Metabolomic Analysis of Vitamin E Supplement Use in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

The effects of vitamin E supplementation on cancer and other chronic diseases are not clear. We compared the serum metabolomic profile of differing vitamin E dosages in order to re-examine the previously observed changes in a novel C22 lactone sulfate compound, androgenic steroids, and other metabolites. A total of 3409 women and men previously selected for metabolomics studies in the PLCO Cancer Screening Trial were included in this investigation. Serum metabolites were profiled using ultrahigh-performance liquid and gas chromatography/tandem mass spectrometry. Seventy known metabolites including C22 lactone sulfate and androgens were significantly associated with vitamin E supplementation. In the sex-stratified analysis, 10 cofactors and vitamins (e.g., alpha-CEHC sulfate and alpha-CEHC glucuronide), two carbohydrates (glyceric and oxalic acids), and one lipid (glycocholenate sulfate) were significantly associated with vitamin E dose in both males and females (FDR-adjusted p-value < 0.01). However, the inverse association between C22 lactone sulfate and daily vitamin E supplementation was evident in females only, as were two androgenic steroids, 5-androstenediol and androsterone glucuronide. Our study provides evidence of distinct steroid hormone pathway responses based on vitamin E dosages. Further studies are needed to gain biological insights into vitamin E biochemical effects relevant to cancer and other chronic diseases.

Interactions between folate intake and genetic predictors of gene expression levels associated with colorectal cancer risk.

Observational studies have shown higher folate consumption to be associated with lower risk of colorectal cancer (CRC). Understanding whether and how genetic risk factors interact with folate could further elucidate the underlying mechanism. Aggregating functionally relevant genetic variants in set-based variant testing has higher power to detect gene-environment (G × E) interactions and may provide information on the underlying biological pathway. We investigated interactions between folate consumption and predicted gene expression on colorectal cancer risk across the genome. We used variant weights from the PrediXcan models of colon tissue-specific gene expression as a priori variant information for a set-based G × E approach. We harmonized total folate intake (mcg/day) based on dietary intake and supplemental use across cohort and case-control studies and calculated sex and study specific quantiles. Analyses were performed using a mixed effects score tests for interactions between folate and genetically predicted expression of 4839 genes with available genetically predicted expression. We pooled results across 23 studies for a total of 13,498 cases with colorectal tumors and 13,918 controls of European ancestry. We used a false discovery rate of 0.2 to identify genes with suggestive evidence of an interaction. We found suggestive evidence of interaction with folate intake on CRC risk for genes including glutathione S-Transferase Alpha 1 (GSTA1; p = 4.3E-4), Tonsuko Like, DNA Repair Protein (TONSL; p = 4.3E-4), and Aspartylglucosaminidase (AGA: p = 4.5E-4). We identified three genes involved in preventing or repairing DNA damage that may interact with folate consumption to alter CRC risk. Glutathione is an antioxidant, preventing cellular damage and is a downstream metabolite of homocysteine and metabolized by GSTA1. TONSL is part of a complex that functions in the recovery of double strand breaks and AGA plays a role in lysosomal breakdown of glycoprotein.

Metabolomic analysis of serum alpha-tocopherol among men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study.

BACKGROUND/OBJECTIVES: The role of vitamin E in chronic disease risk remains incompletely understood, particularly in an un-supplemented state, and evidence is sparse regarding the biological actions and pathways involved in its influence on health outcomes. Identifying vitamin-E-associated metabolites through agnostic metabolomics analyses can contribute to elucidating the specific associations and disease etiology. This study aims to investigate the association between circulating metabolites and serum α-tocopherol concentration in an un-supplemented state. SUBJECTS/METHODS: Metabolomic analysis of 4,294 male participants was conducted based on pre-supplementation fasting serum in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The associations between 1,791 known metabolites measured by ultra-high-performance LC-MS/GC-MS and HPLC-determined α-tocopherol concentration were estimated using multivariable linear regression. Differences in metabolite levels per unit difference in α-tocopherol concentration were calculated as standardized ß-coefficients and standard errors. RESULTS: A total of 252 metabolites were associated with serum α-tocopherol at the Bonferroni-corrected p value (p < 2.79 × 10-5). Most of these metabolites were of lipid and amino acid origin, with the respective subclasses of dicarboxylic fatty acids, and valine, leucine, and isoleucine metabolism, being highly represented. Among lipids, the strongest signals were observed for linoleoyl-arachidonoyl-glycerol (18:2/20:4)[2](ß = 0.149; p = 8.65 × 10-146) and sphingomyelin (D18:2/18:1) (ß = 0.035; p = 1.36 × 10-30). For amino acids, the strongest signals were aminoadipic acid (ß = 0.021; p = 5.01 × 10-13) and l-leucine (ß = 0.007; p = 1.05 × 10-12). CONCLUSIONS: The large number of metabolites, particularly lipid and amino acid compounds associated with serum α-tocopherol provide leads regarding potential mechanisms through which vitamin E influences human health, including its role in cardiovascular disease and cancer.

A 28-year prospective analysis of serum vitamin E, vitamin E-related genetic variation and risk of prostate cancer.

OBJECTIVE: Investigate the relationship between serum α-tocopherol concentration and long-term risk of prostate cancer, and evaluate the interaction with vitamin E-related genetic variants and their polygenic risk score (PRS). METHODS: We conducted a biochemical analysis of 29,102 male Finnish smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Serum α-tocopherol was measured at baseline using high-performance liquid chromatography, and 2724 prostate cancer cases were identified during 28 years of follow-up. Cox proportional hazards models examined whether serum α-tocopherol concentrations were associated with prostate cancer risk. Among 8383 participants, three SNPs related to vitamin E status (rs964184, rs2108622, and rs11057830) were examined to determine whether they modified the relationship between serum α-tocopherol concentrations and prostate cancer risk, both individually and as a PRS using logistic regression models. RESULTS: No association was observed between serum α-tocopherol and prostate cancer risk (fifth quintile (Q5) vs. Q1 hazard ratio (HR) = 0.87, 95% confidence interval (95% CI) 0.75, 1.02; P-trend = 0.57). Though no interactions were seen by population characteristics, high α-tocopherol concentration was associated with reduced prostate cancer risk among the trial α-tocopherol supplementation group (Q5 quintile vs. Q1 HR = 0.79, 95% CI 0.64, 0.99). Finally, no associated interaction between the three SNPs or their PRS and prostate cancer risk was observed. CONCLUSION: Although there was a weak inverse association between α-tocopherol concentration and prostate cancer risk over nearly three decades, our findings suggest that men receiving the trial α-tocopherol supplementation who had higher baseline serum α-tocopherol concentration experienced reduced prostate cancer risk. Vitamin E-related genotypes did not modify the serum α-tocopherol-prostate cancer risk association.

Multivitamin Use and Overall and Site-Specific Cancer Risks in the National Institutes of Health-AARP Diet and Health Study.

BACKGROUND: Multivitamins are among the most commonly used supplements in the United States, but their effectiveness in preventing cancer remains unclear. OBJECTIVES: We prospectively examined the association between multivitamin use and risks of overall and site-specific cancer in a large, well-characterized cohort to ascertain potential preventive or harmful relationships. METHODS: We examined 489,640 participants ages 50-71 in the NIH-American Association of Retired Persons (AARP) Diet and Health Study who were enrolled from 1995 to 1998. We linked to 11 state cancer registries in order to identify incident cancers. Multivitamin use was assessed by a baseline questionnaire. Cox proportional hazards regression models of multivitamin use were used to estimate HRs and 95% CIs for cancer risks in men and women, adjusted for potential confounders, including age, BMI, smoking, physical activity, the Healthy Eating Index 2015 score, and use of single-vitamin/-mineral supplements. RESULTS: A slightly higher overall cancer risk was observed in men (but not women) who consumed 1 or more multivitamins daily compared to nonusers [HRs, 1.02 (95% CI: 1.01-1.04) and 1.03 (95% CI: 1.00-1.07), respectively; P-trend = 0.002]. The latter reflected higher risks for prostate cancer (HR, 1.04; 95% CI: 0.98-1.10; P-trend = 0.005), lung cancer (HR, 1.07; 95% CI: 0.96-1.20; P-trend = 0.003), and leukemia (HR, 1.26; 95% CI: 1.02-1.57; P-trend = 0.003). Taking more than 1 multivitamin daily was also strongly positively associated with the risk of oropharyngeal cancer in women (HR, 1.53, 95% CI: 1.04-2.24; P-trend < 0.0001). By contrast, daily multivitamin use was inversely associated with the colon cancer risk in both sexes (HR, 0.82; 95% CI: 0.73-0.93; P-trend = 0.0003). CONCLUSIONS: We found little evidence to support a cancer-preventive role for multivitamin use, with the exception of colon cancer, in both sexes in the NIH-AARP Diet and Health Study. In addition, slightly higher risks of overall, prostate, and lung cancer, as well as leukemia, were observed for greater multivitamin use in men, with a higher oropharyngeal cancer risk in women.

Coffee intake and trace element blood concentrations in association with renal cell cancer among smokers.

PURPOSE: To determine whether higher coffee intake may reduce the risk of renal cell cancer (RCC) associated with lead (Pb) and other heavy metals with known renal toxicity. METHODS: We conducted a nested case-control study of male smokers (136 RCC cases and 304 controls) within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Cases diagnosed with RCC at 5 or more years following cohort enrollment were matched to controls on age (± 7 years) and whole blood draw date (± 30 days). Conditional logistic regression (using two-sided tests) was used to test for main effects and additive models of effect modification. RESULTS: After a mean follow-up of 16.3 years, coffee consumption was not significantly associated with renal cell cancer risk, when adjusting for blood concentrations of Cd, Hg, and Pb and RCC risk factors (age, smoking, BMI, and systolic blood pressure) (p-trend, 0.134). The association with above median blood Pb and RCC (HR = 1.69, 95% CI 1.06, 2.85) appeared to be modified by coffee consumption, such that RCC risk among individuals with both increased coffee intake and higher blood lead concentration were more than threefold higher RCC risk (HR = 3.40, 95% CI 1.62, 7.13; p-trend, 0.003). CONCLUSION: Contrary to our initial hypothesis, this study suggests that heavy coffee consumption may increase the previously identified association between higher circulating lead (Pb) concentrations and increased RCC risk. Improved assessment of exposure, including potential trace element contaminants in coffee, is needed.

Association between serum retinol and overall and cause-specific mortality in a 30-year prospective cohort study.

How retinol as a clinical indicator of vitamin A status is related to long-term mortality is unknown. Here we report the results of a prospective analysis examining associations between serum retinol and risk of overall and cause-specific mortality. During a 30-year cohort follow-up, 23,797 deaths were identified among 29,104 men. Participants with higher serum retinol experienced significantly lower overall, CVD, heart disease, and respiratory disease mortality compared to men with the lowest retinol concentrations, reflecting 17-32% lower mortality risk (Ptrend < 0.0001). The retinol-overall mortality association is similar across subgroups of smoking intensity, alcohol consumption, body mass index, trial supplementation, serum alpha-tocopherol and beta-carotene concentrations, and follow-up time. Mediation analysis indicated that <3% of the effects of smoking duration and diabetes mellitus on mortality were mediated through retinol concentration. These findings indicate higher serum retinol is associated with lower overall mortality, including death from cardiovascular, heart, and respiratory diseases.

An investigation of cross-sectional associations of a priori-selected dietary components with circulating bile acids.

BACKGROUND: A growing body of literature suggests chronically higher bile acid (BA) concentrations may be associated with multiple health conditions. Diet may affect BA metabolism and signaling; however, evidence from human populations is lacking. OBJECTIVES: We systematically investigated cross-sectional associations of a priori-selected dietary components (fiber, alcohol, coffee, fat) with circulating BA concentrations. METHODS: We used targeted, quantitative LC-MS/MS panels to measure 15 circulating BAs in a subset of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC; n = 2224) and Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO; n = 986) comprising Finnish male smokers and United States men and women, respectively. We used multivariable linear regression to estimate associations of each dietary component with log-transformed BAs; exponentiated coefficients estimate proportional differences. We included the median of the dietary component quartile in linear regression models to test for trend. RESULTS: In ATBC, fiber was inversely associated with multiple circulating BAs. The proportional difference was -10.09% (95% CI: -19.29 to 0.16; P-trend = 0.04) when comparing total BAs among those in the highest relative to the lowest fiber quartile. Alcohol, trans fat, and polyunsaturated fat were positively associated with BAs in ATBC. The proportional difference comparing total BAs among those in the highest relative to the lowest alcohol quartile was 8.76% (95% CI: -3.10 to 22.06; P-trend = 0.03). Coffee and monounsaturated fat were inversely associated with BAs. The proportional difference comparing total BAs among those in the highest relative to the lowest coffee quartile was -24.03% (95% CI: -31.57 to -15.66; P-trend < 0.0001). In PLCO, no dietary components were associated with BAs except fiber, which was inversely associated with tauroursodeoxycholic acid. CONCLUSIONS: Alcohol, coffee, certain fat subtypes, and fiber were associated with circulating concentrations of multiple BAs among Finnish male smokers. Given the potential role of BAs in disease risk, further investigation of the effects of diet on BAs in humans is warranted.

Association Between Plant and Animal Protein Intake and Overall and Cause-Specific Mortality.

Importance: Although emphasis has recently been placed on the importance of high-protein diets to overall health, a comprehensive analysis of long-term cause-specific mortality in association with the intake of plant protein and animal protein has not been reported. Objective: To examine the associations between overall mortality and cause-specific mortality and plant protein intake. Design, Setting, and Participants: This prospective cohort study analyzed data from 416 104 men and women in the US National Institutes of Health-AARP Diet and Health Study from 1995 to 2011. Data were analyzed from October 2018 through April 2020. Exposures: Validated baseline food frequency questionnaire dietary information, including intake of plant protein and animal protein. Main Outcomes and Measures: Hazard ratios and 16-year absolute risk differences for overall mortality and cause-specific mortality. Results: The final analytic cohort included 237 036 men (57%) and 179 068 women. Their overall median (SD) ages were 62.2 (5.4) years for men and 62.0 (5.4) years for women. Based on 6 009 748 person-years of observation, 77 614 deaths (18.7%; 49 297 men and 28 317 women) were analyzed. Adjusting for several important clinical and other risk factors, greater dietary plant protein intake was associated with reduced overall mortality in both sexes (hazard ratio per 1 SD was 0.95 [95% CI, 0.94-0.97] for men and 0.95 [95% CI, 0.93-0.96] for women; adjusted absolute risk difference per 1 SD was -0.36% [95% CI, -0.48% to -0.25%] for men and -0.33% [95% CI, -0.48% to -0.21%] for women; hazard ratio per 10 g/1000 kcal was 0.88 [95% CI, 0.84-0.91] for men and 0.86 [95% CI, 0.82-0.90] for women; adjusted absolute risk difference per 10 g/1000 kcal was -0.95% [95% CI, -1.3% to -0.68%] for men and -0.86% [95% CI, -1.3% to -0.55%] for women; all P < .001). The association between plant protein intake and overall mortality was similar across the subgroups of smoking status, diabetes, fruit consumption, vitamin supplement use, and self-reported health status. Replacement of 3% energy from animal protein with plant protein was inversely associated with overall mortality (risk decreased 10% in both men and women) and cardiovascular disease mortality (11% lower risk in men and 12% lower risk in women). In particular, the lower overall mortality was attributable primarily to substitution of plant protein for egg protein (24% lower risk in men and 21% lower risk in women) and red meat protein (13% lower risk in men and 15% lower risk in women). Conclusions and Relevance: In this large prospective cohort, higher plant protein intake was associated with small reductions in risk of overall and cardiovascular disease mortality. Our findings provide evidence that dietary modification in choice of protein sources may influence health and longevity.

Serum Metabolomic Response to Low- and High-Dose Vitamin E Supplementation in Two Randomized Controlled Trials.

BACKGROUND: Vitamin E is an essential micronutrient and critical human antioxidant previously tested for cancer preventative effects with conflicting clinical trial results that have yet to be explained biologically. METHODS: We examined baseline and on-trial serum samples for 154 men randomly assigned to receive 400 IU vitamin E (as alpha-tocopheryl acetate; ATA) or placebo daily in the Vitamin E Atherosclerosis Prevention Study (VEAPS), and for 100 men administered 50 IU ATA or placebo daily in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC). Over 970 metabolites were identified using ultrahigh-performance LC/MS-MS. Linear regression models estimated the change in serum metabolites of men supplemented with vitamin E versus those receiving placebo in VEAPS as compared with ATBC. RESULTS: Serum alpha-carboxyethyl hydrochroman (CEHC) sulfate, alpha-tocopherol, and beta/gamma-tocopherol were significantly altered by ATA supplementation in both trials (all P values ≤5.1 × 10-5, the Bonferroni multiple comparisons corrected statistical threshold). Serum C22 lactone sulfate was significantly decreased in response to the high-dose vitamin E in VEAPS (ß = -0.70, P = 8.1 × 10-6), but not altered by the low dose in ATBC (ß = -0.17, P = 0.4). In addition, changes in androgenic steroid metabolites were strongly correlated with the vitamin E supplement-associated change in C22 lactone sulfate only in the VEAPS trial. CONCLUSIONS: We found evidence of a dose-dependent vitamin E supplementation effect on a novel C22 lactone sulfate compound that was correlated with several androgenic steroids. IMPACT: Our data add information on a differential hormonal response based on vitamin E dose that could have direct relevance to opposing prostate cancer incidence results from previous large controlled trials.

Prospective Investigation of Serum Metabolites, Coffee Drinking, Liver Cancer Incidence, and Liver Disease Mortality.

BACKGROUND: Coffee has been consistently associated with lower risk of liver cancer and chronic liver disease, suggesting that coffee affects mechanisms underlying disease development. METHODS: We measured serum metabolites using untargeted metabolomics in 1:1 matched nested case-control studies of liver cancer (n = 221 cases) and fatal liver disease (n = 242 cases) in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention cohort (n = 29 133). Associations between baseline coffee drinking and metabolites were identified using linear regression; conditional logistic regression models were used to identify associations with subsequent outcomes. RESULTS: Overall, 21 metabolites were associated with coffee drinking and also each subsequent endpoint; nine metabolites and trigonelline, a known coffee biomarker, were identified. Tyrosine and two bile acids, glycochenodeoxycholic acid (GCDCA) and glycocholic acid (GCA), were inversely associated with coffee but positively associated with both outcomes; odds ratios (ORs) comparing the 90th to 10th percentile (modeled on a continuous basis) ranged from 3.93 (95% confidence interval [CI] = 2.00 to 7.74) for tyrosine to 4.95 (95% CI = 2.64 to 9.29) for GCA and from 4.00 (95% CI = 2.42 to 6.62) for GCA to 6.77 (95% CI = 3.62 to 12.65) for GCDCA for liver cancer and fatal liver disease, respectively. The remaining six metabolites and trigonelline were positively associated with coffee drinking but inversely associated with both outcomes; odds ratio ranged from 0.16 to 0.37. Associations persisted following diet adjustment and for outcomes occurring greater than 10 years after blood collection. CONCLUSIONS: A broad range of compounds were associated with coffee drinking, incident liver cancer, and liver disease death over 27 years of follow-up. These associations provide novel insight into chronic liver disease and liver cancer etiology and support a possible hepatoprotective effect of coffee.

A Prospective Study of Serum Vitamin E and 28-Year Risk of Lung Cancer.

BACKGROUND: Epidemiologic data are inconsistent regarding the vitamin E-lung cancer association, and no study to our knowledge has examined serologic changes in vitamin E status in relation to subsequent risk. METHODS: In a cohort of 22 781 male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, we ascertained 3184 lung cancer cases during up to 28 years of observation. Cox proportional hazards models examined whether higher serum alpha-tocopherol concentrations at baseline, 3 years, or the interval change were associated with lower lung cancer risk. All statistical tests were two-sided. RESULTS: After adjustment for age, body mass index, smoking intensity and duration, serum total cholesterol, and trial intervention group, we found lower lung cancer risk in men with high baseline alpha-tocopherol (fifth quintile [Q5] vs Q1, hazard ratio [HR] = 0.76, 95% confidence interval [CI] = 0.66 to 0.87, Ptrend < .001). A similar reduction in risk was seen for serum alpha-tocopherol at 3 years (Q5 vs Q1, HR = 0.78, 95% CI = 0.67 to 0.91, Ptrend = .004). The inverse risk association appeared stronger for younger men and those who had smoked fewer years but was similar across trial intervention groups. We also found reduced risk among men not supplemented with vitamin E who had a lower serum alpha-tocopherol at baseline and greater increases in concentrations at 3 years (third tertile vs first tertile of serum alpha-tocopherol change, HR = 0.74, 95% CI = 0.59 to 0.91, P = .005). CONCLUSIONS: Higher vitamin E status, as measured by serum alpha-tocopherol concentration, as well as repletion of a low vitamin E state, was related to decreased lung cancer risk during a 28-year period. Our findings provide evidence supporting the importance of adequate physiological vitamin E status for lung cancer risk reduction.

Serum Retinol and Risk of Overall and Site-Specific Cancer in the ATBC Study.

Retinol, the most biologically active form of vitamin A, might influence cancer-related biological pathways. However, results from observational studies of serum retinol and cancer risk have been mixed. We prospectively examined serum retinol and risk of overall and site-specific cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (n = 29,104 men), conducted in 1985-1993, with follow-up through 2012. Serum retinol concentration was measured using reverse-phase high-performance liquid chromatography. Cox proportional hazards models estimated the association between baseline serum retinol quintile and overall and site-specific cancer risk in 10,789 cases. After multivariable adjustment, higher serum retinol was not associated with overall cancer risk (highest vs. lowest quintile: hazard ratio (HR) = 0.97, 95% confidence interval (CI): 0.91, 1.03; P for trend = 0.43). Higher retinol concentrations were, however, associated with increased risk of prostate cancer (highest vs. lowest quintile: HR = 1.28, 95% CI: 1.13, 1.45; P for trend < 0.0001) and lower risk of both liver and lung cancers (highest vs. lowest quintile: for liver, HR = 0.62, 95% CI: 0.42, 0.91; P for trend = 0.004; and for lung, HR = 0.80, 95% CI: 0.72, 0.88; P for trend < 0.0001). No associations with other cancers were observed. Understanding the mechanisms that underlie these associations might provide insight into the role of vitamin A in cancer etiology.

Relationship Between Serum Alpha-Tocopherol and Overall and Cause-Specific Mortality.

RATIONALE: Although there has been a long-standing interest in the human health effects of vitamin E, a comprehensive analysis of the association between circulating vitamin E and long-term mortality has not been conducted. OBJECTIVE: Determine whether serum α-tocopherol (the predominant form of vitamin E) is related to long-term overall and cause-specific mortality and elucidate the dose-response relationships with better quantification of the associations. METHODS AND RESULTS: We conducted a biochemical analysis of 29 092 participants in the ATBC Study (Alpha-Tocopherol, Beta-Carotene Cancer Prevention) that originally tested vitamin E and ß-carotene supplementation. Serum α-tocopherol was measured at baseline using high-performance liquid chromatography, and during a 30-year follow-up we identified 23 787 deaths, including deaths from cardiovascular disease (9867), cancer (7687), respiratory disease (2161), diabetes mellitus (119), injuries and accidents (1255), and other causes (2698). After adjusting for major risk factors, we found that men with higher serum α-tocopherol had significantly lower all-cause mortality (hazard ratios=0.83, 0.79, 0.75, and 0.78 for quintile 2 (Q2)-Q5 versus Q1, respectively; Ptrend<0.0001), and significantly decreased mortality from cardiovascular disease, heart disease, stroke, cancer, respiratory disease, and other causes, with risk reductions from 17% to 47% for the highest versus lowest quintile. The α-tocopherol association with overall mortality was similar across subgroups of smoking intensity, years of smoking, alcohol consumption, trial supplementation, and duration of follow-up. The association was, however, significantly modified by baseline age and body mass index, with stronger inverse associations for younger men and men with a lower body mass index ( Pinteraction≤0.006). CONCLUSIONS: In this long-term prospective cohort study, higher baseline serum α-tocopherol biochemical status was associated with lower risk of overall mortality and mortality from all major causes. Our data support the long-term health benefits of higher serum α-tocopherol for overall and chronic disease mortality and should be replicated in other more diverse populations.

Coffee and tea drinking and risk of cancer of the urinary tract in male smokers.

PURPOSE: We evaluated the association of coffee and tea drinking with risk of the urinary tract cancer in Finnish men, with high coffee consumption, using data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. METHODS: The ATBC trial conducted from 1985 to 1993 enrolled 29,133 male smokers. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and confidence intervals (CIs), using men who drank more than 0 but less than 1 cup coffee/d and tea nondrinkers as our referent group for coffee and tea analyses, respectively. RESULTS: During 472,402 person-years of follow-up, 835 incident cases of bladder cancer and 366 cases of renal cell carcinoma were ascertained. For bladder cancer, we observed no association for coffee consumption (HR ≥4 vs. >0 to <1 cups/d = 1.16, 95% CI = 0.86-1.56) and a borderline statistically significant inverse association for tea consumption (HR ≥1 vs. 0 cup/d = 0.77, 95% CI = 0.58-1.00). For renal cell carcinoma, we observed no association for coffee (HR ≥4 vs. >0 to <1 cups/d = 0.85, 95% CI = 0.55-1.32) or tea consumption (HR ≥1 vs. 0 cup/d = 1.00, 95% CI = 0.68-1.46). We found no impact of coffee preparation on coffee-cancer associations. CONCLUSIONS: Coffee drinking was not associated with urinary tract cancers risk. Further research on tea and bladder cancer is warranted.

Variation in ribosomal DNA copy number is associated with lung cancer risk in a prospective cohort study.

Disruption of ribosomal DNA (rDNA) has been linked to a variety of diseases in humans, including carcinogenesis. To evaluate the associations between rDNA copy number (CN) and risk of lung cancer, we measured 5.8S and 18S rDNA CN in the peripheral blood of 229 incident lung cancer cases and 1:1 matched controls from a nested case-control study within a prospective cohort of male smokers. There was a dose-response relationship between quartiles of both 18S and 5.8S rDNA CN and risk of lung cancer (odds ratio [OR], 95% confidence interval [CI]: 18S: 1.0 [ref]; 1.2 [0.6-2.1]; 1.8 [1.0-3.4]; 2.3 [1.3-4.1; Ptrend = 0.0002; 5.8S: 1.0 [ref]; 1.6 [0.8-2.9]; 2.2 [1.1-4.2]; 2.6 [1.3-5.1]; Ptrend = 0.0001). The associations between rDNA CN and lung cancer risk were similar when excluding cases diagnosed within 5 years of follow-up, and when stratifying by heavy (>20 cigarettes per day) and light smokers (≤20 cigarettes per day). We are the first to report that rDNA CN may be associated with future risk of lung cancer. To further elucidate the relationship between rDNA and lung cancer, replication studies are needed in additional populations, particularly those that include non-smokers.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Is high vitamin B12 status a cause of lung cancer?

Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer etiology via direct measurements of pre-diagnostic circulating vitamin B12 concentrations in a nested case-control study, complemented with a Mendelian randomization (MR) approach in an independent case-control sample. We used pre-diagnostic biomarker data from 5183 case-control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls. Exposures included directly measured circulating vitamin B12 in pre-diagnostic blood samples from the nested case-control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study. Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations. We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12 ] = 1.15, 95% confidence interval (95%CI) = 1.06-1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD ] = 1.08, 95%CI = 1.00-1.16). Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer.

ß-Carotene Supplementation and Lung Cancer Incidence in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study: The Role of Tar and Nicotine.

INTRODUCTION: The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study demonstrated that ß-carotene supplementation increases lung cancer incidence in smokers. Further, cigarettes with higher tar and nicotine content are associated with a higher risk of lung cancer. However, no studies have examined whether the increased risk associated with ß-carotene supplementation in smokers varies by the tar or nicotine content of cigarettes. METHODS: The ATBC Study was a randomized, double-blind intervention trial conducted in southwest Finland. A total of 29 133 male smokers, aged 50-69 years, were enrolled and randomly assigned to one of four groups (α-tocopherol, ß-carotene, both, or placebo). Cox proportional hazards models were used to estimate the hazard ratio (HR) and 95% confidence intervals (CI) of lung cancer risk by ß-carotene trial assignment stratified by a priori categories of cigarette tar and nicotine content. RESULTS: The ß-carotene supplementation group had significantly higher risk of developing lung cancer in all categories of tar content (yes vs. no ß-carotene supplementation-ultralight cigarettes [≤7 mg tar]: HR = 1.31, 95% CI = 0.91 to 1.89; nonfiltered cigarettes [≥21 mg tar]: HR = 1.22, 95% CI = 0.91 to 1.64; p for interaction = .91). Similarly, there was no interaction with nicotine content (yes vs. no ß-carotene supplementation-ventilated cigarettes [≤0.8 µg nicotine]: HR = 1.23, 95% CI = 0.98 to 1.54; nonfiltered cigarettes [≥1.3 µg nicotine]: HR = 1.22, 95% CI = 0.91 to 1.64; p for interaction = .83). CONCLUSION: These findings support the conclusion that supplementation with ß-carotene increases the risk of lung cancer in smokers regardless of the tar or nicotine content of cigarettes smoked. Our data suggest that all smokers should continue to avoid ß-carotene supplementation. IMPLICATIONS: Previous studies demonstrated that ß-carotene supplementation increases risk of lung cancer in smokers. This study moves the field forward by examining the potential for modification of risk of lung cancer with different levels of tar and nicotine in cigarettes smoked, as interaction with carcinogens in these components of cigarette smoke is hypothesized to be the mechanism by which ß-carotene increases risk. Our study provides evidence that the increased risk of lung cancer in smokers who take ß-carotene supplements is not dependent upon the tar or nicotine level of cigarettes smoked and suggests that all smokers should continue to avoid ß-carotene supplementation.

Serum Beta Carotene and Overall and Cause-Specific Mortality.

RATIONALE: Although the health effects of beta carotene have been studied extensively, a systematic examination of serum concentrations and long-term mortality, including cardiovascular disease mortality, has not been reported. OBJECTIVE: Explore whether serum beta carotene is associated with overall and cause-specific mortality and to elucidate the strength and dose-response of the association. METHODS AND RESULTS: We conducted a prospective serological analysis of 29 103 men in the ATBC study (Alpha-Tocopherol, Beta-Carotene Cancer Prevention). During 31 years of follow-up, 23 796 deaths occurred, including deaths because of cardiovascular disease (9869), cancer (7692), respiratory disease (2161), diabetes mellitus (119), injuries and accidents (1255), and other causes (2700). Serum beta carotene was assayed using high-performance liquid chromatography. Adjusting for major risk factors measured, men with higher serum beta carotene had significantly lower all-cause mortality (hazard ratios=0.81, 0.71, 0.69, and 0.64 for quintile 2 (Q2)-Q5 versus Q1, respectively; Ptrend<0.0001). Serum beta carotene was significantly associated with risk of death from cardiovascular disease, heart disease, stroke, cancer, respiratory disease, diabetes mellitus, injuries and accidents, and other causes (Q5 versus Q1, hazard ratio=0.21-0.73, all Ptrend<0.0001). The all-cause mortality association was not materially impacted by adjustment for fruit and vegetable consumption (albeit, estimated with some measurement error) and was generally similar across subgroups of smoking intensity, alcohol consumption, trial supplementation, and duration of follow-up, but was significantly modified by age, years of smoking, and body mass index, with stronger inverse associations among men who were younger, smoked fewer years, and had a lower body mass index (all Pinteraction≤0.0025). CONCLUSIONS: This study provides evidence that higher beta carotene biochemical status is associated with lower overall, cardiovascular disease, heart disease, stroke, cancer, and other causes of mortality. The dose-response associations over a 30-year period were not attenuated by adjustment for other important risk factors and support greater fruit and vegetable consumption as a means to increase beta carotene status and promote longevity.