Associations between diet and cardiometabolic risk among Yup'ik Alaska Native people using food frequency questionnaire dietary patterns.

BACKGROUND AND AIMS: In previous analyses, we identified three dietary patterns from food frequency questionnaire data among a sample of Yup'ik Alaska Native people living in Southwest Alaska: a "subsistence foods" dietary pattern and two market-based dietary patterns "processed foods" and "fruits and vegetables". In this analysis, we aimed to characterize the association between the dietary patterns and cardiometabolic (CM) risk factors (lipids, blood pressure, glucose, adiposity). METHODS AND RESULTS: We used multilevel linear regression to estimate the mean of each CM risk factor, comparing participants in the 4th to the 1st quartile of each dietary pattern (n = 637). Models were adjusted for age, sex, past smoking, current smoking, and physical activity. Mean log triglyceride levels were significantly higher among participants in the 4th compared to the 1st quartile of the processed foods dietary pattern (ß = 0.11). Mean HbA1c percent was significantly lower (ß = -0.08) and mean diastolic blood pressure (DBP) mm Hg was significantly higher (ß = 2.87) among participants in the 4th compared to the 1st quartile of the fruits and vegetables dietary pattern. Finally, mean log triglyceride levels and mean DBP mm Hg were significantly lower among participants in the 4th compared to the 1st quartile of the subsistence foods dietary pattern (ß = -0.10 and ß = -3.99 respectively). CONCLUSIONS: We found increased CM risk, as reflected by increased triglycerides, associated with eating a greater frequency of processed foods, and reduced CM risk, as reflected by lower triglycerides and DBP, associated with eating a greater frequency of subsistence foods.

Recreational physical activity and endometrial cancer risk.

To investigate the association between recreational physical activity and endometrial cancer risk, a population-based case-control study was conducted in Washington State. The study included 822 incident cases of endometrial cancer diagnosed between 1985 and 1991 and 1,111 randomly selected population-based controls. Detailed information on recreational physical activities as well as other endometrial cancer risk factors was obtained in structured, in-person interviews. Unconditional logistic regression, adjusted for age, county, energy intake, unopposed estrogen use, income, and, in separate models, body mass index (kg/m(2)), was used to estimate the odds ratios and their 95% confidence intervals, relating endometrial cancer to each level of physical activity. A greater proportion of controls (49.3%) than cases (40.5%) reported doing regular exercise (compared with no exercise: adjusted odds ratio = 0.62, 95% confidence interval: 0.51, 0.76) in the 2-year period prior to diagnosis date. There was little evidence of a trend of decreasing risk with increasing duration or intensity of recreational physical activities. These results provide support for an association between the lack of recent recreational physical activity and endometrial cancer risk. However, the absence of a difference by duration or intensity levels and the inconsistent results from other studies suggest caution before interpreting this association as causal.

Risk factors for synchronous primary endometrial and ovarian cancers.

PURPOSE: The incidence of synchronous primary endometrial and ovarian cancer is 2- to 10-fold higher than that expected based on the incidence of each cancer alone. We sought to evaluate reasons for this in a case-control study. METHODS: We combined data on a maternal history of cancer and reproductive and menstrual factors from 56 women with synchronous multiple primary disease who had participated in three population-based studies of gynecologic cancer. For comparison, we analyzed the same information from 280 women with endometrial cancer alone, 280 with ovarian cancer alone, and 280 without a history of either cancer. RESULTS: The reduced risk of multiple primary disease associated with high parity (2 or more births vs 0: OR = 0.37, 95% Cl, 0.19-76) and long-term use of oral contraceptives (12 or more months vs none: OR = 0.60, 95% Cl, 0.24-1.5) tended to be more pronounced than that associated with endometrial cancer alone or with ovarian cancer alone. CONCLUSIONS: Though limited by relatively small numbers, our results suggest that the presence of some common etiologies is a basis for the unusually high co-occurrence of endometrial and ovarian cancers.

Folic acid: are current fortification levels adequate?

OBJECTIVE: Beginning on January 1, 1998, all cereal and grain products in the United States were fortified with folic acid to reduce the occurrence of the very common congenital malformations known as neural-tube defects. Three years have passed since the fortification program began, and it is time to evaluate whether the current fortification levels have met their intended objective. METHODS: We offer an overview of folate and its potential role in the etiology of neural-tube defects, review some of the highlights of the deliberations that led to the decision by the Food and Drug Administration to fortify the food supply, and offer a perspective on how to measure whether current fortification levels are adequate. RESULTS: There is no national system in the United States that monitors neural-tube and other birth defects over time, and no postmarketing surveillance was mandated to monitor the safety of the fortification program. Therefore, we must evaluate the program in other ways. Blood biomarkers of folate status such as the levels of folate in red blood cells and homocysteine in plasma provided the best evidence of the effectiveness of the folic-acid-fortification program because of their relatively high sensitivities in relation to their specificities as markers of folate status. In addition, these biomarkers might provide information about the risks of other diseases related to folate status such as vascular disease. CONCLUSION: Federal agencies should coordinate efforts to gather and evaluate markers of folate status at the population level. These measures can be used to evaluate the safety and efficacy of folic-acid fortification and whether changes are warranted in fortification levels.

Effect of health lifestyle pattern on dietary change.

PURPOSE: To examine the effect of lifestyle on the effectiveness of a low-intensity dietary intervention. DESIGN: A secondary data analysis was performed using data from the Eating Patterns Study, a randomized controlled trial that found that self-help materials with physician advice was effective in changing dietary intake and behavior. SETTING: Primary care clinics in a large health maintenance organization. SUBJECTS: A total of 2111 patients with a routine scheduled appointment with their primary care physicians. MEASURES: Participants were grouped into one of six health lifestyle patterns based on similarities in baseline measures of alcohol intake, smoking, diet quality, and exercise. Within each lifestyle pattern, changes from baseline in usual fat and fiber intake (based on a food frequency) and a fat and fiber behavior score were compared at 3 months and 12 months for intervention vs. control participants. INTERVENTION: Self-help materials delivered by a physician with advice to change diet. RESULTS: Intervention participants in the fitness lifestyle group made the largest changes relative to controls for each dietary outcome at 3 and 12 months. For intervention participants defined by their alcohol intake or current smoking, either no changes in diet were observed compared with controls, or early changes were not sustained over time. Intervention-control comparisons within the remaining lifestyle patterns showed smaller dietary changes compared with the fitness lifestyle. This finding was similar to previously published results. CONCLUSIONS: This randomized controlled trial had limited power to detect subgroup differences; however, these results suggest that lifestyle patterns may be useful in the development of effective, targeted interventions to change behavior.

The association of dietary fat and plant foods with endometrial cancer (United States).

OBJECTIVES: To examine the associations of dietary fat and selected plant foods with endometrial cancer in a population-based case-control study. METHODS: Six hundred and seventy-nine incident cases of endometrial cancer diagnosed between 1985 and 1991, and 944 population-based controls completed a 98-item semi-quantitative food-frequency questionnaire and a detailed in-person interview which collected information on endometrial cancer risk factors. Logistic regression was used to estimate odds ratios (OR) and their 95% confidence intervals (CI) of endometrial cancer, adjusted for age, county, energy intake, hormone use, smoking and, in separate models, for body mass index (BMI: kg/m2). RESULTS: Percent energy from fat was associated with an increased risk of endometrial cancer (highest quintile cf. lowest: OR = 1.8, 95% CI 1.3-2.6), with saturated and monounsaturated fats being the main contributors of risk. There was a stronger association between dietary fat and endometrial cancer among groups with higher circulating estrogen levels (i.e. women with higher BMI, users of unopposed estrogens, non-smokers, and younger age at menarche). Consumption of fruits or vegetables was inversely associated with endometrial cancer risk (highest quintile cf. lowest: OR = 0.65, 95% CI 0.46-0.93 and OR = 0.61, 95% CI 0.43-0.88, respectively). Further adjustment for BMI resulted in little or no attenuation of the ORs and associated CIs. CONCLUSIONS: These results provide support for the theory that a low-fat, high-fruit and high-vegetable diet may reduce the risk of endometrial cancer, and that these dietary factors may act independently of the effect of BMI.

Differential effects of phosphatidylinositol-3/Akt-kinase inhibition on apoptotic sensitization to cytokines in LNCaP and PCc-3 prostate cancer cells.

Alterations in phosphatidylinositol 3'-kinase (PI3'-kinase) and Akt activation frequently occur in prostate cancer and may disrupt apoptotic induction by such cytokines as tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand (TRAIL). To examine the role of PI3' phosphorylation in the cellular response to cytokines, two prostate cancer cell lines with constitutively activated PI3'-kinase cascades (LNCaP and PC-3) were examined for direct sensitivity to cytokines. TNF or TRAIL alone failed to activate apoptosis in either LNCaP or PC-3 cells, and drug-mediated inhibition of the PI3k/Akt cascade caused only minimal activation of apoptosis in either cell line. Suppression of PI3'-kinase/Akt signaling markedly enhanced the apoptotic activity of both TNF and TRAIL in LNCaP cells but not in PC-3 cells. Adenovirus-mediated PTEN/MMAC1 expression in LNCaP cells reduced Akt activation, activated apoptosis, and sensitized cells to TNF but not to TRAIL. Together, these results suggest that PI3'-kinase signaling inhibits both TNF-mediated and TRAIL-mediated apoptosis but may represent one of several apoptotic resistance mechanisms that inhibit cytokine-mediated killing of prostate cancer cells.

Continuous combined hormone replacement therapy and risk of endometrial cancer.

OBJECTIVE: Postmenopausal women who receive sequential hormone replacement therapy with estrogen combined with progestogen for 10 to 24 d/mo for a prolonged period may have an elevated endometrial cancer risk relative to those who have never received hormone replacement therapy. We investigated whether daily use of estrogen and progestogen (continuous combined hormone replacement therapy) could diminish any excess endometrial cancer risk. STUDY DESIGN: A population-based study in Washington State obtained interview data from 969 women aged 45 to 74 years with endometrial cancer diagnosed during 1985 through 1991 or 1994 through 1995 and from 1325 age-matched control subjects selected primarily by random digit dialing. Women who had received only continuous combined hormone replacement therapy were compared with women who had only received another hormone replacement therapy regimen or who had never received hormone replacement therapy. RESULTS: The risk of endometrial cancer among users of continuous combined hormone replacement therapy (n = 9 case patients, n = 33 control subjects) relative to women who had never received hormone replacement therapy was 0.6 (95% confidence interval, 0.3-1.3); the risk relative to women who received hormone replacement that included progestogen for 10 to 24 d/mo was 0.4 (95% confidence interval, 0.2-1.1). Most continuous combined hormone replacement therapy use was short-term (<72 months) or recent (in the previous 24 months). CONCLUSION: Women who had received continuous combined hormone replacement therapy for several years did not appear to be at any increased risk for endometrial cancer relative to women who had never received hormone replacement therapy and may in fact be at decreased risk for endometrial cancer.

The controversy over homocysteine and cardiovascular risk.

Elevated plasma total homocysteine (tHcy) is a risk factor for occlusive cardiovascular disease (CVD). This concept is based on the observations of premature vascular disease in patients with homocystinuria, the relation between tHcy and both clinical CVD as well as preclinical atherosclerotic disease, the relation between tHcy in children and CVD in their parents or relatives, and reduction in CVD or surrogate endpoints after tHcy-lowering intervention with B vitamins. Plausible mechanisms include the in vivo interference with nitric oxide-dependent reactive vasodilatation. Some observations have raised questions about tHcy as a risk factor. 1) Some prospective studies showed a weak relation or no relation between tHcy and CVD. 2) Several traditional risk factors are associated with tHcy and may confound the relation between tHcy and CVD. 3) tHcy is related to renal function, and hyperhomocysteinemia may reflect early nephrosclerosis. 4) The C677T transition of the methylenetetrahydrofolate reductase gene causes a moderate increase in tHcy but no or only minor increased CVD risk. However, the strength of some of these arguments can be questioned because there is increasing evidence that tHcy is a proximate risk factor provoking the acute event, it strongly interacts with traditional risk factors, and it may predict CVD or death in patients with chronic renal failure. Furthermore, the studies of the C677T polymorphism lack statistical power, and the TT genotype may even modulate CVD risk independently of homocysteine. Thus, only placebo-controlled intervention studies with tHcy-lowering B vitamins and clinical endpoints can provide additional valid arguments for the debate over whether tHcy is a causal CVD risk factor.

Lack of association between the C677T MTHFR polymorphism and colorectal hyperplastic polyps.

Colorectal hyperplastic polyps are benign lesions that share many risk factors with colorectal adenomas and cancers. Low folate intakes are associated with an increased risk of colon cancer. The enzyme 5,10-methylene-tetrahydrofolate reductase (MTHFR) may be linked to DNA methylation and nucleotide synthesis and thus play a role in the etiology of colorectal neoplasia. We investigated an association between the common MTHFR polymorphism (C677T) and colorectal hyperplastic polyps within the Minnesota Cancer Prevention Research Unit case-control study. Cases (n = 200) were diagnosed with colonoscopically confirmed hyperplastic polyps; controls (n = 645) were derived from the same gastroenterology practice and were polyp-free at colonoscopy. Dietary intakes were estimated from a self-administered food-frequency questionnaire prior to colonoscopy. Multivariate adjusted odds ratios (ORs) and 95% confidence intervals for MTHFR status were 0.8 (0.6-1.2; CT versus CC wild-type) and 0.9 (0.5-1.6; TT versus CC). In subgroup analyses stratified on dietary intakes of folate, vitamin B12, vitamin B6, or methionine, those with the TT genotype and either low intakes of folate or vitamin B6 were at increased risk relative to those with normal or high vitamin intake. However, most 95% confidence intervals included 1.0, and no consistent trends were observed. In contrast to our findings on colorectal adenomas, increasing alcohol consumption was associated with an elevated risk of colorectal hyperplastic polyps, regardless of genotype. The MTHFR (C677T) variant genotype does not appear to be related to risk of colorectal hyperplastic polyps, and there is no convincing evidence that MTHFR shows a different relation to risk, dependent on dietary intakes of nutrients related to its pathway.

The additional risk of endometrial cancer associated with unopposed estrogen use in women with other risk factors.

We analyzed data from a population-based case-control study of endometrial cancer. Our goal was to identify a subgroup of women in whom the additional cancer risk associated with unopposed estrogen use was sufficiently small so as to not be a deterrent to taking a hormone preparation of this type. Researchers interviewed women with endometrial cancer (N = 553) and controls (N = 752) regarding hormone use. The additional risk of endometrial cancer associated with unopposed estrogen use did not vary substantially in the presence or absence of hypertension, parity, oral contraceptive use, or smoking. The results suggest that, although heavier women may experience a greater risk of endometrial cancer associated with unopposed estrogen use (8.2 per 1,000 per year) than lighter women (4.2 per 1,000 per year), long-term users in the latter group nonetheless face a substantial absolute increase in risk. We conclude that subdividing women on the basis of the presence or absence of other known risk factors for endometrial cancer fails to delineate a subgroup that is exempt from the increased risk of this cancer associated with use of unopposed estrogens. 83.6% of estrogen users reported taking conjugated estrogens.

Stages of change for increasing fruit and vegetable consumption among adults and young adults participating in the national 5-a-Day for Better Health community studies.

Higher fruit and vegetable consumption is associated with a reduced risk of certain cancers and chronic diseases. The 5-a-Day for Better Health community studies are evaluating population-based strategies to achieving dietary behavior change using the stages-of-change model and associated theories. The authors present baseline comparisons of stages of change for fruit and vegetable consumption among adults and young adults in eight study sites representing diverse regions of the United States and diverse populations and settings. Three dominant stages, precontemplation, preparation, and maintenance, were found across sites. Women and those with college degrees were more likely to be in action/maintenance. Fruit and vegetable consumption, self-efficacy, and knowledge of the 5-a-Day recommendation were positively associated with more advanced stages of change in all study sites. The authors discuss the findings in relation to possible limitations of this and other dietary stages-of-change measures and suggest directions for future research.

Colorectal adenomas and the C677T MTHFR polymorphism: evidence for gene-environment interaction?

5,10-Methylene-tetrahydrofolate reductase (MTHFR), an enzyme in folate metabolism, may play a role in the etiology of colorectal adenomas via effects on DNA methylation and nucleotide synthesis. We investigated the association between a common polymorphism (C677T, reduced MTHFR activity) and colorectal adenomas within the Minnesota CPRU case-control study. Cases (n = 527) were diagnosed with colonoscopically confirmed adenomas; controls (n = 645) were derived from the same gastroenterology practice and were polyp free at colonoscopy. Dietary intakes were obtained from a self-administered food-frequency questionnaire prior to colonoscopy. Age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals for the MTHFR genotype were 0.9 (0.7-1.2; CT versus CC wild-type) and 0.8 (0.6-1.3; TT versus CC). The associations between dietary intakes of folate, vitamin B12, vitamin B6, or methionine and risk of adenomas showed consistent patterns dependent upon MTHFR genotype. Individuals with the TT genotype and intakes of any of these nutrients in the lowest tertile were at elevated risk for adenomas (about 2-3-fold when compared with TT genotype with high intakes). These trends were more pronounced among individuals over age 60, resulting in a 3-6-fold increase for low intakes of folate, B12, and B6. An increased risk with increasing alcohol consumption was observed only among those with the CC genotype (P-trend = 0.005); among those with the TT genotype, those with moderate alcohol consumption were at lowest risk (P for interaction P = 0.02). In conclusion, nutrients involved in the MTHFR metabolic pathway may modify the relationship between the MTHFR C677T polymorphism and colorectal adenomas. Low intakes of folate, vitamin B12, and vitamin B6 increase risk among those (particularly the elderly) with the MTHFR TT genotype.

Absorption of dietary and supplemental folate in women with prior pregnancies with neural tube defects and controls.

BACKGROUND: The Public Health Service of the United States recommends that all women capable of childbearing consume .4 mg (400 microg) folic acid per day to decrease the risk of having a pregnancy affected by a neural tube defect such as spina bifida or anencephaly. Three strategies are available to women to achieve this goal: use of dietary supplements; use of fortified foods; and/or increased intake of naturally occurring folate from foods. Identification of the most effective vehicle for delivery of folate to all women is critical in order to prevent these devastating congenital defects. OBJECTIVE: To investigate the difference in response to an oral load of folate both from naturally occurring food sources and synthetic supplements among women with prior pregnancies affected by neural tube defects and controls. METHODS: We compared the absorption of test doses of 400 microg pteroylglutamic acid (unconjugated or synthetic folic acid found in supplements) and 400 microg pteroylpolyglutamic acid (conjugated or food folate) in 10 women with a history of neural tube defect affected pregnancies and eight controls with normal birth outcomes. The folate test dose was given as either 32 fluid ounces of orange juice or a folic acid single supplement pill. All participants received each test dose at separate clinic visits. The response to each test dose was measured by constructing an area under the curve (AUC) from the serum folate levels at 1, 2 and 3 hours post dose and applying a t-test to compare within and between cases and controls. We also compared red cell folate, vitamin B12, zinc and homocysteine between cases and controls. RESULTS: Within group comparisons showed that the area under the curve was significantly greater for the pteroylglutamic acid dose compared to the pteroylpolyglutamic acid dose for both cases and controls (p=0.02 and p=0.03, respectively). In a between group comparison, control women had a greater serum folate response to both forms of the vitamin compared to the case women, but the difference reached statistical significance only for the pteroylglutamic acid dose (p=0.02). Other measured nutrients differed between cases and controls, but did not reach statistical significance. CONCLUSION: We conclude that for all women synthetic folic acid as supplements or fortified foods may be the best way to increase acute folate levels in the blood, and thus delivery to the developing embryo. Further, since case women had a diminished response to both forms of the vitamin, and some case women had almost no response, we speculate that women with prior affected pregnancies may need a larger dose of folate to elicit a plasma response equivalent to the general population.

Risk of endometrial cancer in relation to use of low-dose, unopposed estrogens.

OBJECTIVE: To determine whether a low dosage (0.3 mg/day) of unopposed conjugated estrogens can be used without incurring an elevated risk of endometrial cancer. METHODS: In this case-control study, cases (n = 484) consisted of women diagnosed with endometrial cancer between 1985 and 1991 in three counties in Western Washington. Controls (n = 780) were identified using random digit dialing within the same three counties. Subjects were interviewed in person to obtain basic demographic and medical history information, as well as specific information about hormone use. RESULTS: Eighteen cases and eight controls had taken 0.3 mg/day of unopposed conjugated estrogens and no other dose or preparation of estrogens (risk relative to that of women who had not taken postmenopausal hormones = 5.4, 95% confidence interval [CI] 2.3, 13.0). The risk was particularly high in women whose use of this dose was both current and of more than 8 years' duration (odds ratio = 9.2, 95% CI 2.9, 29.0). The elevation in risk in users of 0.3 mg/day was similar in size to that associated with the daily unopposed use of 0.625 mg of conjugated estrogens. CONCLUSION: The results suggest that a dosage of 0.3 mg per day of unopposed conjugated estrogens is associated with an increased risk of endometrial cancer.

Menopausal hormone use and endometrial cancer, by tumor grade and invasion.

We analyzed data from a population-based case-control study to investigate whether combined hormone replacement therapy influences the incidence of high-grade and -stage endometrial cancer. Subjects were women with epithelial endometrial cancer (N = 730) diagnosed during 1985-1991 and controls identified through random digit dialing (N = 1,002). Relative to hormone nonusers, women who took unopposed estrogens (mostly conjugated estrogens) for 3 or more years had a fivefold increase in the risk of tumors with myometrial invasion; the corresponding relative risk associated with combined therapy (estrogen and cyclic or continuous progestogen) for 3 or more years was only 1.3 (95% confidence interval = 0.8-2.2). We found a similar pattern of association for high-grade tumors.

Application of a behavioral approach to measuring dietary change: the fat- and fiber-related diet behavior questionnaire.

This study reports the validity, reliability, and responsiveness of a 33-item fat- and fiber-related behavior questionnaire (FFB) and describes how this instrument provides insight into the process of adopting healthy diets. Data are from the Eating Patterns Study, a randomized clinical trial of a physician-delivered, self-help intervention to reduce fat and increase fiber intake. Intervention (n = 850) and control participants (n = 945) completed both a food frequency questionnaire and the FFB at baseline and at 3 and 12 months postintervention. Validity, as assessed by correlation of the FFB with the food frequency questionnaire at baseline, was 0.53 for fat (fat scale with percentage energy from fat) and 0.50 for fiber (fiber scale with fiber g/1000 kcal; both P < 0.001). Reliability, as assessed by the intraclass correlation in controls across all three time points, was 0.77 for the fat scale and 0.74 for the fiber scale (both P < 0.001). The largest changes in fat-related behavior were in avoiding fat as a flavoring and in using specially manufactured low-fat foods, and the largest changes in fiber-related behavior were in substituting high-fiber versions of common foods. Overall, the FFB was a reasonably valid and reliable measure of dietary intake, which provided insight into the behavioral effects of the dietary intervention.