Genome-wide interaction analysis of folate for colorectal cancer risk.

BACKGROUND: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC. OBJECTIVES: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. METHODS: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). RESULTS: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. CONCLUSIONS: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.

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.

Incidence of liver-related morbidity and mortality in a population cohort of non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) increases morbidity and mortality. However, patients in biopsy-based cohorts are highly selected and the absolute risks of liver- and non-liver outcomes in NAFLD in population remains undefined. We analysed both liver-related and non-liver-related outcomes in Finnish population cohorts of NAFLD. METHODS: We included 10 993 individuals (6707 men, mean age 53.3 ± 12.6 years) with NAFLD (fatty liver index ≥60) from the Finnish population-based FINRISK and Health 2000 studies. Liver fibrosis was assessed by the dAAR score, and genetic risk by a recent polygenic risk score (PRS-5). Incident liver-related outcomes, cardiovascular disease (CVD), cancer and chronic kidney disease (CKD) were identified through linkage with national registries. RESULTS: Mean follow-up was 12.1 years (1128 069 person-years). The crude incidence rate of liver-related outcomes in NAFLD was 0.97/1000 person-years. The cumulative incidence increased with age, being respectively 2.4% and 1.5% at 20 years in men and women aged 60 years at baseline, while the relative risks for CVD and cancer were 9-16 times higher. The risk of CKD exceeded that of liver outcomes at a baseline age around 50 years. 20-year cumulative incidence of liver-related outcomes was 4.3% in the high, and 1.5% in the low PRS-5 group. The dAAR score associated with liver outcomes, but not with extra-hepatic outcomes. CONCLUSION: The absolute risk of liver-related outcomes in NAFLD is low, with much higher risk of CVD and cancer, emphasizing the need for more individualized and holistic risk-stratification in NAFLD.

Substitution of sugar-sweetened beverages for other beverages and the risk of developing coronary heart disease: Results from the Harvard Pooling Project of Diet and Coronary Disease.

Sugar-sweetened beverage (SSB) intake is associated with metabolic disorders. The reduction of SSB intake has been promoted to prevent death and disability from chronic diseases. We investigated the association between SSB intake and the risk of coronary events and death, and assessed if substitution of coffee, tea, milk, fruit juice and artificially-sweetened beverages (ASB) for SSBs was associated with a reduced risk of coronary events and death. This was a follow-up study in which data from six studies were pooled and standard observational analyses were performed. Diet intake was assessed at baseline by food-frequency questionnaires. Hazard ratios (HRs) with 95% confidence intervals for the incidence of coronary events and deaths were calculated by Cox proportional hazards regression. The effect of substituting another beverage for SSBs was calculated by taking the difference in the individual effect estimates. During the median 8.2-year follow-up, 4248 coronary events and 1630 coronary deaths were documented among 284,345 individuals. 355 ml daily increase of SSB intake was associated with an increased risk of coronary events (HR: 1.08; 95%CI: 1.02, 1.14) and possibly coronary death (HR: 1.05; 95%CI: 0.96, 1.16). Substitution analyses suggested that replacing SSBs with coffee (HR: 0.93; 95%CI: 0.87, 1.00) or ASB (HR: 0.89; 95%CI: 0.83, 0.97), might be associated with a lower risk of developing coronary events. We found that SSB intake was associated with an increased risk of coronary events and possibly coronary death. Our findings also suggest that replacing SSB's with ASBs or coffee may lower the risk of developing CHD.

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.

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.

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.

Low vitamin B12 increases risk of gastric cancer: A prospective study of one-carbon metabolism nutrients and risk of upper gastrointestinal tract cancer.

Previous studies have found associations between one-carbon metabolism nutrients and risk of several cancers, but little is known regarding upper gastrointestinal tract (UGI) cancer. We analyzed prediagnostic serum concentrations of several one-carbon metabolism nutrients (vitamin B12, folate, vitamin B6, riboflavin and homocysteine) in a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of male smokers, which was undertaken in Finland between 1985 and 1988. We conducted a nested case-control study including 127 noncardia gastric adenocarcinoma (NCGA), 41 esophagogastric junctional adenocarcinoma and 60 esophageal squamous cell carcinoma incident cases identified within ATBC. Controls were matched to cases on age, date of serum collection and follow-up time. One-carbon nutrient concentrations were measured in fasting serum samples collected at baseline (up to 17 years prior to cancer diagnosis). Odds ratios and 95% confidence intervals (CI) were calculated using conditional logistic regression. Lower prediagnostic vitamin B12 concentrations at baseline were associated with a 5.8-fold increased risk of NCGA (95% CI = 2.7-12.6 for lowest compared to highest quartile, p-trend <0.001). This association remained in participants who developed cancer more than 10 years after blood collection, and after restricting the analysis to participants with clinically normal serum vitamin B12 (>300 pmol/L). In contrast, pepsinogen I, a known serologic marker of gastric atrophy, was not associated with NCGA in this population. As vitamin B12 absorption requires intact gastric mucosa to produce acid and intrinsic factor, our findings suggest vitamin B12 as a possible serologic marker for the atrophic gastritis that precedes NCGA, one more strongly associated with subsequent NCGA than pepsinogen.

The positive impact of general vitamin D food fortification policy on vitamin D status in a representative adult Finnish population: evidence from an 11-y follow-up based on standardized 25-hydroxyvitamin D data.

Background: A systematic vitamin D fortification of fluid milk products and fat spreads was started in 2003 in Finland to improve vitamin D status. Objective: We investigated the effects of the vitamin D fortification policy on vitamin D status in Finland between 2000 and 2011.Design: Serum 25-hydroxyvitamin D [S-25(OH)D] concentrations of a nationally representative sample comprising 6134 and 4051 adults aged ≥30 y from the Health 2000 and Health 2011 surveys, respectively, were standardized according to the Vitamin D Standardization Program with the use of liquid chromatography-tandem mass spectrometry. Linear and logistic regression models were used to assess the change in S-25(OH)D concentrations.Results: Between 2000 and 2011, the mean S-25(OH)D increased from 48 nmol/L (95% CI: 47, 48 nmol/L) to 65 nmol/L (95% CI: 65, 66 nmol/L) (P < 0.001). The prevalence of vitamin D supplement users increased from 11% to 41% (P < 0.001). When analyzing the effect of fortification of fluid milk products, we focused on supplement nonusers. The mean increase in S-25(OH)D in daily fluid milk consumers (n = 1017) among supplement nonusers was 20 nmol/L (95% CI: 19, 21 nmol/L), which was 6 nmol/L higher than nonconsumers (n = 229) (14 nmol/L; 95% CI: 12, 16 nmol/L) (P < 0.001). In total, 91% of nonusers who consumed fluid milk products, fat spreads, and fish based on Finnish nutrition recommendations reached S-25(OH)D concentrations >50 nmol/L in 2011.Conclusions: The vitamin D status of the Finnish adult population has improved considerably during the time period studied. The increase is mainly explained by food fortification, especially of fluid milk products, and augmented vitamin D supplement use. Other factors, such as the difference in the ultraviolet radiation index between 2000 and 2011, may partly explain the results. When consuming vitamin D sources based on the nutritional recommendations, vitamin D status is sufficient [S-25(OH)D ≥50 nmol/L], and supplementation is generally not needed.

Successful nutrition policy: improvement of vitamin D intake and status in Finnish adults over the last decade.

Background: Due to vitamin D intake below recommendation (10 µg/day) and low (<50 nmol/l) serum 25-hydroxycholecalciferol (25(OH)D) concentration in Finnish population, the fortification of liquid dairy products with 0.5 µg vitamin D/100 g and fat spreads with 10 µg/100 g started in Finland in December 2002. In 2010, the fortification recommendation was doubled. The aim of this study was to investigate whether the vitamin D intake and status have improved among Finnish adults as a consequence of these nutrition policy actions. A further aim was to study the impact of vitamin supplement use to the total vitamin D intake. Methods: A cross-sectional survey was conducted every 5 years. The National FINDIET Survey was conducted in Finland as part of the National FINRISK health monitoring study. Dietary data were collected by using a computer-assisted 48-h dietary recall. In 2002, dietary data comprised 2007, in 2007, 1575 and 2012, 1295 working aged (25-64 years) Finns. Results: The mean D-vitamin intake increased from 5 µg/day to 17 µg/day in men and from 3 µg/day to 18 µg/day in women from 2002 to 2012. The most important food sources of vitamin D were milk products, fat spreads and fish dishes. The share of milk products was 39% among younger men and 38% among younger women, and 29% among older men and 28% among older women. Fat spreads covered on average 28% of vitamin D intake, except for younger men for which it covered 23%. Fish dishes provided 28% of vitamin D intake for older men and women, and approximately 18% for younger ones. In January-April 2012, the average serum 25-hydroxycholecalciferol (25(OH)D) concentration for men was 63 nmol/l for men and for women 67 nmol/l for women. Conclusions: The fortification of commonly used foods with vitamin D and vitamin D supplementation seems to be an efficient way to increase the vitamin D intake and the vitamin D status in the adult population.

Serum Metabolomic Response to Long-Term Supplementation with all-rac-α-Tocopheryl Acetate in a Randomized Controlled Trial.

Background. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a randomized controlled cancer prevention trial, showed a 32% reduction in prostate cancer incidence in response to vitamin E supplementation. Two other trials were not confirmatory, however. Objective. We compared the change in serum metabolome of the ATBC Study participants randomized to receive vitamin E to those who were not by randomly selecting 50 men from each of the intervention groups (50 mg/day all-rac-α-tocopheryl acetate (ATA), 20 mg/day ß-carotene, both, placebo). Methods. Metabolomic profiling was conducted on baseline and follow-up fasting serum (Metabolon, Inc.). Results. After correction for multiple comparisons, five metabolites were statistically significantly altered (ß is the change in metabolite level expressed as number of standard deviations on the log scale): α-CEHC sulfate (ß = 1.51, p = 1.45 × 10-38), α-CEHC glucuronide (ß = 1.41, p = 1.02 × 10-31), α-tocopherol (ß = 0.97, p = 2.22 × 10-13), γ-tocopherol (ß = -0.90, p = 1.76 × 10-11), and ß-tocopherol (ß = -0.73, p = 9.40 × 10-8). Glutarylcarnitine, beta-alanine, ornithine, and N6-acetyllysine were also decreased by ATA supplementation (ß range 0.40 to -0.36), but not statistically significantly. Conclusions. Comparison of the observed metabolite alterations resulting from ATA supplementation to those in other vitamin E trials of different populations, dosages, or formulations may shed light on the apparently discordant vitamin E-prostate cancer risk findings.

Metabolomics analysis of serum 25-hydroxy-vitamin D in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study.

BACKGROUND: Vitamin D has been discussed in the context of cardiovascular disease, cancer, bone health and other outcomes. Epidemiological studies have reported on the importance of vitamin D in cancer prevention and treatment. The discovery of vitamin D-associated metabolites through agnostic metabolomics analyses offers a new approach for elucidating disease aetiology and health-related pathway identification. METHODS: Baseline serum 25-hydroxy-vitamin D [25(OH)D] and 940 serum metabolites were measured in 392 men from eight nested cancer case-control studies in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish male smokers (aged 50-69 years). The metabolomic profiling was conducted using mass spectrometry. We used linear regression to estimate the standardized beta-coefficient as the effect metric for the associations between metabolites and 25(OH)D levels. RESULTS: A majority of the metabolites associated with 25(OH)D were of lipid origin, including 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) [beta-estimate 0.38 per 1 standard deviation (SD) increment], stearoyl-arachidonoyl-glycerophosphoethanolamine (GPPE) (-0.38 per SD) and two essential fatty acids: eicosapentaenoate (EPA; 0.17 per SD) and docosahexaenoate (DHA; 0.13 per SD). Each of these lipid metabolites was associated with 25(OH)D at the principal components corrected P-value of 3.09 × 10-4 CONCLUSIONS: The large number of metabolites, particularly lipid compounds, found to be associated with serum 25(OH)D provide new biological clues relevant to the role of vitamin D status and human health outcomes. The present findings should be re-examined in other metabolomics studies of diverse populations.

Prospective study of serum cysteine and cysteinylglycine and cancer of the head and neck, esophagus, and stomach in a cohort of male smokers.

BACKGROUND: The nonessential amino acid cysteine is known to be involved in many antioxidant and anticarcinogenic pathways. Cysteinylglycine is a pro-oxidant metabolite of glutathione and a precursor of cysteine. OBJECTIVE: To examine the relation between serum cysteine and cysteinylglycine and risk of gastric adenocarcinomas, esophageal squamous cell carcinomas, and head and neck squamous cell carcinomas, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention study of male Finnish smokers aged 50-69 y at baseline. DESIGN: In total, 170 gastric adenocarcinomas, 68 esophageal squamous cell carcinomas, and 270 head and neck squamous cell carcinomas (identified from the Finnish Cancer Registry) were matched one-to-one with cancer-free control subjects on age and the date of serum collection. We calculated ORs and 95% CIs with the use of a multivariate-adjusted conditional logistic regression. RESULTS: Cysteine had a U-shaped association with gastric adenocarcinomas; a model that included a linear and a squared term had a significant global P-test (P = 0.036). Serum cysteinylglycine was inversely associated with adenocarcinomas of the gastric cardia (OR for above the median compared with below the median: 0.07; 95% CI: 0.01, 0.70; n = 38 cases) but not for other sites. Both cysteine and cysteinylglycine were not associated with esophageal squamous cell carcinoma or head and neck squamous cell carcinoma. CONCLUSIONS: We observed associations between serum cysteine and cysteinylglycine with upper gastrointestinal cancer risk. Future studies are needed to replicate these findings. This trial was registered at clininicaltrials.gov as NCT00342992.

Circulating Folate and Vitamin B12 and Risk of Prostate Cancer: A Collaborative Analysis of Individual Participant Data from Six Cohorts Including 6875 Cases and 8104 Controls.

BACKGROUND: Folate and vitamin B12 are essential for maintaining DNA integrity and may influence prostate cancer (PCa) risk, but the association with clinically relevant, advanced stage, and high-grade disease is unclear. OBJECTIVE: To investigate the associations between circulating folate and vitamin B12 concentrations and risk of PCa overall and by disease stage and grade. DESIGN, SETTING, AND PARTICIPANTS: A study was performed with a nested case-control design based on individual participant data from six cohort studies including 6875 cases and 8104 controls; blood collection from 1981 to 2008, and an average follow-up of 8.9 yr (standard deviation 7.3). Odds ratios (ORs) of incident PCa by study-specific fifths of circulating folate and vitamin B12 were calculated using multivariable adjusted conditional logistic regression. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Incident PCa and subtype by stage and grade. RESULTS AND LIMITATIONS: Higher folate and vitamin B12 concentrations were associated with a small increase in risk of PCa (ORs for the top vs bottom fifths were 1.13 [95% confidence interval (CI), 1.02-1.26], ptrend=0.018, for folate and 1.12 [95% CI, 1.01-1.25], ptrend=0.017, for vitamin B12), with no evidence of heterogeneity between studies. The association with folate varied by tumour grade (pheterogeneity<0.001); higher folate concentration was associated with an elevated risk of high-grade disease (OR for the top vs bottom fifth: 2.30 [95% CI, 1.28-4.12]; ptrend=0.001), with no association for low-grade disease. There was no evidence of heterogeneity in the association of folate with risk by stage or of vitamin B12 with risk by stage or grade of disease (pheterogeneity>0.05). Use of single blood-sample measurements of folate and B12 concentrations is a limitation. CONCLUSIONS: The association between higher folate concentration and risk of high-grade disease, not evident for low-grade disease, suggests a possible role for folate in the progression of clinically relevant PCa and warrants further investigation. PATIENT SUMMARY: Folate, a vitamin obtained from foods and supplements, is important for maintaining cell health. In this study, however, men with higher blood folate levels were at greater risk of high-grade (more aggressive) prostate cancer compared with men with lower folate levels. Further research is needed to investigate the possible role of folate in the progression of this disease.

A healthy Nordic diet and physical performance in old age: findings from the longitudinal Helsinki Birth Cohort Study.

Epidemiological studies have shown that a number of nutrients are associated with better physical performance. However, little is still known about the role of the whole diet, particularly a healthy Nordic diet, in relation to physical performance. Therefore, we examined whether a healthy Nordic diet was associated with measures of physical performance 10 years later. We studied 1072 participants from the Helsinki Birth Cohort Study. Participants' diet was assessed using a validated 128-item FFQ at the mean age of 61 years, and a priori-defined Nordic diet score (NDS) was calculated. The score included Nordic fruits and berries, vegetables, cereals, PUFA:SFA and trans-fatty acids ratio, low-fat milk, fish, red and processed meat, total fat and alcohol. At the mean age of 71 years, participants' physical performance was measured using the Senior Fitness Test (SFT), and an overall SFT score was calculated. Women in the highest fourth of the NDS had on average 5 points higher SFT score compared with those in the lowest fourth (P for trend 0·005). No such association was observed in men. Women with the highest score had 17% better result in the 6-min walk test, 16% better arm curl and 20% better chair stand results compared with those with the lowest score (all P values<0·01). In conclusion, a healthy Nordic diet was associated with better overall physical performance among women and might help decrease the risk of disability in old age.

Higher serum 25-hydroxyvitamin D concentrations are related to a reduced risk of depression.

Vitamin D has been suggested to protect against depression, but epidemiological evidence is scarce. The present study investigated the relationship of serum 25-hydroxyvitamin D (25(OH)D) with the prevalence of depressive and anxiety disorders. The study population consisted of a representative sample of Finnish men and women aged 30-79 years from the Health 2000 Survey. The sample included 5371 individuals, of which 354 were diagnosed with depressive disorder and 222 with anxiety disorder. Serum 25(OH)D concentration was determined from frozen samples. In a cross-sectional study, a total of four indicators of depression and one indicator of anxiety were used as dependent variables. Serum 25(OH)D was the risk factor of interest, and logistic models used further included sociodemographic and lifestyle variables as well as indicators of metabolic health as confounding and/or effect-modifying factors. The population attributable fraction (PAF) was estimated. Individuals with higher serum 25(OH)D concentrations showed a reduced risk of depression. The relative odds between the highest and lowest quartiles was 0.65 (95% CI 0.46, 0.93; P for trend = 0.006) after adjustment for sociodemographic, lifestyle and metabolic factors. Higher serum 25(OH)D concentrations were associated with a lower prevalence of depressive disorder especially among men, younger, divorced and those who had an unhealthy lifestyle or suffered from the metabolic syndrome. The PAF was estimated to be 19% for depression when serum 25(OH)D concentration was at least 50 nmol/l. These results support the hypothesis that higher serum 25(OH)D concentrations protect against depression even after adjustment for a large number of sociodemographic, lifestyle and metabolic factors. Large-scale prospective studies are needed to confirm this finding.

Determinants of serum 25(OH)D concentration in young and middle-aged adults. The Cardiovascular Risk in Young Finns Study.

INTRODUCTION: We studied prevalence of hypovitaminosis D, its determinants, and whether achievement of recommended dietary vitamin D intake (10 µg/d) is associated with absence of hypovitaminosis D in adults. METHODS: The study is part of the Cardiovascular Risk in Young Finns Study. We collected serum samples of 25-hydroxyvitamin D as part of the 27-year follow-up (994 men and 1,210 women aged 30-45 years). Hypovitaminosis was defined as vitamin D concentration ≤ 50 nmol/L. RESULTS: Hypovitaminosis D was found in 38% of men and 34% of women. Dietary vitamin D intake (OR 0.90, 95% CI 0.86-0.93), use of vitamin-mineral supplements (0.66, 0.51-0.85), sunny holiday (0.55, 0.41-0.75), and oral contraceptive use in women (0.45, 0.27-0.75) were independently associated with reduced odds of hypovitaminosis. Increase in body mass index (1.06, 1.03-1.09), being a smoker (1.36, 0.97-1.92), investigation month (December versus other) (1.35, 1.12-1.61), and risk alleles in genotypes rs12785878 (1.31, 1.00-1.70) and rs2282679 (2.08, 1.66-2.60) increased odds of hypovitaminosis. Hypovitaminosis D was common also when recommended dietary intake was obtained (men 29%, women 24%). CONCLUSION: Several factors were associated with hypovitaminosis D. The condition was common even when recommended vitamin D intake was reported. The results support the importance of vitamin D fortification and nutrient supplement use.

Associations between serum 25-hydroxyvitamin d and periodontal pocketing and gingival bleeding: results of a study in a non-smoking population in Finland.

BACKGROUND: Apart from the effects of vitamin D on bone metabolism, it is also known for its immunomodulatory properties. However, so far, it is not clear whether serum 25-hydroxyvitamin D [25(OH)D] exerts any beneficial effect on the periodontium. The aim of the present study is to investigate whether the serum level of 25(OH)D is related to periodontal condition, measured by means of pocketing and gingival bleeding. METHODS: This cross-sectional study is based on a non-smoking subpopulation without diabetes of the Finnish Health 2000 Survey (N = 1,262). Periodontal condition was measured as the number of teeth with deep (≥4 mm) periodontal pockets and the number of bleeding sextants per individual. Serum 25(OH)D level was determined by means of a standard laboratory measurement. Prevalence rate ratios and 95% confidence intervals were estimated using Poisson regression models. RESULTS: There were practically no associations between serum 25(OH)D level and teeth with deep (≥4 mm) periodontal pockets or bleeding sextants. A somewhat lower proportion of teeth with deep periodontal pockets was found in higher serum 25(OH)D quintiles among individuals with a good oral hygiene level. CONCLUSION: Serum 25(OH)D did not seem to be related to periodontal condition, measured as periodontal pocketing and gingival bleeding in this low-risk, low-25(OH)D status population.

Serum phytanic and pristanic acid levels and prostate cancer risk in Finnish smokers.

Phytanic acid is a saturated branched-chain fatty acid found predominantly in red meat and dairy products, and may contribute to the elevated risks of prostate cancer associated with higher consumption of these foods. Pristanic acid is formed during peroxisomal oxidation of phytanic acid, and is the direct substrate of α-Methyl-CoA-Racemase (AMACR)--an enzyme that is consistently overexpressed in prostate tumors relative to benign tissue. We measured phytanic and pristanic acids as percentages of total fatty acids by gas chromatography-mass spectrometry in prediagnostic blood samples from 300 prostate cancer cases and 300 matched controls, all of whom were participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study supplementation trial and follow-up cohort. In addition to providing a fasting blood sample at baseline, all men completed extensive diet, lifestyle, and medical history questionnaires. Among controls, the strongest dietary correlates of serum phytanic and pristanic acids were saturated fat, dairy fat, and butter (r = 0.50 and 0.40, 0.46 and 0.38, and 0.40 and 0.37, respectively; all P-values <0.001). There was no association between serum phytanic acid and risk of total or aggressive prostate cancer in multivariate logistic regression models (for increasing quartiles, odds ratios (OR) and 95% confidence intervals (CI) for aggressive cancer were 1.0 (referent), 1.62 (0.97-2.68), 1.12 (0.66-1.90), and 1.14 (0.67-1.94), P(trend) = 0.87). Pristanic acid was strongly correlated with phytanic acid levels (r = 0.73, P < 0.0001), and was similarly unrelated to prostate cancer risk. Significant interactions between phytanic and pristanic acids and baseline circulating ß-carotene concentrations were noted in relation to total and aggressive disease among participants who did not receive ß-carotene supplements as part of the original ATBC intervention trial. In summary, we observed no overall association between serum phytanic and pristanic acid levels and prostate cancer risk. Findings indicating that the direction and magnitude of these associations depended upon serum levels of the antioxidant ß-carotene among men not taking ß-carotene supplements should be interpreted cautiously, as they are likely due to chance.