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Nutritional Epidemiology

Polymorphisms in Cytoplasmic Serine Hydroxymethyltransferase and Methylenetetrahydrofolate Reductase Affect the Risk of Cardiovascular Disease in Men¹

Unhee Lim^*, Kun Peng, Barry Shane, Patrick J. Stover^*, Augusto A. Litonjua^**, Scott T. Weiss^**, J. Michael Gaziano, Robert L. Strawderman, Farbod Raiszadeh^*, Jacob Selhub, Katherine L. Tucker and Patricia A. Cassano^*,2

^* Division of Nutritional Sciences, Cornell University, Ithaca, NY; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA; ^** Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; Brigham and Women’s Hospital, Division of Aging, Boston, MA; Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY; and Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA

²To whom correspondence should be addressed. E-mail: pac6{at}cornell.edu.

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 1420CT) 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 677CT genotype on CVD risk varied by cSHMT 1420CT genotype. Among men with cSHMT 1420CT TT genotype, the odds ratios (OR) for CVD risk for MTHFR 677CT CT and TT genotypes compared with the MTHFR 677CT 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 1420CT 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 677CT TT and cSHMT 1420CT 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.

KEY WORDS: • homocysteine • folate • men • cardiovascular disease

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