The overall objective of this research is to examine the joint effect of multiple variants in folate metabolism on CVD outcome. The intermediary outcome, homocysteine, will be investigated as the primary endpoint because the metabolic disruption characterized by elevated homocysteine levels is proposed to mediate the risk of CVD. Because epidemiologic studies are limited by small sample size, and thus reduced statistical power to examine genetic interactions and their combined effects on disease outcome, we utilize computer simulations to study five SNPs in four candidate genes that code for enzymes that are all linked through sequential metabolic steps in homocysteine remethylation. These enzymes are either directly involved in homocysteine remethylation or indirectly linked because they provide essential substrates required for the conversion of homocysteine to methionine by MTR. Using MTR as our focal point, we also considered gene-nutrient interactions among the five variants and varying levels of folate and vitamin B12 to account for the possible effects of nutritional status on disease risk. This approach led to the key finding that having double variants for all possible polymorphisms in a pathway does not necessarily equate to the most deleterious effects, and that only vitamin B12 had an effect on the homocysteine levels as a nutrient cofactor. Our simulations also illustrate how pathways have built-in regulatory mechanisms that researchers might not be able to account for when taking a single candidate gene approach to studying disease outcome. We anticipate that our model will serve as an example of how simulations can help advance the growing idea that disease treatment can be personalized by examining an individual's unique genetic and nutritional profile.