Genetic And Nutritional Variation In The Folate-Mediated One-Carbon Metabolic Network And Cardiovascular Disease (Cvd) Risk
The aim of this research was to investigate the role of genetic and nutritional variation within the folate-mediated one-carbon network in relation to cardiovascular disease risk. The enzymes serine hydroxymethyltransferase 1 (gene name SHMT1) and methylenetetrahydrofolate reductase (gene name MTHFR) regulate key reactions in folate-mediated one-carbon metabolism. We investigated the effect of the SHMT1 rs1979277 SNP and the SHMT1 rs1979277 - MTHFR rs1801133 interaction in two epidemiologic cohorts. In the Nurses' Health Study, the MTHFR rs1801133 variant genotypes were associated with an increased CVD risk, and there was an interaction between SHMT1 and MTHFR such that the association of MTHFR rs1801133 CT genotype (vs. CC; the TT genotype could not be evaluated) was stronger in the presence of the SHMT1 rs1979277 TT genotype. In the Health Professionals FollowUp Study, the MTHFR rs1801133 genotype was not associated with CVD risk nor was there an interaction with SHMT1 rs1979277. Next, using data from the Normative Aging Study, 330 SNPs in 52 genes were studied in relation to cardiovascular disease biomarkers. Using a nominal significance threshold of P[LESS-THAN OR EQUAL TO]0.005, 20 SNPs were associated with homocysteine, 8 with Alu methylation, and 1 with LINE-1 methylation. Using a more stringent false discovery rate threshold, SNPs in FTCD, SLC19A1, and SLC19A3 genes were associated with plasma homocysteine, gene x vitamin B-6 interactions were identified for Alu and LINE-1 methylation, and epistatic interactions involving the MTHFR rs1801133 SNP were identified for the plasma homocysteine phenotype. Finally, the SNPs were prospectively evaluated for their association with cardiovascular disease in a U.S. population studied prior to mandatory folate fortification. Using a nominal significance threshold of P[LESS-THAN OR EQUAL TO]0.005, 8 SNPs were associated with CVD risk. Using a more stringent false discovery rate threshold, a polymorphism in the GGH gene was associated with reduced CVD risk. A gene x folate interaction was identified (MAT2B) and two gene x vitamin B-12 interactions were identified (BHMT and SLC25A32). Hypotheses related to SHMT1 were explored and significant gene x gene interactions were identified. Overall, genetic variation in folate-mediated one-carbon metabolism, other than the wellknown effects of the MTHFR 677 C[RIGHTWARDS ARROW]T rs1801133, is predictive of cardiovascular disease risk.
Folate; snp; Cardiovascular
Cassano, Patricia Ann
Clark, Andrew; Wells, Martin Timothy; Stover, Patrick J; Stipanuk, Martha Harney
Ph.D. of Nutrition
Doctor of Philosophy
dissertation or thesis