Alpha-Tocopherol Beta-Carotene Cancer Prevention Study Research Articles

COMT Effects on Vitamin E and Colorectal Cancer, in-vitro and in Two Randomized Trials (P15-005-19)

ObjectivesDespite promising observational data and compelling mechanisms of action, vitamin E has failed to demonstrate evidence of benefit in randomized clinical trials (RCTs). In two large long-term placebo-controlled RCTs, we reported that vitamin E effects on total cancer were modified by genetic variation in catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. Here we investigate COMT effects on colorectal cancer (CRC) in the two RCTs and a CRC cell line. MethodsWe analyzed COMT rs4680 association with rates of CRC in the Women’s Health Study (WHS), N = 23,294 and a case/control (N = 2396/2235) subset of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC). Cell survival and apoptosis were examined in-vitro in HCT116 cells treated with increasing doses of vitamin E when COMT gene expression was inhibited by silencing RNA (siRNA). ResultsRates of CRC were higher with randomized vitamin E compared to placebo among COMT high-activity val/val homozygotes in ATBC (HR, [CI] = 3.00, [1.48–6.09]), but not WHS (HR, [CI] = 0.99, [0.63–1.57]). Among low-activity met/met homozygotes randomized to vitamin E compared to placebo, rates of CRC were borderline lower in WHS (HR, [CI] = 0.66, [0.44–1.01]), but not in ATBC (HR, [CI] = 0.93, [0.63–1.62]).In cell culture, vitamin E at 3 μg/ml and 10 μg/mL had no effect on cell viability or apoptosis. However, silencing COMT resulted in a modest apoptotic effect that vitamin E enhanced in a dose-dependent manner. Human apoptosis arrays indicated that in the absence of COMT expression, vitamin E induced protein expression related to the intrinsic apoptotic pathway through p53 activation, dysregulation of Bcl-2 family protein expression and down-regulation of IAP family protein expression. ConclusionsDifferential COMT effects on vitamin E and CRC were similar to those previously reported for all invasive cancers, but were only significant for val/val homozygotes. Further, inhibiting COMT in the presence of vitamin E in a CRC in-vitro model, recapitulated the RCT observation that among individuals homozygous for the low-activity allele (met/met) vitamin E tended to reduce invasive cancer and here CRC. Funding SourcesNational Institutes of Health: NCI and NHLBI.

COMT and Alpha-Tocopherol Effects in Cancer Prevention: Gene-Supplement Interactions in Two Randomized Clinical Trials.

Vitamins are among the most frequently used supplements (48% of US adults). However, little is known about contributions of genetic variation to their efficacy and safety. Multiple pathways link catechol-O-methyltransferase (COMT) to the vitamin E supplement, alpha-tocopherol, and cancer. Here we determined if COMT exerted pharmacogenetic effects on cancer prevention in two randomized trials of alpha-tocopherol supplementation. Pharmacogenetic effects of common COMT rs4680 (val158met), which encodes a nonsynonymous valine-to-methionine substitution, were examined in the trial plus a 10-year post-trial follow-up (overall) period of The Women's Genome Health Study (WGHS, N = 23 294), a 10-year alpha-tocopherol and aspirin trial with 10 years post-trial follow-up. Results were validated in a case/control (N = 2396/2235) subset of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC, N = 29 133). The primary outcome was total cancers. Rates of cancer types prevalent in women (colorectal, breast, lung, uterine, and lymphoma/leukemia) were also examined. All statistical tests were two-sided. Random-effects meta-analysis of rs4680 genotype strata, in WGHS and ATBC overall periods, revealed differential alpha-tocopherol effects compared with placebo: met/met (hazard ratio [HR] = 0.88; 95% confidence interval [CI] = 0.80 to 0.97; P = .01), val/met (HR = 0.99; 95% CI = 0.92 to 1.06; P = .74), and val/val (HR = 1.18; 95% CI = 1.06 to 1.31; P = .002) with a statistically significant COMT by alpha-tocopherol interaction (Pinteraction <.001). Timing of effects differed, with stronger effects in WGHS trial and ATBC post-trial. Pharmacogenetic analysis of COMT and cancer prevention in two large randomized trials revealed statistically significant COMT by alpha-tocopherol interaction, such that alpha-tocopherol was beneficial among rs4680 met-allele (28.0%), but not val-allele (22.8%) homozygotes. These effects indicate the need for additional studies of genetic variation as a determinant of the benefits and possible harms of over-the-counter supplements, like alpha-tocopherol, used for health promotion.

Chemoprevention with Vitamins and Minerals: There's Still A Lot to Learn

The health benefits of adequate intake of vitamins, minerals and a host of other natural products are supported by extensive epidemiological data and have become a mainstay of nutritional counseling. The potential for some of these nutrients to reduce cancer mortality is particularly important for patients whose cancer has metastasized and have poor prognosis. Furthermore, efforts to develop vitamins and minerals as dietary supplements to reduce cancer incidence have been ongoing for decades, yet in recent years there has been a decline in both interest and effort in this area. A major reason for this has been the lack of success of large supplementation trials investigating the efficacy of individual supplements in preventing either the development or progression of a variety of cancer types. The failure to detect benefits has been compounded by data obtained from the same trials indicating that for several of the most promising supplements intake was associated with elevated cancer incidence [1]. For example, two large randomized supplementation trials, the AlphaTocopherol Beta-Carotene Cancer Prevention Study (ATBC) and the Beta–Carotene and Retinol Efficiency Trial (CARET) both reported significant increases in lung cancer incidence and mortality among high risk individuals provided beta-carotene. In the largest prostate cancer prevention trial ever conducted, the randomized Selenium and Vitamin E Chemoprevention Trial (SELECT), approximately 35,000 men over the age of 50 were provided vitamin E, selenium, or both and the incidence and grade of prostate cancers developing over a 7 year period were compared to those in men provided placebo. The results of this study indicated that the risk of prostate cancer was increased by 17% in those provided the vitamin E supplement and in the selenium supplemented group, those men who had the highest baseline selenium status experienced an increased risk of high grade prostate cancer by 91% [2]. In a prospective study of men diagnosed with prostate cancer, use of selenium supplements was associated with a significant increase in prostate cancer-specific mortality [3]. More and more, supplementation studies are revealing what is described as a “U shaped dose-response curve” [4], where a supplement is beneficial when provided to individuals with low baseline levels of that substance, but detrimental when provided to those at adequate or above adequate levels.

Hepatology Highlights

Hepatology Highlights

A prospective analysis of telomere length and pancreatic cancer in the alpha-tocopherol beta-carotene cancer (ATBC) prevention study

Smoking and diabetes, consistent risk factors for pancreatic cancer, are also factors that influence telomere length maintenance. To test whether telomere length is associated with pancreatic cancer risk, we conducted a nested case-control study in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort of male smokers, aged 50-69 years at baseline. Between 1992 and 2004, 193 incident cases of pancreatic adenocarcinoma occurred (mean follow-up from blood draw: 6.3 years) among participants with whole blood samples available for telomere length assays. For these cases and 660 controls, we calculated odds ratios (OR) and 95% confidence intervals using unconditional logistic regression, adjusting for age, number of years smoked regularly, and history of diabetes mellitus. Telomere length was categorized into quartiles (shortest to longest) and analyzed as both a categorical and a continuous normal variable (reported per 0.2 unit increase in telomere length). All statistical tests were two-sided. Longer telomere length was significantly associated with increased pancreatic cancer risk (continuous OR = 1.26 95% CI = 1.09-1.46; highest quartile compared to lowest, OR = 1.57, 95% CI = 1.01-2.43, p-trend = 0.007). This association remained for subjects diagnosed within the first five years of blood draw (continuous OR = 1.46, 95% CI = 1.19-1.79 highest quartile OR = 2.92, 95% CI = 1.47-5.77, p-trend = 0.002), but not those diagnosed greater than five years after blood draw (continuous OR = 1.03, 95% CI = 0.85-1.22; highest quartile OR = 1.04, 95% CI = 0.60-1.79). This is the first prospective study to suggest an association between longer blood leukocyte telomere length and increased pancreatic cancer risk.

Abstract 13: Telomere length and pancreatic cancer in the alpha-tocopherol beta-carotene cancer prevention (ATBC) study.

Abstract Genome-wide association studies have found an association between pancreatic cancer and the TERT or telomerase gene. Smoking and diabetes, consistent risk factors for pancreatic cancer, are also factors that influence telomere length maintenance. To test whether blood leukocyte telomere length is associated with pancreatic cancer risk, we conducted a nested case-control study in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort of male smokers, aged 50-69 years at baseline. Between 1992 and 2004, 193 incident cases of pancreatic adenocarcinoma occurred (mean follow-up from blood draw: 6.3 years) among participants with whole blood samples available for telomere length assays. For these cases and 660 controls, we calculated odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, adjusting for age, number of years smoked regularly, and history of diabetes mellitus. Telomere length was categorized into quartiles (shortest to longest) and analyzed as both a categorical and a continuous normal variable (reported per 0.2 unit increase in telomere length). All statistical tests were two-sided. Longer telomere length was significantly associated with increased pancreatic cancer risk (continuous OR=1.26 95% CI=1.09-1.46; highest quartile compared to lowest, OR=1.57, 95% CI=1.01-2.43, p-trend=0.007). This effect remained for subjects diagnosed within the first five years of blood draw (continuous OR=1.46, 95% CI=1.19-1.79 highest quartile OR=2.92, 95%CI=1.47-5.77, p-trend=0.002), but not subjects diagnosed greater than five years from blood draw (continuous OR=1.03, 95%CI=0.85-1.22; highest quartile OR=1.04, 95%CI=0.60-1.79). This is the first study to suggest an association between longer blood leukocyte telomere length and increased pancreatic cancer risk. Citation Format: Shannon M. Lynch, Jacqueline M. Major, Richard Cawthon, Stephanie J. Weinstein, Jarmo Virtamo, Qing Lan, Nathaniel Rothman, Demetrius Albanes, Rachael Z. Stolzenberg-Solomon. Telomere length and pancreatic cancer in the alpha-tocopherol beta-carotene cancer prevention (ATBC) study. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 13.

Pre-diagnostic circulating vitamin D and risk of melanoma in men.

PurposeVarious studies have examined the association between serum vitamin D levels and different cancers; however, this is the first prospective study of this association with melanoma risk. The aim of this study is to investigate the association between serum vitamin D [25(OH)D] levels and melanoma in a cohort of older, middle-aged Finnish male smokers.MethodsWe conducted a nested case-control study within the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study. From the ATBC cohort, 368 subjects were chosen for our study; 92 participants that developed melanoma and 276 matched control subjects. At study baseline, lifestyle questionnaires and blood samples were collected. Serum 25(OH)D was modeled as three sets of categorical variables: clinically-defined categories, season-specific quartiles and season-adjusted residual quartiles. Conditional logistic regression was used to obtain odds ratios (ORs) and 95% confidence intervals (95% CIs) to estimate the association between circulating vitamin D and melanoma risk.ResultsOverall no association of serum 25(OH)D and melanoma risk was observed. A decreased risk of developing melanoma was observed in the middle categories compared to the lowest category, albeit not significant.ConclusionResults indicate no association between serum 25(OH)D levels and melanoma. Additional studies, including possibly consortium efforts, are needed to investigate the association between serum 25(OH)D levels and risk of melanoma in larger, more diverse study populations.

Mitochondrial DNA Copy Number and Pancreatic Cancer in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study

Diabetes, obesity, and cigarette smoke, consistent risk factors for pancreatic cancer, are sources of oxidative stress in humans that could cause mitochondrial DNA (mtDNA) damage and increase mtDNA copy number. To test whether higher mtDNA copy number is associated with increased incident pancreatic cancer, we conducted a nested case-control study in the Alpha-Tocopherol Beta Carotene Cancer Prevention (ATBC) Study cohort of male smokers, aged 50 to 69 years at baseline. Between 1992 and 2004, 203 incident cases of pancreatic adenocarcinoma occurred (follow-up: 12 years) among participants, with whole blood samples used for mtDNA extraction. For these cases and 656 controls, we calculated ORs and 95% CIs using unconditional logistic regression, adjusting for age, smoking, and diabetes history. All statistical tests were two sided. Higher mtDNA copy number was significantly associated with increased pancreatic cancer risk (highest vs. lowest mtDNA copy number quintile, OR = 1.64, 95% CI = 1.01-2.67, continuous OR = 1.14, 95% CI 1.06-1.23), particularly for cases diagnosed during the first 7 years of follow-up (OR = 2.14, 95% CI = 1.16-3.96, P(trend) = 0.01, continuous OR = 1.21, 95% CI = 1.10-1.33), but not for cases occurring during follow-up of 7 years or greater (OR = 1.14, 95% CI = 0.53-2.45, continuous OR = 1.05, 95% CI = 0.93-1.18). Our results support the hypothesis that mtDNA copy number is associated with pancreatic cancer and could possibly serve as a biomarker for pancreatic cancer development.

Subgroup analysis of large trials can guide further research: a case study of vitamin E and pneumonia

Background:Biology is complex and the effects of many interventions may vary between population groups. Subgroup analysis can give estimates for specific populations, but trials are usually too small for such analyses.Purpose:To test whether the effect of vitamin E on pneumonia risk is uniform over subgroups defined by smoking and exercise.Methods:The Alpha-Tocopherol Beta-Carotene Cancer Prevention Study examined the effects of vitamin E (50 mg per day) and β-carotene (20 mg per day) on lung cancer in 29,133 male smokers aged 50–69 years using a 2 × 2 factorial design. The trial was conducted among the general community in Finland during 1985–1993; the intervention lasted for 6.0 years (median). In the present study, we tested the uniformity of vitamin E effect on the risk of hospital-treated pneumonia (898 cases) by adding a dummy variable to allow each subgroup its own vitamin E effect in a Cox model covering all participants.Results:Vitamin E effect was not uniform over eight subgroups defined by baseline smoking (5–19 vs ≥20 cigarettes per day), age of smoking initiation (≤20 vs ≥21 years), and exercise during leisure time (yes vs no). Vitamin E decreased pneumonia risk by 69% (95% CI: 43% to 83%) among participants who had the least exposure to smoking and exercised during leisure time. Vitamin E increased pneumonia risk by 79% (95% CI: 27% to 150%) among those who had the highest exposure to smoking and did not exercise.Limitations:Although the evidence of heterogeneity is strong, it is not evident to what extent the estimates of effect or the limits between the subgroups can be extrapolated to other populations.Conclusion:Subgroup analysis of large trials should be encouraged, though caution is needed in the interpretation of findings. The role of vitamin E in susceptibility to pneumonia in physically active nonsmokers warrants further study.Trial registration:ClinicalTrials.gov NCT00342992.

How can a chemically well established antioxidant work differently when in the body?

Is There An Answer? is intended to serve as a forum in which readers to IUBMB Life may pose questions of the type that intrigue biochemists but for which there may be no obvious answer or one may be available but not widely known or easily accessible. Readers are invited to e-mail ascenzi@uniroma3.it if they have questions to contribute or if they can provide answers to questions that are provided here from time to time. In the latter case, instructions will be sent to interested readers. Answers should be, whenever possible, evidence-based and provide relevant references. Paolo Ascenzi The idea that an antioxidant can work as nonantioxidant in the human body looks indeed like a molecular ‘‘to be or not to be’’. Indeed, it is not a dilemma, but an opportunity. Let us proceed with some order. Oxidation reactions are essential for life, being responsible, among others, for the liberation of free energy from lipid and carbohydrates for its subsequent storage in form of adenosine triphosphate. Oxidation reactions can also be disadvantageous when creating chemical modifications of phospholipid, protein, DNA, and regulatory molecules. Increased, uncontrolled oxidations may be part of the pathogenesis of many human ailments such as cancer, atherosclerosis heart disease, stroke, cataracts, Parkinson’s disease, Alzheimer’s disease, and arthritis. However, it is not clear whether the excess oxidations are a cause or consequence of the disease. Uncontrolled oxidation reactions may be detrimental for cells especially via the formation of free radicals and associated chain reactions (1–3). Antioxidants are molecules that retard or prevent the oxidation of other compounds. Not only soluble antioxidants but also complex enzymatic systems such as catalase, superoxide dismutase and some peroxidases may be used by cells to avoid undesired oxidations. A number of molecules are provided with chemically established antioxidant properties, among them are the well-known tocopherols, tocotrienols, ascorbic acid, glutathione, uric acid, bilirubin, lipoic acid, ubiquinol, and polyphenols. Other molecules are also considered to possess antioxidant properties such as carotenes, estrogens, melatonin, etc. On the assumption that increased oxidative damage represents an important part of human disease initiation and progression, antioxidant supplements have been automatically adopted as health promoters. The euphoric application of this paradigm has created a huge popularity for all antioxidants as food additives, in cosmetic products and in pharmaceutical preparations. Such an enthusiasm has a cost and is costing to the consumers many billions of $ each year and, with the purpose of providing scientific evidence for their action, has resulted in a large number of needed (and highly expensive) intervention studies. Unfortunately, most of the clinical trials carried out to test the in vivo efficacy of antioxidants could not measure any benefit of antioxidant administration (4). The following are three important relevant studies. The Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (ATBC) (5) involved Finnish men who were heavy

Fish, Vitamin D, and Flavonoids in Relation to Renal Cell Cancer Among Smokers

Fish, vitamin D, flavonoids, and flavonoid-containing foods may have cardiovascular benefits and therefore may also reduce the risk of renal cell cancer. Risk was prospectively assessed in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study (1985-2002) cohort (N = 27,111; 15.2 mean person-years of follow-up). At enrollment, demographic, health, and dietary history information was recorded. Individuals who smoked less than 5 cigarettes/day, with chronic renal insufficiency or prior cancer, were excluded. Hazard ratios and 95% confidence intervals from Cox regression were used to compare upper quartiles (quartiles 2-4) with the lowest quartile (quartile 1) of dietary intake. Among 228 cases, risk (quartile 4 vs. quartile 1) was associated with consumption of the flavonoid quercetin (hazard ratio = 0.6, 95% confidence interval: 0.4, 0.9; P(trend) = 0.015) and Baltic herring (hazard ratio = 2.0, 95% confidence interval: 1.4, 3.0; P(trend) < 0.001), with adjustment for age, body mass index, smoking, blood pressure, alcohol use, physical activity, urban residence, and education. In geographically stratified models, the risks associated with herring and total fish intake appeared to be highest in the urban coast region, although the interaction was not statistically significant. These results suggest that the flavonoid quercetin may prevent renal cell cancer among male smokers. The possible risk associated with fish intake warrants further investigation before conclusions may be drawn.

A prospective investigation of serum 25‐hydroxyvitamin D and risk of lymphoid cancers

Studies indicate that higher sun exposure, especially in the recent past, is associated with reduced risk of non-Hodgkin lymphoma (NHL). Ultraviolet radiation-derived vitamin D may be protective against lymphomagenesis. We examined the relationship between prediagnostic serum 25-hydroxyvitamin D (25(OH)D) and lymphoid cancer risk in a case-control study nested within the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study cohort (1985-2002) of 29,133 Finnish male smokers (ages 50-69). We identified 270 incident lymphoid cancer cases and matched them individually with 538 controls by birth-year and month of fasting blood draw at baseline. In conditional logistic regression models for 10 nmol/L increments or tertile comparisons, serum 25(OH)D was not associated with the risk of overall lymphoid cancers, NHL (n = 208) or multiple myeloma (n = 41). Odds ratios (OR) for NHL for higher tertiles were 0.75 (95% confidence interval (CI), 0.50, 1.14) and 0.82 (95% CI, 0.53, 1.26). The 25(OH)D-NHL association, however, differed by follow-up duration at diagnosis. Cases diagnosed less than 7 years from the baseline showed an inverse association (OR for highest vs. lowest tertile = 0.43; 95% CI: 0.23, 0.83; p for trend = 0.01), but not later diagnoses (OR = 1.52; 95% CI: 0.82, 2.80; p for trend = 0.17). The inverse association found for close exposure to diagnosis was not confounded by other risk factors for lymphoma or correlates of 25(OH)D. Although our findings suggest that circulating 25(OH)D is not likely associated with overall lymphoid cancer, they indicate a potentially protective effect on short-term risk of NHL.

Vitamin E supplementation and pneumonia risk in males who initiated smoking at an early age: effect modification by body weight and dietary vitamin C

BackgroundWe had found a 14% higher incidence of pneumonia with vitamin E supplementation in a subgroup of the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study cohort: participants who had initiated smoking by the age of 20 years. In this study, we explored the modification of vitamin E effect by body weight, because the same dose could lead to a greater effect in participants with low body weight.MethodsThe ATBC Study recruited males aged 50–69 years who smoked at least 5 cigarettes per day at the baseline; it was conducted in southwestern Finland in 1985–1993. The current study was restricted to 21,657 ATBC Study participants who initiated smoking by the age of 20 years; the median follow-up time was 6.0 years. The hospital-diagnosed pneumonia cases were retrieved from the national hospital discharge register (701 cases).ResultsVitamin E supplementation had no effect on the risk of pneumonia in participants with body weight in a range from 70 to 89 kg (n = 12,495), risk ratio (RR) = 0.99 (95% CI: 0.81 to 1.22). Vitamin E increased the risk of pneumonia in participants with body weight less than 60 kg (n = 1054), RR = 1.61 (1.03 to 2.53), and in participants with body weight over 100 kg (n = 1328), RR = 2.34 (1.07 to 5.08). The harm of vitamin E supplementation was restricted to participants with dietary vitamin C intake above the median.ConclusionVitamin E supplementation may cause harmful effects on health in certain groups of male smokers. The dose of vitamin E used in the ATBC Study, 50 mg/day, is substantially smaller than conventional vitamin E doses that are considered safe. Our findings should increase caution towards taking vitamin E supplements.Trial registrationClinicalTrials.gov NCT00342992.

Vitamin E supplementation may transiently increase tuberculosis risk in males who smoke heavily and have high dietary vitamin C intake

Vitamin E and beta-carotene affect the immune function and might influence the predisposition of man to infections. To examine whether vitamin E or beta-carotene supplementation affects tuberculosis risk, we analysed data of the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC)Study, a randomised controlled trial which examined the effects of vitamin E (50 mg/d) and beta-carotene (20 mg/d) on lung cancer. The trial was conducted in the general community in Finland in 1985-93; the intervention lasted for 6.1 years (median). The ATBC Study cohort consists of 29,023 males aged 50-69 years, smoking at baseline, with no tuberculosis diagnosis prior to randomisation. Vitamin E supplementation had no overall effect on the incidence of tuberculosis (risk ratio (RR) = 1.18; 95% CI 0.87, 1.59) nor had beta-carotene (RR = 1.07; 95% CI 0.80, 1.45). Nevertheless, dietary vitamin C intake significantly modified the vitamin E effect. Among participants who obtained 90 mg/d or more of vitamin Cin foods (n 13,502), vitamin E supplementation increased tuberculosis risk by 72 (95% CI 4, 185)%. This effect was restricted to participants who smoked heavily. Finally, in participants not supplemented with vitamin E, dietary vitamin C had a negative association with tuberculosis risk so that the adjusted risk was 60 (95% CI 16, 81)% lower in the highest intake quartile compared with the lowest. Our finding that vitamin E seemed to transiently increase the risk of tuberculosis in those who smoked heavily and had high dietary vitamin C intake should increase caution towards vitamin E supplementation for improving the immune system.

Vitamin E supplementation may transiently increase tuberculosis risk in males who smoke heavily and have high dietary vitamin C intake – comments by Hernández-Garduño

Hemilä &amp; Kaprio(1) found a 72 % increase in the risk of tuberculosis (TB) in males taking vitamin E supplements and having high dietary vitamin C intake; the effect was restricted to heavy smokers as part of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study.

Association of IL-10 polymorphisms with prostate cancer risk and grade of disease

Animal and in vitro models of prostate cancer demonstrate high IL-10 levels result in smaller tumors, fewer metastases, and reduced angiogenesis compared to controls. We sought to examine the hypothesis that genotypes correlated with low IL-10 production may be associated with increased prostate cancer risk among Finnish male participants from the Alpha-tocopherol Beta-carotene Cancer Prevention Study. DNA from 584 prostate cancer cases and 584 controls was genotyped for four IL-10 alleles, -1082, -819, -592, and 210. DNA from more of the controls than cases failed to amplify, resulting in 509 cases and 382 controls with genotype data for -1082; 507 and 384 for -819; 511 and 386 for -592; and 491 and 362 for 210. Odds ratios for the association between the IL-10 genotypes and risk of prostate cancer or, among cases only, high-grade disease were calculated using logistic regression. In this population, the -819 TT and -592 AA low expression genotypes were highly correlated. These two genotypes also were associated with increased prostate cancer susceptibility (OR = 1.92, 95% CI 1.07-3.43 for -819) and, among cases, with high-grade tumors (OR = 2.56, 95% CI 1.26-5.20 for -819). These data demonstrate genotypes correlated with low IL-10 production are associated with increased risk of prostate cancer and with high-grade disease in this population.

Predictors of sustained smoking cessation: a prospective analysis of chronic smokers from the alpha-tocopherol Beta-carotene cancer prevention study.

Because US smoking rates have not declined during the past decade, there is a renewed need to identify factors associated with smoking cessation. Using a nested case-control design, we explored the association between ability to sustain cessation over an extended period and demographic, smoking, medical, and behavioral variables. We selected a sample of 1379 sustained quitters (abstinent from smoking for at least 40 months) and 1388 relapsers (abstinent for more than 8 months before relapse) from participants in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study, a nutritional intervention study involving Finnish men aged 50 to 69 years at baseline. Contingency table and multiple regression analyses were used to evaluate potential differences between the 2 groups on baseline variables. Compared with sustained quitters, relapsers were more likely to report symptoms of emotional distress and higher levels of nicotine dependence, to drink more alcohol, and to report more medical conditions. Factors associated with both tobacco use and comorbid conditions impact an individual's ability to maintain long-term smoking cessation. Understanding the underlying mechanisms of action and potential common pathways among these factors may help to improve smoking cessation therapies.

Serum High-Density Lipoprotein Cholesterol and Risk of Non-Hodgkin Lymphoma

Lymphoma patients often exhibit abnormal lipid metabolism. Recent evidence, however, suggests that a decrease in circulating high-density lipoprotein cholesterol (HDL-C) may occur during lymphomagenesis, reflecting underlying etiology such as inflammation. We investigated the relationship between prediagnostic HDL-C and non-Hodgkin lymphoma (NHL) in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study cohort. At baseline, serum HDL-C and total cholesterol concentrations from fasting blood, information on diet and lifestyle, and direct measurements of height, weight, and blood pressure were obtained from 27,074 healthy male smokers of ages 50 to 69 years. Cox proportional hazards models with age as underlying time metric was used to estimate relative risks (RR) and 95% confidence intervals (95% CI). We found no association between total or non-HDL cholesterol and the 201 incident NHL cases ascertained during the follow-up (1985-2002), but observed an inverse association between HDL-C and NHL, which changed with length of follow-up. High HDL-C was associated with lower risk of all NHL during the first 10 years (n = 148; RR for 5th versus 1st quintile, 0.35; 95% CI, 0.19-0.62; P(trend) < 0.0001), but not with diagnoses during later follow-up (n = 53; RR, 1.31; 95% CI, 0.55-3.10). The inverse association was similar for NHL subtypes and was not modified by obesity, blood pressure, physical activity, or alcohol intake, but seemed to be stronger in men with lower duration of smoking (P(interaction) = 0.06). Our findings implicate HDL-C as a preclinical indicator of NHL and warrant further prospective investigations for its etiologic contribution.

The Effect of Vitamin E on Common Cold Incidence Is Modified by Age, Smoking and Residential Neighborhood

Background: We have previously found a 28% reduction in common cold incidence with 50 mg/day vitamin E supplementation in a subgroup of the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Study cohort: older city-dwelling men (≥65 years) who smoked only 5–14 cigarettes/day.Objective: To carry out more detailed analyses to explore the modification of vitamin E effect by age, smoking, and residential neighborhood.Methods: We examined the effect of vitamin E on common cold risk in subjects consisting of the placebo and vitamin E arms (n = 14,573) of the ATBC Study, which recruited males aged 50–69 years who smoked ≥5 cigarettes/day at the baseline. The ATBC Study was conducted in southwestern Finland in 1985–1993; the active follow-up lasted for 4.7 years (mean). We modeled common cold risk as a function of age-at-follow-up in the vitamin E arm compared with the placebo arm using linear splines in Poisson regression.Results: In participants of 72 years or older at follow-up, the effect of vitamin E diverged. Among those smoking 5–14 cigarettes per day at baseline and living in cities, vitamin E reduced common cold risk (RR = 0.54; 95% CI 0.37–0.80), whereas among those smoking more and living away from cities, vitamin E increased common cold risk (RR = 1.58; 1.23–2.01).Conclusions: Vitamin E may cause beneficial or harmful effects on health depending on various modifying factors. Accordingly, caution should be maintained in public health recommendations on vitamin E supplementation until its effects are better understood.

Dietary Factors of One-Carbon Metabolism in Relation to Non-Hodgkin Lymphoma and Multiple Myeloma in a Cohort of Male Smokers

Reported associations between genetic polymorphisms in folate-metabolizing enzymes and lymphoid malignancies suggest etiologic involvement of one-carbon metabolism and its related dietary exposures. We examined dietary factors of one-carbon metabolism in relation to non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) among 27,111 healthy male smokers who completed baseline dietary questionnaires in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study cohort. During a follow-up of up to 16.4 years (1985-2001), 195 NHL and 32 MM cases were ascertained. Cox proportional hazard models were used to estimate multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (95% CI). There was no significant association between dietary folate and NHL (HR comparing fourth to first quartile, 1.03; 95% CI, 0.68-1.55). Dietary vitamin B12 was inversely associated with NHL (HR, 0.61; 95% CI, 0.37-1.00; P(trend) = 0.06). The inverse association of vitamin B12 was evident for diffuse subtype but did not reach statistical significance. There were no significant associations of dietary vitamin B6 or B2, methionine, or alcohol with NHL. None of the dietary or supplemental one-carbon nutrients were associated with MM, although the power of these analyses was limited. Our results suggest that high intake of vitamin B12 among heavy smokers may be protective against NHL but warrant further studies, including among nonsmokers.