Abstract:
Background: Homocysteine (Hcy) has been implicated in cardiovascular disease (CVD) and is influenced by demographic, environmental and genetic factors including single nucleotide polymorphisms (SNPs) within the genes encoding for methylenetetrahydrofolate reductase (MTHFR), cystathione-β-synthase (CBS) and methionine synthase (MTR). Objective: The overall aim of this investigation was to elucidate the possible role of various dietary, environmental and genetic risk factors on the regulation of Hcy concentrations. Specifically, to determine interactions between alcohol consumption and the MTHFR C677T genotype and the prevalence of the MTHFR C677T, MTR A2756G and CBS T833C/844ins68 and G9276A SNPs and their relationship to and
epistatic interactions with total (t)Hcy concentrations. Study design and methods: Chapters 5 and 6 outline cross-sectional data of 1,827 black South Africans nested within the international Prospective Urban and Rural Epidemiology study. Fasting plasma tHcy concentrations were determined by fluorescence polarisation immunoassay technology. The SNPs were determined through polymerase chain reaction based restriction fragment length polymorphism analysis. Dietary intake was ascertained with a quantitative food frequency questionnaire. Gamma glutamyl transferase (GGT) and percentage carbohydrate deficient transferrin (%CDT) were measured as alcohol biomarkers. Results: Age and GGT correlated best with tHcy (r = 0.26 and r = 0.27; p < 0.05) while %CDT and the B-vitamins were weakly associated with tHcy concentrations (r < 0.1 for both; p < 0.05). Age, GGT, gender, MTHFR genotype status and vitamin B6 explained 16.8% of the variation in tHcy concentrations (p < 0.01). The frequencies of SNPs adhered to the assumptions of Hardy-Weinberg equilibrium, but differed when compared to those reported for other ethnic groups. There was no interaction between alcohol consumption and the MTHFR 677 CCICT genotypes (p > 0.05). The MTHFR 677 TT and MTR 2756 AA genotypes were associated with significantly higher tHcy concentrations (16.6 and 10.1)µmol/L; p < 0.05) than subjects harbouring the MTHFR 677 CT/CC and the MTR 2756 AG (10.5, 9.7 and 9.5 µmol/L respectively). Between the CBS 844ins68, T833C or CBS G9276A and MTHFR C677T genotypes, there were significant two-way interactions (p < 0.05), however, there was not an interaction between MTHFR C677T and MTR A2756G or between the CBS 844ins68/T833C or G9276A and MTR A2756G genotypes with regard to tHcy concentrations. Conclusions: There is no interaction between alcohol intake and the MTHFR 677 CC/CT genotypes, however, MTHFR C677T genotype status, age, gender and GGT are more important determinants of tHcy concentrations than B-vitamin intake. Gene-gene interactions exist thus highlighting the epistatic nature of CVD. Ethnicity is a major modulating factor in genetic susceptibility to CVD.
