Prospective Study of Coronary Heart Disease Incidence in Relation to Fasting Total Homocysteine, Related Genetic Polymorphisms, and B Vitamins

Abstract

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 (PϽ0.05) with tHcy in women but not men, and CHD was associated negatively (PϽ0.05) with plasma folate (women only), plasma pyridoxal 5Ј-phosphate (both sexes), and vitamin supplementation (women only). However, after accounting for other risk factors, only plasma pyridoxal 5Ј-phosphate was associated with CHD incidence; the relative risk for the highest versus lowest quintile of pyridoxal 5Ј-phosphate was 0.28 (95% CIϭ0.1 to 0.7). There was no association of CHD with the C 677 T mutation of the methylenetetrahydrofolate reductase gene or with 3 mutations of the cystathionine ␤-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 B 6 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. (Circulation. 1998;98:204-210.)

Low serum folate concentrations are associated with an excess incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study

“…In the Atherosclerosis Risk in Communities Study, neither plasma folate concentration nor folic acid dietary intake had an association with CHD (Folsom et al, 1998). In the prospective First National Health and Nutrition Examination Survey Epidemiologic Follow-Up Study (Giles et al, 1998), the relative risk of CHD was the greatest for persons in the lowest serum folate quarter among persons aged 35 ± 55 y, whereas among persons over 55 y the relative risk for CHD was the greatest in persons in the highest serum folate quarter.…”

“…An association between dietary intake of folic acid or circulating folate concentration and CVD has been studied earlier in several studies (Chasan-Taber et al, 1996; Morrison et al, 1996; Rimm et al 1988; Folsom et al, 1998;Giles et al, 1995Giles et al, , 1998 Study (Chasan-Taber et al, 1996), men with the lowest 20% of plasma folate concentrations had a 1.4 fold (95% CI 0.9 ± 2.3) relative risk compared with those in the top 80%, adjusting for common cardiovascular risk factors. Although the results were not statistically signi®cant, the authors concluded that low dietary intake of folic acid contributes to the risk of MI.…”

“…This association has been con®rmed in some, but not in all prospective studies (Stampfer et al, 1992;Verhoef et al, 1994;Perry et al, 1995;Arnesen et al, 1995;Folsom et al, 1998;Wald et al, 1998;Alfthan et al, 1994;Evans et al, 1997). In a cross-country study with WHO MONICA data (Alfthan et al, 1997) high plasma tHcy concentrations were associated with increased cardiovascular mortality, and both the mean plasma tHcy concentration and cardiovascular mortality were the highest in Finland.…”

Homocysteine, hypertension and stroke

“…28 The difficulties in this area are well illustrated in further data from the European Concerted Action Project 29 and in a recent report from the ARIC study. 30 In the European Concerted Action Project, concentrations of red cell folate below the lowest 10th percentile and plasma vitamin B6 below the lowest 20th percentile for control subjects were associated with increased risk of vascular disease. As one would expect, the association with folate was explained in part by increased homocysteine levels.…”

Homocysteine and coronary heart disease risk in the PRIME study

“…Although recent meta-analyses [8,9,11] and most retrospective case-control studies support the hypothesis that homocysteine is a CHD risk factor [7], several prospective studies have failed to demonstrate an association between homocysteine concentration and CHD risk [15][16][17][18][19].…”