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Nutrient-Gene Interactions

The Interaction between MTHFR 677 CT Genotype and Folate Status Is a Determinant of Coronary Atherosclerosis Risk

Domenico Girelli^*,2, Nicola Martinelli^*, Francesca Pizzolo^*, Simonetta Friso^*,, Oliviero Olivieri^*, Chiara Stranieri, Elisabetta Trabetti, Giovanni Faccini, Elisa Tinazzi^*, Pier Franco Pignatti and Roberto Corrocher^*

^* Department of Clinical and Experimental Medicine, Institute of Biology and Genetics, and Institute of Clinical Chemistry, University of Verona, Policlinico G.B. Rossi, 37134 Verona, Italy and Vitamin Metabolism Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research on Aging at Tufts University, Boston, MA 02111

²To whom correspondence should be addressed. E-mail: domenico.girelli{at}univr.it.

The 677 CT polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene interacts with folate status in determining elevated total plasma levels of homocysteine, a risk factor for coronary atherosclerotic disease (CAD). The present study had the following goals: 1) to define the 677 CT genotype-specific threshold values of both plasma and RBC folate, associated with hyperhomocysteinemia (>15 µmol/L); and 2) to determine the risk of CAD among subjects with levels of folate below the genotype-specific threshold considered at risk for hyperhomocysteinemia. We examined 655 subjects, with (433) or without (222) angiographically documented CAD. The MTHFR 677 CT genotype-specific threshold values of plasma folate corresponded to the 40th, 30th and 10th percentile in the TT, CT and CC genotype, respectively. A multivariate logistic regression analysis showed that the risk of CAD among subjects with plasma folate levels below the genotype-specific thresholds was 1.6 (95% CI, 1.04–2.46). Similar results were obtained when RBC folate was considered as a measure of folate status (odds ratio = 1.8, 95% CI, 1.03–3.15). A gene-nutrient interaction that defines a higher risk for CAD is determined by folate levels below specific thresholds, which differ depending on the MTHFR 677 CT genotype.

KEY WORDS: • MTHFR • folate • gene-nutrient interaction • coronary artery disease • homocysteine

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