Gene-diet interactions in relation to circulating homocysteine concentrations

Abstract

Background: Elevated homocysteine (Hcy) is associated with several disease pathologies and can be manipulated by modifiable factors such as diet, nutritional status, physical activity and smoking, but can also be altered by non-modifiable factors such as age, gender and the genetic susceptibility of an individual. Although both dietary factors and genetic make-up influence plasma Hcy concentrations, very few investigations have examined the interactive effects i.e. gene-diet interactions. Objective: The overall aim of this study was to elucidate the interactive effects between six known single-nucleotide polymorphisms (SNPs) of the Hcy metabolism (i.e. methylenetetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, methionine synthase (MTR) A2756G, cystathionine β synthase gene (CBS) T833C, CBS 844ins68 and CBS G9276A) and markers of nutritional status (anthropometry, biochemical variables i.e. blood lipids, and dietary components) in relation to Hcy concentrations. Study design and methods: As explained in detail in Chapter 3, six SNPs of Hcy-metabolising enzymes were analysed in 2010 black South Africans nested within the North-West arm of the Prospective Urban and Rural Epidemiology (PURE) study. Fasting Hcy concentrations were determined by fluorescence polarisation immunoassay technology and five of the SNPs through polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) analysis. The MTHFR A1298C variant was genotyped using competitive allele-specific PCR (KASP) technology. Dietary intake was assessed by means of quantitative food frequency questionnaires and serum lipids were measured by using a sequential multiple analyser computer. Results: Hcy presented positive correlations with age (r = 0.28; p <0.0001) and gamma glutamyl transferase (GGT) (r = 0.24; p <0.0001) and was adjusted accordingly. Hcy increased with each addition of the MTHFR C677T minor allele, but decreased in the MTR 2756AA genotype compared with the heterozygote genotype. Individuals harbouring the CBS C833T/844ins68 polymorphism had the lowest Hcy concentrations of all the SNPs. Significant interactions were observed for MTHFR C677T*high density lipoprotein cholesterol (HDL-c) (p = 0.02), CBS T833C/844ins68*HDL-c (p = 0.001), CBS T833C/844ins68*protein as % of total energy intake (%TE) (p <0.001), CBS T833C/844ins68*animal protein intake (p = 0.02), MTHFR C677T*added sugar intake as % of total carbohydrate (%T CHO) (p = 0.004) and CBS T833C/844ins68*biotin intake (p = 0.04) and Hcy. Both MTHFR C677T and CBS T833C/844ins68 minor allele carriers were inversely associated with HDL-c. In terms of the CBS T833C/844ins68 interaction with protein, the homozygote minor allele carriers displayed an increase in Hcy as protein intake increased, whereas Hcy decreased significantly in the major homozygote TT (p <0.01) and heterozygote TC (p =0.01) alleles when consumption of animal protein was high. Sugar and the MTHFR 677TT genotype presented an increase in Hcy as sugar intake increased. In CBS T833C major allele carriers, elevated biotin intake was associated with lowered Hcy whereas Hcy was elevated in those harbouring the homozygous minor allele. Conclusion: The SNPs associated with Hcy concentrations are modulated by diet and this opens up the possibility of establishing dietary interventions to treat hyperhomocysteinaemia. Future intervention trials should explore the observed gene-diet and gene-blood lipid interactions further.