for the c ommon alleles; although these differences were not statistically significan t. The thermolabile valine variant caused by a substitution of a C for a T at nucleotide 677 in the methylenetetrahydrofolate reductase (MTHFR) has pr eviously been shown to have profound effects on plasma levels of homocystei ne in this sample. but the homocysteine-raising effect associated with this thermolabile variant was not seen in carriers of the 68 bp insertion, with this interaction being statistically significant (p < 0.001). These data d emonstrate that variation in the CBS gene as detected with these four polym orphisms, had no statistically significant effect on plasma homocysteine le vels in these healthy young men. However, the presence of the 68 bp inserti on, which is found in approximately 7.5% of individuals in the populations of Europe sampled, abolishes the raising effect of thermolabile MTHFR Val/V al genotype, and may be of importance in the situation of high homocysteine .