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Genetic determinants of plasma homocysteine concentration.

Dekou, Evangelia Vanessa; (2000) Genetic determinants of plasma homocysteine concentration. Doctoral thesis (Ph.D.), University College London. Green open access

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Abstract

Mild hyperhomocysteinaemia occurs commonly in individuals in the general population and has been associated with increased risk of developing atherosclerosis and coronary artery disease. Mutations in the enzymes regulating homocysteine metabolism have been associated with elevated plasma homocysteine levels. There are three main enzymes involved in homocysteine metabolism; Methylenetetrahydrofolate reductase (MTHFR), that is involved in the remethylation pathway, Methionine synthase (MS) that is also involved in the remethylation pathway and Cystathionine beta synthase (CBS) that is involved in the transsulphuration pathway. Healthy middle aged men, from eight general practices across Britain (Northwick Park Heart Study II) were examined for plasma homocysteine levels and genotyped for the C677T polymorphism in the MTHFR gene, the 68 bp insertion polymorphism in exon 8 of the CBS gene and the A2756G polymorphism in the MS gene. Genotype at all three loci were associated with differences in plasma homocysteine level. Individuals homozygous for the MTHFR 677T allele had highest median homocysteine levels when compared to the other two genotypes (p<0.001). The raising effect associated with homozygosity for the 677T allele was greater in men in the lowest quartile of folate (interaction p=0.02). Furthermore there was an interaction between MTHFR and CBS genotypes and between MS and CBS genotypes. Age, folate, B12 and smoking explained 24.2% of the variance while the three genotypes combined and with interaction terms explained an additional 3.8%. This interaction between CBS genotype and MTHFR and MS genotypes points to a key role of the CBS transsulphuration pathway in the metabolism of homocysteine that may be particularly important in subjects with low dietary folate. Elderly men and women from two towns, of contrasting risk of developing of coronary artery disease, Dewsbury and Maidstone, were examined for plasma homocysteine levels and genotyped for the C677T and the A1298C polymorphisms in the MTHFR gene. Plasma homocysteine levels were significantly higher in men from the coronary artery disease high risk town of Dewsbury than in the low coronary artery disease risk town of Maidstone (p<0.001), but not in women. Women in both towns had significantly lower plasma homocysteine than men. There was no difference between towns in plasma folate or B12 levels but the conventional inverse relationship with plasma homocysteine was seen. There was a significantly higher number of males homozygous for the 677T allele in Dewsbury than in Maidstone; 12.8 % vs. 6.7% respectively (p=0.05). Similar frequency difference for homozygosity were seen for women; 13.3% vs. 8.0% (p=0.05) suggesting a true regional frequency difference. The regional differences in plasma homocysteine levels were still present after the adjustment for folate levels, B12 levels, smoking and the effect of the C677T polymorphism. These observations may have a bearing on regional differences in plasma homocysteine levels and the variation in coronary artery disease risk between regions in the UK. The degree of reduction of homocysteine levels after administration of folic acid from different sources was examined in relation to common polymorphisms that have been identified in the MTHFR gene. Fifty-nine subjects from New Zealand received similar doses of folic acid in different forms, i.e. synthetic supplements, fortified cereals and fruits. The most effective way to lower homocysteine levels was through administration of synthetic supplements of folate. The genotype response to folate administration was examined and it was concluded that individuals with the thermolabile variant have a more profound response than any of the other genotypes after folate administration for 12 weeks. However, the homocysteine levels at the end of the intervention period were very similar between groups that received the same folate treatment irrespective of genotype.

Type: Thesis (Doctoral)
Qualification: Ph.D.
Title: Genetic determinants of plasma homocysteine concentration.
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis Digitised by Proquest.
URI: https://discovery.ucl.ac.uk/id/eprint/10124743
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