title: Polymorphisms in cytoplasmic serine hydroxymethyltransferase and methylenetetrahydrofolate reductase affect the risk of cardiovascular disease in men.
abstract: Genetic variation in folate-regulating enzymes contributes to the risk of cardiovascular disease (CVD). The cytoplasmic serine hydroxymethyltransferase (cSHMT) enzyme is proposed to regulate a key metabolic intersection in folate metabolism. We hypothesized that a variant in cSHMT (cSHMT 1420C-->T) affects CVD risk, and that the effect depends on a linked step in the metabolic pathway catalyzed by methylenetetrahydrofolate reductase (MTHFR). A nested case-control study of incident CVD was conducted within the all-male Normative Aging Study cohort. Of the incident CVD cases, 507 had DNA samples; 2 controls/case were selected by risk set sampling (matched on age and birth year). A significant gene-gene interaction (P-values 0.0013, 0.0064) was found between MTHFR and cSHMT, and there was little or no change in the coefficients in covariate-adjusted models. The effect of MTHFR 677C-->T genotype on CVD risk varied by cSHMT 1420C-->T genotype. Among men with cSHMT 1420C-->T TT genotype, the odds ratios (OR) for CVD risk for MTHFR 677C-->T CT and TT genotypes compared with the MTHFR 677C-->T CC genotype were 3.6 (95% CI, 1.7-7.8) and 10.6 (95% CI, 2.5-46.0), respectively. Among men with the cSHMT 1420C-->T CC/CT genotype, the corresponding ORs were 1.0 (95% CI, 0.8-1.2) and 1.3 (95% CI, 0.9-1.8). Plasma total homocysteine concentrations were highest in the subgroup of men with both polymorphisms, MTHFR 677C-->T TT and cSHMT 1420C-->T TT, consistent with a higher risk of CVD in this subgroup. A more complete understanding of the molecular mechanism awaits identification of the functional effect of the polymorphism.
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
authors.forename: Unhee
authors.initials: U
authors.lastname: Lim
authors.forename: Kun
authors.initials: K
authors.lastname: Peng
authors.forename: Barry
authors.initials: B
authors.lastname: Shane
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Stover
authors.forename: Augusto A
authors.initials: AA
authors.lastname: Litonjua
authors.forename: Scott T
authors.initials: ST
authors.lastname: Weiss
authors.forename: J Michael
authors.initials: JM
authors.lastname: Gaziano
authors.forename: Robert L
authors.initials: RL
authors.lastname: Strawderman
authors.forename: Farbod
authors.initials: F
authors.lastname: Raiszadeh
authors.forename: Jacob
authors.initials: J
authors.lastname: Selhub
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Tucker
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Cassano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000235:genetics; D016022:Case-Control Studies; D003593:Cytoplasm / Q000201:enzymology; D005838:Genotype; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012016:Reference Values
chemical_list: D042965:Methylenetetrahydrofolate Reductase (NADPH2); D012696:Glycine Hydroxymethyltransferase