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Relationships between smoking, homocysteine & folate

Institution: University of California, San Diego
Investigator(s): Archana McEligot, Ph.D.
Award Cycle: 2000 (Cycle 9) Grant #: 9DT-0046 Award: $48,651
Subject Area: Epidemiology
Award Type: Dissertation Awards

Initial Award Abstract
The relationship between cigarette smoking and increased risk of cardiovascular disease (CVD) has been well established. Studying the biological link between smoking and CVD needs further investigation.

Increased blood levels of homocysteine may increase risks of heart disease. Homocysteine is an amino acid, and consuming a diet high in meat and dairy products has been shown to increase blood homocysteine levels.

Studies have suggested that smokers have higher blood levels of homocysteine than non-smokers and the levels of homocysteine increase with the number of cigarettes smoked. Homocysteine levels can be lowered by consuming three vitamins: folate (mostly found in fruits and vegetables), vitamin B-12 and vitamin B-6. Folate, in particular, has been shown to substantially reduce homocysteine levels. Some studies that have reported on the link between cigarette smoking and homocysteine have not examined folate levels in smokers and non-smokers, which could alter the results. Also most studies use folate from vitamin supplements rather than from fruit and vegetables to lower homocysteine levels, and therefore the effects of consuming a high vegetable diet on homocysteine concentrations have not been widely investigated.

We would like to examine blood homocysteine and folate levels in a group of female smokers participating in a randomized clinical trial. The randomized trial is investigating the effects of consuming a diet low in fat and high in vegetable, fruit and fiber on breast cancer recurrence. We will examine homocysteine and folate levels upon entry into the study and one-year after randomization into either the intensive diet group (high vegetable and fruit diet) or the control group (usual diet). We expect that the smokers in the intensive diet group will have lower homocysteine concentrations than the control group at one-year post-randomization, which will show that a high vegetable diet may be protective for smokers by reducing homocysteine. Also, we will be able to compare homocysteine levels in smokers and non-smokers at entry into the study and one-year post-randomization. If smokers have higher amounts of homocysteine concentrations than non-smokers, regardless of their folate levels, then we could hypothesize on a possible mechanism for higher CVD rates in smokers. Thus, reducing homocysteine levels in smokers and investigating possible explanations for higher rates of heart disease in this population may provide future avenues of preventing or curbing the risk for CVD in smokers.

Final Report
Numerous studies have reported on the association between elevated plasma homocysteine and coronary, cerebral, and peripheral arterial disease. A meta-analysis by Boushey et al. (1995) of 27 studies examining the relationship between homocysteine and heart disease revealed that a 5 mol/L increase in homocysteine corresponded to a 60% increased risk of heart disease in men and an 80% increased risk for women. Also, several studies have reported that smokers have higher plasma homocysteine concentrations compared to non-smokers. Increasing consumption of folate, primarily found in dark, green leafy vegetables, has been shown to reduce plasma homocysteine concentrations.

We examined plasma homocysteine and folate concentrations in women smokers participating in a diet intervention trial, which investigated the effect of diet on breast cancer recurrence. Women enrolled in the trial and randomized into the intervention group consumed a diet high in vegetables, fruit, fiber and low in fat, while the control group was encouraged to follow the National Cancer Institutes dietary guidelines. Plasma homocysteine, folate and other key variables were examined at baseline, and 12 months. For the final sample at baseline, participants were 92 smokers matched on baseline dietary folate intake, age and intervention status to 92 non-smokers. The statistical analysis included, independent t-test analysis to compare differences in plasma homocysteine and serum folate concentrations, and key dietary variables between smokers and non-smokers. No significant differences were observed for plasma homocysteine and serum folate concentrations at baseline between smokers and non-smokers. Examination of dietary intakes at baseline showed that smokers consumed significantly less vegetables, fruit and fiber, and consumed significantly more alcohol, caffeine and percent energy from fat compared to non-smokers (P < 0.05). However, at follow-up, paired t-test analysis revealed that, similar to non-smokers, smokers in the intervention group significantly increased vegetable, fruit and fiber intakes and decreased percent energy from fat from baseline (P < 0.05). To examine whether smokers were at a higher dietary folate requirement we conducted a mean percent change analysis. This analysis suggested that even with a proportional increase in dietary folate intake for smokers and non-smokers in the intervention group, plasma homocysteine concentrations significantly decreased only in non-smokers (P < 0.05), but this was not observed in the control group.

For the immediate future, we will focus on refining the analysis and submit the results for publication. The findings from this study suggest that at baseline (pre-randomization) smokers have a less healthful diet compared with non-smokers, but that smokers in a diet intervention trial can adhere to dietary goals and increase fruit and vegetable consumption. The mean percent change analysis for the intervention group suggests that further examination, in a larger study, is required to assess higher dietary folate requirements for smokers compared with non-smokers, which could contribute to the understanding of the mechanism associated with cigarette smoking and increased cardiovascular disease risk.