Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: The atherosclerosis risk in communities (ARIC) study

Background - Elevated plasma total homocysteine (tHcy), low B-vitamin intake, and genetic polymorphisms related to tHcy metabolism may play roles in coronary heart disease (CHD). More prospective studies are needed. Methods and Results - We used a prospective case-cohort design to determine whether tHcy-related factors are associated with incidence of CHD over an average of 3.3 years of follow-up in a biracial sample of middle-aged men and women. Age-, race-, and field center-adjusted CHD incidence was associated positively (P<0.05) with tHcy in women but not men, and CHD was associated negatively (P<0.05) with plasma folate (women only), plasma pyridoxal 5'- phosphate (both sexes), and vitamin supplementation (women only). However, after accounting for other risk factors, only plasma pyridoxal 5'-phosphate was associated with CHD incidence; the relative risk for the highest versus lowest quintile of pyridoxal 5'-phosphate was 0.28 (95% CI=0.1 to 0.7). There was no association of CHD with the C₆₇₇T mutation of the methylenetetrahydrofolate reductase gene or with 3 mutations of the cystathionine β-synthase gene. Conclusions - Our prospective findings add uncertainty to conclusions derived mostly from cross-sectional studies that tHcy is a major, independent, causative risk factor for CHD. Our findings point more strongly to the possibility that vitamin B₆ offers independent protection. Randomized trials, some of which are under way, are needed to better clarify the interrelationships of tHcy, B vitamins, and cardiovascular disease.