Joint Association of Alcohol and Folate Intake with Risk of Major Chronic Disease in Women
Rui Jiang1,2 ,
Frank B. Hu1,2,3,
Edward L. Giovannucci1,2,3,
Eric B. Rimm1,2,3,
Meir J. Stampfer1,2,3,
Donna Spiegelman2,4,
Bernard A. Rosner3,4 and
Walter C. Willett1,2,3
1 Department of Nutrition, Harvard School of Public Health, Boston, MA.
2 Department of Epidemiology, Harvard School of Public Health, Boston, MA.
3 Channing Laboratory, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, MA.
4 Department of Biostatistics, Harvard School of Public Health, Boston, MA.
Received for publication February 13, 2003; accepted for publication April 9, 2003.
 |
ABSTRACT
|
---|
Alcohol interferes with folate metabolism and has opposing effects on the risks of cardiovascular disease and cancer. The authors examined the joint association of alcohol and folate intake with risk of major chronic disease, defined as fatal or nonfatal cardiovascular disease or cancer, or other nontraumatic death. This study included 83,929 women aged 3459 years with no previous history of cardiovascular disease or cancer who provided dietary data in 1980. During 16 years of follow-up, the authors documented 10,666 new cases of major chronic disease. Overall, heavy drinkers (>30 g/day) with a lower total folate intake (<180 µg/day) had the highest risk; in comparison with abstainers with a folate intake of 400599 µg/day, the multivariate relative risk was 1.36 (95% confidence interval: 1.10, 1.70). However, the increased risk of major chronic disease associated with heavy drinking was largely diminished among women with a higher folate intake (p for interaction = 0.02). The positive association between heavy alcohol/low folate intake and risk of major chronic disease was most apparent among women younger than age 60 years. Adequate folate intake may be important in the primary prevention of overall major chronic disease in women, especially among younger women consuming more than two alcoholic drinks per day.
alcohol drinking; cardiovascular diseases; chronic disease; effect modifiers (epidemiology); folic acid; neoplasms; women
Abbreviations:
Abbreviation: CI, confidence interval.
 |
INTRODUCTION
|
---|
Alcohol interferes with normal folate transport and metabolism by disrupting intestinal absorption, reducing uptake and storage in the liver, increasing urinary loss, inhibiting methionine synthase activity, and activating oxidative catabolism of folate (1). Diminished folate status contributes to elevated blood homocysteine levels, which have been associated with increased risk of cardiovascular disease (2). Diminished folate status can also lead to abnormal DNA synthesis, repair, and methylation, which may increase the risk of cancer (35). A statistical interaction between alcohol and folate intake has been observed for risk of coronary heart disease (6), breast cancer (79), and colon cancer (10) in large prospective cohort studies. For example, in one study (6), the inverse association between folate intake and risk of coronary heart disease was stronger with increasing levels of alcohol consumption, and the inverse relation between alcohol consumption and risk of coronary heart disease was stronger with increasing levels of folate intake. For breast and colon cancer, alcohol consumption was associated with increased risk only among persons with lower folate intake, and a benefit of higher folate intake was seen primarily among persons with higher alcohol consumption (710). The opposing effects of alcohol consumption on the risks of cardiovascular disease and cancer further complicate the overall balance of risks and benefits associated with alcohol and folate intake. Therefore, we examined prospectively the joint associations of alcohol and folate intake with risk of major chronic diseases combined, as well as with cardiovascular disease and cancer separately, in a large cohort of women.
 |
MATERIALS AND METHODS
|
---|
The Nurses Heath Study cohort
The Nurses Health Study was established in 1976, when 121,700 female registered nurses aged 3055 years from 11 US states completed a mailed questionnaire designed to study the etiologies of heart disease and cancer. Updated information on lifestyle and disease status has been collected biennially by mailed questionnaire since 1976, and updated information on vitamin supplement use has been collected since 1980. Diet was assessed in 1980, 1984, 1986, 1990, and 1994 using semiquantitative food frequency questionnaires, before mandatory folic acid fortification of cereal-grain products started in 1998.
Dietary assessment
The semiquantitative food frequency questionnaire administered at baseline (1980) included 61 foods, and it was revised and expanded to include approximately twice that number in subsequent cycles (11). Participants were asked to report their average frequency of consumption of selected foods and beverages during the previous year, with a specified commonly used unit or portion size. We computed nutrient intakes by multiplying the consumption frequency of each food by the nutrient content of the portion specified and then summing these products over all of the food items. The food composition values were obtained from the Harvard University Food Composition Database, which was derived from US Department of Agriculture sources (12), and from supplemental manufacturer information. We also asked questions on the frequency and dose of specific vitamin supplements used and the frequency, duration, brand, and type of any multivitamin supplement used. The reproducibility and validity of the dietary questionnaires have been described in detail elsewhere (11).
Total alcohol intake was the sum of the values for three types of beverages: beer, wine, and spirits. We assumed an ethanol content of 13.1 g for a 12-ounce (38-dl) can or bottle of beer, 11.0 g for a 4-ounce (12-dl) glass of wine, and 14.0 g for a standard portion of spirits (13). Total folate intake was the sum of folate intake from both food and vitamin supplement sources.
In validation studies of the dietary instrument, we found that the food frequency questionnaire measured alcohol consumption well; the correlation coefficient for the correlation between alcohol consumption derived from the 1980 questionnaire and that derived from the average of four 1-week diet records was 0.90 (14). We also found that the food frequency questionnaire predicted circulating levels of folate. Correlation coefficients were 0.55 for the correlation between total folate intake calculated from the 1980 questionnaire and erythrocyte folate concentrations measured in 1987 in this cohort (15) and 0.63 for the correlation between total folate intake calculated from the same food frequency questionnaire and plasma folate levels in the Framingham Heart Study (16). In addition, the relation of homocysteine level to dietary folate was virtually the same as its relation to blood levels of folate (16).
Population for analysis
After up to four mailings had been sent, 98,462 women returned the 1980 dietary questionnaire. We excluded from our study women with inadequate assessment of diet (10 or more food items left blank or an implausibly high (>3,500 kcal/day) or low (<500 kcal/day) total energy intake). We also excluded women with a history of cancer (except for nonmelanoma skin cancer) or cardiovascular disease (angina, coronary bypass or angioplasty, myocardial infarction, and stroke), because diagnosis of these conditions can lead to changes in diet and lifestyle. We further excluded women who reported both no alcohol intake at baseline and a substantial decrease in drinking in the previous 10 years (n = 3,120), since these women may have stopped drinking because of illness. After these exclusions, 83,929 participants remained.
Outcome ascertainment
The primary endpoint in this study was incidence of major chronic disease, defined as fatal or nonfatal cardiovascular disease or cancer, or other nontraumatic deathwhichever came first. We also examined cardiovascular disease and cancer as separate outcomes. Cardiovascular disease was defined as fatal or nonfatal myocardial infarction or stroke.
We asked all women who reported incident nonfatal myocardial infarction, cancer, or stroke on any biennial follow-up questionnaire to confirm the report and provide permission to review their medical records. Study physicians blinded to the risk factors reviewed the records. Cancer was confirmed according to hospital records and pathology reports. Myocardial infarction was confirmed using the World Health Organization criteria, requiring symptoms plus either diagnostic electrocardiographic changes or elevated cardiac enzyme levels (17). Stroke was confirmed using the criteria of the National Survey of Stroke, which require a constellation of neurologic deficits that are sudden or rapid in onset, lasting at least 24 hours or until death (18). Deaths were reported by next of kin, coworkers, or postal authorities or ascertained through a search for nonrespondents using the National Death Index (19); confirmation rates were more than 98 percent. We attempted to confirm the cause of each death by referring medical records or autopsy reports.
Statistical analysis
Each participant contributed follow-up time from the date of returning the 1980 questionnaire to the date of the first event of cardiovascular disease, cancer, or death or June 1, 1996. During the follow-up period, confirmed cases and reported cancers were censored from subsequent follow-up, and the cohort at risk included those who were alive and remained free of cardiovascular disease or cancer at the beginning of each of the eight 2-year follow-up intervals. Thus, each woman could contribute only one major chronic disease event.
To reduce within-subject variation and best represent long-term dietary intake, we used the cumulative average of dietary intakes from all available questionnaires up to the start of each 2-year follow-up interval (20). For example, 1980 intake was used for follow-up between 1980 and 1984; the average of the 1980 and 1986 intakes was used for follow-up between 1984 and 1986; and the average of the 1980, 1984, and 1986 intakes was used for follow-up between 1986 and 1990. Diet for women who developed angina or underwent coronary bypass or angioplasty was not updated for major chronic disease and cardiovascular disease outcomes, because change in diet after development of the intermediate events of cardiovascular disease might have biased our estimate of the true exposure-disease association. For women who reported other chronic conditions, such as diabetes mellitus, hypercholesterolemia, and hypertension, we used the cumulative average intakes and controlled for these chronic conditions in the multivariate analyses. Intakes of all nutrients (except for alcohol) were energy-adjusted using the residual method (11, 21). Information on nondietary covariates was updated biennially.
We categorized alcohol intake into four groups (0, 0.110, 10.130, and >30 g/day) and folate intake into five groups (<180, 180299, 300399, 400599, and
600 µg/day) to examine the joint associations with alcohol and total folate intake. The alcohol categories used in this study are consistent with those of previously published studies (2224). We used the previous Recommended Dietary Allowance for folate (180 µg/day) (25) as the cutoff point for the lowest category of folate intake and the current Recommended Dietary Allowance (400 µg/day) (25) as the cutoff point for the reference category. We conducted further stratified analyses to determine whether the combined association of alcohol and total folate intake with risk of major chronic disease was modified by age. We used odds ratios calculated from pooled logistic regression models with eight 2-year time intervals to estimate relative risks (26, 27). In an additional analysis, we used restricted cubic spline regressions with four knots to flexibly model the association between alcohol or folate intake (as a continuous variable) and risk of major chronic disease (28, 29).
In Cox proportional hazards models, including the spline regression models, we adjusted for age, smoking, and other covariates listed in the footnotes of the tables. All p values were two-sided. Tests for trend were conducted using the median value for each category of alcohol or folate intake analyzed as a continuous variable in multivariate models. We performed tests for interaction by entering a cross-product term for the interaction between alcohol and folate intake (as continuous variables using the median value for each category of alcohol and folate intake).
 |
RESULTS
|
---|
Of the 83,929 participants, 23.8 percent reported no alcohol intake and 4.3 percent reported alcohol intake of more than 30 g/day. For total folate intake, 9 percent reported less than 180 µg/day and 13.7 percent reported at least 600 µg/day.
During the 16 years (1,242,821 person-years) of follow-up, we documented 10,666 incident cases of major chronic disease (2,381 first cardiovascular disease events, 7,478 first diagnoses of cancer, and 807 other nontraumatic deaths mostly related to chronic disease). Breast cancer (42.4 percent), colorectal cancer (9.3 percent), uterine cancer (8.7 percent), and lung cancer (8.1 percent) were the most common cancers in the cohort, and 59.6 percent of cardiovascular disease was coronary heart disease (nonfatal myocardial infarction and fatal coronary heart disease).
We first examined alcohol and total folate intakes independently in relation to risk of major chronic disease, cardiovascular disease, and cancer (table 1). Heavy alcohol consumption (>30 g/day) was not associated with significantly increased risk of major chronic disease because of its opposing effects on the risks of cardiovascular disease and cancer. A lower folate intake (<180 µg/day) was associated with a statistically significant increased risk of cardiovascular disease, but total folate intake was not appreciably associated with risk of cancer or major chronic disease.
View this table:
[in this window]
[in a new window]
|
TABLE 1. Relative risks of major chronic disease, cancer, and cardiovascular disease according to cumulative average alcohol intake and total folate intake, Nurses Health Study, United States, 19801996
|
|
We next examined the joint association of alcohol and total folate intake with risk of major chronic disease (table 2). Overall, heavy drinkers with low folate intake (<180 µg/day) had the highest risk; in comparison with abstainers with a folate intake of 400599 µg/day, the relative risk was 1.36 (95 percent confidence interval (CI): 1.10, 1.70). However, the increased risk of major chronic disease associated with heavy drinking was largely diminished by a higher folate intake (table 2). The test for interaction between alcohol and total folate intake gave a statistically significant result (p = 0.02).
View this table:
[in this window]
[in a new window]
|
TABLE 2. Relative risk of major chronic disease according to joint levels of cumulative average alcohol intake and total folate intake, Nurses Health Study, United States, 19801996*
|
|
The joint associations with alcohol and total folate intake are presented separately for cardiovascular disease (table 3) and cancer (table 4). Although the greatest risk for both cardiovascular disease and cancer among heavy drinkers was observed at the lowest level of folate intake, the dose-response relations were different. Folate intake greater than or equal to 600 µg/day was needed for maximal reduction of the excess cancer risk associated with alcohol drinking (table 4), whereas intake of relatively less folate (<180 µg/day) seemed to be sufficient for a higher level of alcohol consumption to be protective against cardiovascular disease (table 3). The test for interaction between alcohol and total folate intake gave statistically significant results for both cardiovascular disease (p = 0.03) and total cancer (p = 0.01). Because of the opposite relations of alcohol to the risks of cardiovascular disease and cancer, the joint association of alcohol and folate intake with major chronic disease risk (table 2) lay between the associations for cardiovascular disease and cancer.
View this table:
[in this window]
[in a new window]
|
TABLE 3. Relative risk of cardiovascular disease according to joint levels of cumulative average alcohol intake and total folate intake, Nurses Health Study, United States, 19801996*
|
|
View this table:
[in this window]
[in a new window]
|
TABLE 4. Relative risk of cancer according to joint levels of cumulative average alcohol intake and total folate intake, Nurses Health Study, United States, 19801996
|
|
Because previous studies have demonstrated alcohol-folate interactions for breast and colon cancer, we also separated total cancer into two subgroups: breast and colon cancer and other cancers (table 4). The pattern of the combined association of alcohol and folate intake was similar for these two cancer groups; however, the increased risk associated with alcohol consumption was much stronger for breast and colon cancer.
Cubic regression splines clearly demonstrated that lower folate intake was associated with markedly higher major chronic disease risk among women who consumed more than 30 g/day of alcohol (figure 1), and higher folate intake appeared to diminish the increased risk of major chronic disease related to heavy alcohol consumption (figure 2). The relations were in concordance with the results of the categorical analyses (table 2).

View larger version (13K):
[in this window]
[in a new window]
|
FIGURE 1. Estimated incidence of major chronic disease according to total folate intake, by level of alcohol consumption, Nurses Health Study, United States, 19801996. Dotted lines are 95 percent confidence intervals for the estimated incidence rates. The results, from spline regression models, were adjusted for the same variables as in table 1. Incidence rates were estimated using the reference levels for all covariates represented as sets of indicator variables. Within each level of alcohol, the alcohol variable was set to the median for that group. P-Y, person-years.
|
|

View larger version (13K):
[in this window]
[in a new window]
|
FIGURE 2. Estimated incidence of major chronic disease according to alcohol consumption, by level of total folate intake, Nurses Health Study, United States, 19801996. Dotted lines are 95 percent confidence intervals for the estimated incidence rates. The results, from spline regression models, were adjusted for the same variables as in table 1. Incidence rates were estimated using the reference levels for all covariates represented as sets of indicator variables. Within each level of folate, the folate variable was set to the median for that group. P-Y, person-years.
|
|
Younger women are at lower risk of cardiovascular disease, whereas cardiovascular disease risk is proportionally greater among older women (30). Because of the opposing effects of alcohol on the risks of cardiovascular disease and cancer, we also evaluated the combined association of alcohol and total folate intake with major chronic disease risk by age group (<60 years or
60 years) (table 5). Heavy alcohol consumption and low folate intake were significantly associated with increased major chronic disease risk among women younger than age 60 years but not among women aged 60 years or more. The test for interaction between alcohol and total folate intake gave a statistically significant result among women younger than age 60 years (p = 0.01) but not among women aged 60 years or more (p = 0.57).
View this table:
[in this window]
[in a new window]
|
TABLE 5. Relative risk of major chronic disease according to joint levels of cumulative average alcohol intake and total folate intake, by age group, Nurses Health Study, United States, 19801996
|
|
To exclude the possibility that other beneficial constituents (e.g., anticarcinogens or protective factors for cardiovascular disease) present in multivitamin supplements or healthy behaviors associated with multivitamin use could contribute to the apparent benefit of folate intake observed in our study, we conducted separate analyses limited to women who did not use supplements and examined the combined associations with alcohol and folate obtained from foods only. Since the range of folate from foods was smaller, folate intake was recategorized into three groups (<180, 180299, and
300 µg/day). With substantially fewer cases, the associations of folate and alcohol intake with risk of major chronic disease, cardiovascular disease, and cancer persisted, though the tests for interaction did not produce statistically significant results. In comparison with abstainers with folate intakes of
300 g/day, the relative risk of major chronic disease for heavy drinkers with a low folate intake (<180 µg/day) was 1.56 (95 percent CI: 1.14, 2.13). The corresponding relative risk for cardiovascular disease was 1.38 (95 percent CI: 0.76, 2.50), and the relative risk for total cancer was 1.63 (95 percent CI: 1.12, 2.37). The relative risk comparing a folate intake of
300 µg/day with an intake of <180 µg/day among heavy drinkers was 0.62 (95 percent CI: 0.39, 0.99) for major chronic disease, 0.52 (95 percent CI: 0.21, 1.25) for cardiovascular disease, and 0.62 (95 percent CI: 0.35, 1.08) for cancer.
Because the biologic functions of folate, methionine, vitamin B12, and vitamin B6 are closely related and heavy drinking may also increase the possibility of iron deficiency, we added methionine, vitamin B12, vitamin B6, and iron to the models and found that the results persisted. Because women who consumed more folate were more likely to have greater intakes of fiber, ß-carotene, lutein/zeaxanthin, preformed vitamin A, and vitamin C, we further adjusted the data for these variables but did not see appreciable differences in our results.
We also examined the joint association of alcohol consumption and multivitamin use with risk of major chronic disease. Heavy drinkers and never users of multivitamins were at highest risk; in comparison with abstainers and current users of multivitamins, the relative risk was 1.26 (95 percent CI: 1.08, 1.47). Heavy drinking was not associated with increased risk among current multivitamin users; in comparison with abstainers, the relative risk was 1.05 (95 percent CI: 0.89, 1.23).
 |
DISCUSSION
|
---|
Results from this large prospective cohort study with 16 years of follow-up indicate that the joint effects of alcohol and folate intake substantially affect the overall health of women. Heavy alcohol intake and lower folate intake were associated with an increased risk of major chronic diseases combined. The increased risk of major chronic disease, particularly cancer, associated with heavy alcohol consumption was largely diminished by higher folate intake. Moreover, a higher level of alcohol consumption, even at levels exceeding 30 g/day, was associated with a further reduction in cardiovascular disease risk when folate intake was higher, but the expected benefit of alcohol with regard to cardiovascular disease was not observed when folate intake was low.
The joint association of alcohol and folate intake with risk of major chronic disease depended largely on the balance of the association of alcohol and folate intake with risk of cardiovascular disease and cancer. In comparison with women aged 60 years or more, heavy alcohol intake and low folate intake appeared to be more detrimental for women younger than age 60 years, who were at lower risk of cardiovascular disease. In the younger women, more folate was needed to reduce the increased major chronic disease risk, because a higher level of folate appeared to be needed to optimize risk of cancer than for cardiovascular disease.
Although multivitamin supplements are a major source of folate, the observed benefit of high folate intake is unlikely to be confounded by other beneficial constituents of multivitamins or by healthy behaviors associated with multivitamin use, because the risk pattern of the combined associations of alcohol and folate intake remained for each of the three disease outcomes even after multivitamin users had been excluded. Several other micronutrients considered to be related to a healthy diet, such as ß-carotene, lutein/zeaxanthin, preformed vitamin A, and total vitamin C, were not associated independently with our disease outcomes and were therefore unlikely to confound or explain our results.
There are possible biases that may limit these findings. In this study, dietary intake and multivitamin use were self-reported, which raises the issue of misclassification. However, in addition to the prospective study design, the repeated measurements of diet and multivitamin use assessed by means of a validated food frequency questionnaire minimized the likelihood of bias due to error in the measurement of folate or alcohol. Confounding due to unmeasured and imperfectly measured confounders is impossible to eliminate. Although the sample size for this study was large, only 0.5 percent of this cohort simultaneously reported alcohol consumption of >30 g/day and total folate intake of <180 µg/day, which limited our power to detect a significant interaction between alcohol and folate intake. Nevertheless, we still found a statistically significant interaction of alcohol and total folate intake for major chronic disease, cardiovascular disease, and total cancer.
Our findings regarding the joint associations of alcohol and folate intake with risk of cardiovascular disease and cancer not only reflect the biochemical interactions between alcohol and folate metabolism but also are consistent with previous findings on joint associations with different diseases and even with different cancer sites. A significant interaction of alcohol-folate intake was observed for breast cancer in previous studies (79, 31). An interaction of alcohol-folate intake was also observed for colon cancer in men (10, 32) and for precancerous adenomas in women in this cohort (15). Breast and colon cancer accounted for 42.4 percent and 7.7 percent of total cancer cases in this cohort, respectively. To address whether our results for total cancer risk may have been mostly accounted for by these two cancers, we also examined the joint effects of alcohol and folate intake on other cancers after excluding breast and colon cancer. We observed a pattern for other cancers that was similar to, though somewhat weaker than, the pattern for breast and colon cancer. High folate intake appeared beneficial for breast and colon cancer risk among moderate drinkers. The consistent presence of similar patterns of alcohol-folate interaction for different diseases (cardiovascular disease and cancer) and cancer sites indicates that folate deficiency might be one important common mechanism by which heavy alcohol consumption causes human cancer and increases cardiovascular disease risk. Because the joint associations of alcohol and folate intake appear to be different in both magnitude and direction for cardiovascular disease and cancer, the study of major chronic disease provides an overall measure of the risks and benefits of alcohol and folate intake.
Combined with those of other studies, our results suggest that the role of folate should be expanded from prevention of megaloblastic anemia and neural tube defects to prevention of cancer, cardiovascular disease, and possibly other chronic diseases. Increasing ones folate intake, especially among women who consume alcohol regularly, to the level of the current Recommended Dietary Allowance (
400 µg/day) may provide an important benefit in reducing the overall risk of chronic disease. It has been estimated that mandatory fortification of cereal-grain products with folic acid, introduced by the Food and Drug Administration in 1998, will add approximately 100 µg of folic acid per day to the average diet (33). Although the amount of folate obtained from cereal-grain products may play a role in reducing the total risk of chronic diseases, it may still be suboptimal. Even after fortification, only 25 percent of adult women in the general population will have a dietary folate intake above 400 µg/day. On the basis of our findings, some women would have unnecessary and preventable chronic diseases due to insufficient folate intake.
Our findings suggest that adequate folate intake may be important in the primary prevention of major chronic disease in women, especially among younger women consuming more than two alcoholic drinks per day. Because the risks of cardiovascular disease and cancer differ in men and women, the findings of this study cannot be directly applied to men, and further studies in men are needed.
 |
ACKNOWLEDGMENTS
|
---|
This study was supported by research grants CA87969 and HL36798 from the National Institutes of Health.
 |
NOTES
|
---|
Correspondence to Dr. Rui Jiang, Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115 (e-mail: rjiang{at}hsph.harvard.edu). 
 |
REFERENCES
|
---|
- Halsted C. Alcohol and folate interaction: clinical implication. In: Bailey LB, ed. Folate in health and disease. New York, NY: Marcel Dekker, 1995:31328.
- Boushey CJ, Beresford SA, Omenn GS, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995;274:104957.[Abstract]
- Blount BC, Mack MM, Wehr CM, et al. Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A 1997;94:32905.[Abstract/Free Full Text]
- Mason JB, Levesque T. Folate: effects on carcinogenesis and the potential for cancer chemoprevention. Oncology 1996;10:172736, 423.[Medline]
- Kim YI. Folate and cancer prevention: a new medical application of folate beyond hyperhomocysteinemia and neural tube defects. Nutr Rev 1999;57:31421.[ISI][Medline]
- Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA 1998;279:35964.[Abstract/Free Full Text]
- Zhang S, Hunter DJ, Hankinson SE, et al. A prospective study of folate intake and the risk of breast cancer. JAMA 1999;281:16327.[Abstract/Free Full Text]
- Rohan TE, Jain MG, Howe GR, et al. Dietary folate consumption and breast cancer risk. J Natl Cancer Inst 2000;92:2669.[Free Full Text]
- Sellers TA, Kushi LH, Cerhan JR, et al. Dietary folate intake, alcohol, and risk of breast cancer in a prospective study of postmenopausal women. Epidemiology 2001;12:4208.[CrossRef][ISI][Medline]
- Giovannucci E, Rimm EB, Ascherio A, et al. Alcohol, low-methioninelow-folate diets, and risk of colon cancer in men. J Natl Cancer Inst 1995;87:26573.[Abstract]
- Willett WC. Nutritional epidemiology. 2nd ed. New York, NY: Oxford University Press, 1998.
- US Department of Agriculture. Composition of foodsraw, processed, and prepared. (Agricultural handbook no. 8). Washington, DC: US GPO, 1963.
- Nutrition Information Service, US Department of Agriculture. Human provisional table on nutrient content of beverages. Washington, DC: US Department of Agriculture, 1982.
- Willett WC, Stampfer MJ, Colditz GA, et al. Moderate alcohol consumption and the risk of breast cancer. N Engl J Med 1987;316:117480.[Abstract]
- Giovannucci E, Stampfer MJ, Colditz GA, et al. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst 1993;85:87584.[Abstract]
- Selhub J, Jacques PF, Wilson PW, et al. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993;270:26938.[Abstract]
- Rose G, Blackburn H. Cardiovascular survey methods. (WHO monograph series no. 58). Geneva, Switzerland: World Health Organization, 1982.
- Walker AE, Robins M, Weinfeld FD. The National Survey of Stroke: clinical findings. Stroke 1981;12(suppl 1):I1344.[Medline]
- Stampfer MJ, Willett WC, Speizer FE, et al. Test of the National Death Index. Am J Epidemiol 1984;119:8379.[ISI][Medline]
- Hu FB, Stampfer MJ, Rimm E, et al. Dietary fat and coronary heart disease: a comparison of approaches for adjusting total energy intake and modeling repeated dietary measurements. Am J Epidemiol 1999;149:53140.[Abstract]
- Willett WC, Stampfer MJ. Total energy intake: implications for epidemiologic analyses. Am J Epidemiol 1986;124:1727.[Abstract]
- Rimm EB, Giovannucci EL, Willett WC, et al. Prospective study of alcohol consumption and risk of coronary disease in men. Lancet 1991;338:4648.[ISI][Medline]
- Fuchs CS, Stampfer MJ, Colditz GA, et al. Alcohol consumption and mortality among women. N Engl J Med 1995;332:124550.[Abstract/Free Full Text]
- Rimm EB, Williams P, Fosher K, et al. A biologic basis for moderate alcohol consumption and lower coronary heart disease risk: a meta-analysis of effects on lipids and hemostatic factors. BMJ 1999;319:15238.[Abstract/Free Full Text]
- Food and Nutrition Board, National Research Council. Recommended Dietary Allowances. 10th revised ed. Washington, DC: National Academy Press, 1989.
- Cupples LA, DAgostino RB, Anderson K, et al. Comparison of baseline and repeated measure covariate techniques in the Framingham Heart Study. Stat Med 1988;7:20522.[ISI][Medline]
- DAgostino RB, Lee ML, Belanger AJ, et al. Relation of pooled logistic regression to time dependent Cox regression analysis: The Framingham Heart Study. Stat Med 1990;9:150115.[ISI][Medline]
- Easton DF, Peto J, Babiker AG. Floating absolute risk: an alternative to relative risk in survival and case-control analysis avoiding an arbitrary reference group. Stat Med 1991;10:102535.[ISI][Medline]
- Greenland S, Michels KB, Robins JM, et al. Presenting statistical uncertainty in trends and dose-response relations. Am J Epidemiol 1999;149:107786.[Abstract]
- Mosca L, Manson JE, Sutherland SE, et al. Cardiovascular disease in women: a statement for healthcare professionals from the American Heart Association. Writing Group. Circulation 1997;96:246882.[Free Full Text]
- Negri E, La Vecchia C, Franceschi S. Re: "Dietary folate consumption and breast cancer risk." (Letter). J Natl Cancer Inst 2000;92:12701.[Free Full Text]
- Freudenheim JL, Graham S, Marshall JR, et al. Folate intake and carcinogenesis of the colon and rectum. Int J Epidemiol 1991;20:36874.[Abstract]
- Oakley GP Jr. Lets increase folic acid fortification and include vitamin B-12. (Editorial). Am J Clin Nutr 1997;65:188990.[ISI][Medline]