Home

There is uncertainty about the importance of plasma levels of homocysteine, vitamin B-12, and fotate for all-cause and cardiovascular disease (CVD) mortality in older people. We examined the associations between plasma levels of folate, vitamin B-12, and homocysteine, and all-cause and CVD mortality among community-dwelling adults aged ≥75 y living in the United Kingdom. In a population-based prospective cohort study, 853 men and women aged ≥75 y were examined in 1995-98 as part of the Medical Research Council Trial of Assessment and Management of Older People in the Community. During a median follow-up of 7.6 y (5528 person-years of follow-up), 429 individuals (50.3%) died, including 185 from CVD. Individuals with plasma homocysteine levels in the top one-third compared with the bottom one-third had a 2-fold higher risk of all-cause mortality (hazard ratio, 2.20; 95% CI, 1.76, 2.75; P < 0.001) and CVD mortality (hazard ratio, 1.96; 95% CI, 1.39, 2.78; P < 0.001) after adjustment for age, sex, and other covariates. There was no association of plasma folate or vitamin B-12 levels with mortality. Our results extend previously reported associations of homocysteine with mortality, and the absence of associations of folate and vitamin B-12 with mortality, to the older population.

Discussion

Individuals with plasma homocysteine levels in the top third compared with the bottom third had a 2-fold higher risk of allcause mortality (hazard ratio, 2.20; 95% CI, 1.76, 2.75; P < 0.001) and CVD mortality (hazard ratio, 1.96; 95% CI, 1.39,2.78; P < 0.001 ) after adjustment for age, sex, and other covariates in a population aged ≥75 y in the UK. Although renal function was associated with homocysteine level, it did not explain the association of homocysteine with mortality. Plasma folate and vitamin B-12 were not associated with all-cause mortality in the setting of voluntary fortification. It is possible, for folate and vitamin B-12, that this study was based on too few events and lacked the statistical power to detect a modest association with CVD and all-cause mortality. The 95% CI for the hazard ratio indicates that the present study could exclude effects greater than 1.58 for folate and 1.33 for vitamin B-12. Moreover, no associations were detected when these nutrients were categorized into thirds or when treated as continuous variables and no interaction between folate and vitamin B-12 was detected in the relationship with mortality.

Although evidence for the existence of an association of folate or of vitamin B-12 with all-cause or CVD mortality is inconsistent, the association of homocysteine with mortality is well established, at least among younger adults. A meta-analysis of 72 studies (mean subject age 55 y), both genetic and prospective, into the association between plasma homocysteine and ischemic heart disease, deep vein thrombosis, and pulmonary embolism has provided support for a causal association (4). Our study similarly found a significant increased risk of all-cause and CVD mortality across all levels of plasma homocysteine concentration even in adults aged ≥75 y at baseline.

Two studies have provided weak evidence that low folate concentrations are associated with increased risk of death, although neither found evidence of a gradual increase in risk with declining folate but instead suggested a threshold effect with only those with the very lowest folate concentrations being at high risk (8,14). More studies have looked specifically at CVD mortality in relation to folate levels, but the picture here is also inconclusive. Some studies have found significant negative associations, with lower folate concentrations being associated with higher risk of CVD mortality (6,11,12,16), whereas others have found no evidence of an association of folate with CVD or CVD mortality (5,7,9,10,15,17). The longest study to date (2950 adults followed for 29 y) showed no association between folate and CVD mortality but was based on adults aged 20-90 at baseline (mean age 48 y) (9). The null results of many of the North American studies of folate and CVD mortality may reflect greater use of multivitamin supplements and folic acid fortification in North America (5,7,10,17). The much more limited data on vitamin B-12 concentration and mortality risk suggested no association between vitamin B-12 concentration and CHD or CVD mortality in 2 studies (9,13), a negative association with vascular disease mortality in 1 study (15), and a positive association with all cause mortality in the remaining study (17). Our analysis adds to the literature in finding no association between plasma vitamin B-12 concentration and mortality even in this older cohort aged ≥75 y at baseline.

The mean plasma folate, homocysteine, and vitamin B-12 concentrations in our study were similar to those found for participants aged ≥75 y in 2 other UK-based studies: the Oxford Healthy Aging Project and the National Diet and Nutrition Survey (42). The mean plasma folate concentrations are slightly higher in our current study than in either of the latter studies, possibly due to improvements in folate status resulting from voluntary fortification in the UK population.

Measurements of folate, vitamin B-12, and homocysteine were based on a single nonfasting blood sample and this is likely to underestimate the associations with mortality due to regression dilution bias. A previous study of the within-person variability in plasma levels of homocysteine reported intraclass correlation coefficients of 0.89 for homocysteine, 0,84 for vitamin B-12, and 0.81 for folate [(43) and unpublished data]. Similarly, for eGFR, the use of a single blood sample may have resulted in some residual confounding in our analysis including CKD. There is considerable variability between assays and between laboratories in the measurement of folate (44-46), although this will likely not affect the associations presented in this study, which were all conducted in the same laboratory. Finally, although the stability of homocysteine determinations may have been impaired by the delay in separation of plasma from red cells, the samples in this study were stored at 4°C, which should minimize the release of homocysteine from red cells (47).

As anticipated (42), in our study, plasma folate and vitamin B-12 concentrations were inversely associated with homocysteine concentration, and plasma folate and vitamin B-12 concentrations were positively associated with each other. In general, high plasma folate and vitamin B-12 concentrations and low homocysteine concentrations in our study were related to features of good heath or health- seeking behavior, consistent with the literature (8,12,14,16,42). Several large randomized trials are currently assessing the relevance of lowering homocysteine levels for prevention of cardiovascular events and the results of the totality of the available evidence should guide public health policy on using folic acid supplements or folic acid fortification for the prevention of cardiovascular events (48).