title: Gene-environment and gene-gene interactions of specific MTHFR, MTR and CBS gene variants in relation to homocysteine in black South Africans.
abstract: The methylenetetrahydrofolate reductase (MTHFR), cystathione-β-synthase (CBS) and methionine synthase (MTR) genes interact with each other and the environment. These interactions could influence homocysteine (Hcy) and diseases contingent thereon. We determined single nucleotide polymorphisms (SNPs) within these genes, their relationships and interactions with total Hcy concentrations within black South Africans to address the increased prevalence of diseases associated with Hcy. The MTHFR 677 TT and MTR 2756 AA genotypes were associated with higher Hcy concentrations (16.6 and 10.1 μmol/L; p<0.05) compared to subjects harboring the MTHFR 677 CT/CC and the MTR 2756 AG genotypes (10.5, 9.7 and 9.5 μmol/L, respectively). The investigated CBS genotypes did not influence Hcy. We demonstrated interactions between the area of residence and the CBS T833C/844ins68 genotypes (p=0.005) so that when harboring the wildtype allele, rural subjects had significantly higher Hcy than their urban counterparts, but when hosting the variant allele the environment made no difference to Hcy. Between the CBS T833C/844ins68 or G9276A and MTHFR C677T genotypes, there were two-way interactions (p=0.003 and=0.004, respectively), with regard to Hcy. Subjects harboring the MTHFR 677 TT genotype in combination with the CBS 833 TT/homozygous 844 non-insert or the MTHFR 677 TT genotype in combination with the CBS 9276 GA/GG displayed higher Hcy concentrations. Therefore, some of the investigated genotypes affected Hcy; residential area changed the way in which the CBS T833C/844ins68 SNPs influenced Hcy concentrations highlighting the importance of environmental factors; and gene-gene interactions allude to epistatic effects.
authors: Centre of Excellence for Nutrition (CEN), North-West University, Potchefstroom Campus, South Africa. Electronic address: 12632449@nwu.ac.za.
authors: Cornelie
authors: C
authors: Nienaber-Rousseau
authors: Suria M
authors: SM
authors: Ellis
authors: Sarah J
authors: SJ
authors: Moss
authors: Alida
authors: A
authors: Melse-Boonstra
authors: G Wayne
authors: GW
authors: Towers
mesh_terms: D000328:Adult; D003541:Cystathionine beta-Synthase / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D059647:Gene-Environment Interaction; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006710:Homocysteine / Q000097:blood; D006801:Humans; D020138:Hyperhomocysteinemia / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013019:South Africa
chemical_list: D006710:Homocysteine; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D017853:Phosphotransferases (Alcohol Group Acceptor); C021787:5-methylthioribose kinase; D003541:Cystathionine beta-Synthase
keywords: CBS; CV; CVD; Cystathionine beta-synthase; GGT; HWE; Hardy–Weinberg equilibrium; Hcy; Hyperhomocysteinemia; MTHFR; MTR; Methionine synthase; Methylenetetrahydrofolate reductase; PURE; Prospective Urban and Rural Epidemiology study; QFFQ; Quantitative food frequency questionnaire; RFLP; SNPs; THUSA; Transition and Health during Urbanization of South Africans study; Urbanization; cardiovascular disease; coefficient of variance; cystathione-β-synthase; gamma (γ)-glutamyl transferase; high sensitivity C-reactive protein; homocysteine; hs-CRP; methionine synthase; methylenetetrahydrofolate reductase; restriction fragment length polymorphism; single nucleotide polymorphisms; tHcy