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Background: Higher blood levels of a-tocopherol, the predominant form of vitamin E, have been associated in some studies with a reduced risk of lung cancer, but other studies have yielded conflicting results. To clarify this association, we examined the relationship between prospectively collected serum a-tocopherol and lung cancer in the Alpha-Tocopherol, BetaCarotene Cancer Prevention (ATBC) Study cohort. Methods: The ATBC Study was a randomized, clinical trial of 29 133 white male smokers from Finland who were 50‐69 years old and who had received a-tocopherol (50 mg), b-carotene (20 mg), both, or neither daily for 5‐8 years. Data regarding medical histories, smoking, and dietary factors were obtained at study entry, as was a serum specimen for baseline a-tocopherol determination. a-Tocopherol measurements were available for 29 102 of the men, among whom 1144 incident cases of lung cancer were diagnosed during a median observation period of 7.7 years. The association between a-tocopherol and lung cancer was evaluated with the use of multivariate proportional hazards regression. Results: A 19% reduction in lung cancer incidence was observed in the highest versus lowest quintile of serum a-tocopherol (relative risk = 0.81; 95% confidence interval = 0.67‐0.97). There was a stronger inverse association among younger men (

Genetic susceptibility polymorphisms may be of substantial importance in the modulation of cancer risk. The prevalence for an array of polymorphic genes was determined in a cohort of male smokers who participated in a cancer prevention trial in Finland. A random sample of 120 individuals was selected from the trial cohort and the prevalence of variant alleles for nine genes was determined using a polymerase chain reaction-based approach. The prevalence values from this study were also compared with those of other populations derived from previous studies. Our results show that, with the exception of cytochrome P450-1A1 (CYP1A1) and cytochrome P450-2E1 (CYP2E1), all genes tested were sufficiently polymorphic to warrant an investigation of gene-environment studies. Most of the variant alleles, including alcohol dehydrogenase 3 (ADH 3 ), glutathione-S-transferase (GSTM1), methionine synthase (MS), methylene tetrahydofolater reductase (MHTFR), CYP2E1 and CYP1A1, exhibited similar frequencies to other Caucasian populations. Interestingly, the prevalence of androgen receptor-CAG repeat (AR-CAG) and vitamin D receptor (VDR) polymorphisms differed significantly between the alpha-trocopherol, beta-carotene (ATBC) Study and other Caucasian populations. We present herein results from this survey and conclude that the ATBC study population in Finland is sufficiently heterogeneous to facilitate analysis of genetic polymorphisms and disease associations.

Background —Studies on alcohol consumption and incidences of stroke subtypes have suggested distinct dose-response relationships. Blood pressure and HDL cholesterol mediate the effect of alcohol on coronary heart disease, but similar evidence on cerebrovascular diseases is not available. Methods and Results —We studied the risk of stroke in 26 556 male cigarette smokers 50 to 69 years of age without history of stroke. The men were categorized as nondrinkers, light (≤24 g/d), moderate (25 to 60 g/d), or heavy (>60 g/d) drinkers. A total of 960 men suffered from incident stroke: 83 with subarachnoid and 95 with intracerebral hemorrhage, 733 with cerebral infarction, and 49 with unspecified stroke. The adjusted relative risk of subarachnoid hemorrhage was 1.0 in light drinkers, 1.3 in moderate drinkers, and 1.6 in heavy drinkers compared with nondrinkers. The respective relative risks of intracerebral hemorrhage were 0.8, 0.6, and 1.8; of cerebral infarction, 0.9, 1.2, and 1.5. Systolic blood pressure attenuated the effect of alcohol consumption in all subtypes of stroke, whereas HDL cholesterol strengthened the effect of alcohol in subarachnoid hemorrhage and cerebral infarction but attenuated the effect in intracerebral hemorrhage. Conclusions —Alcohol consumption may have a distinct dose-response relationship within each stroke subtype—linear in subarachnoid hemorrhage, U-shaped in intracerebral hemorrhage, and J-shaped in cerebral infarction—but further studies are warranted. Systolic blood pressure and HDL cholesterol seem to mediate the effect of alcohol on stroke incidence, but evidently additional mechanisms are involved.

There is evidence supporting a role for sex hormones in the etiology of prostate cancer. Supplementation with alpha-tocopherol reduced prostate cancer in the alpha-Tocopherol, beta-Carotene Prevention Study (ATBC Study). The objective of this study was to assess the relation of baseline levels of serum alpha-tocopherol and serum sex hormones in older men. A cross-sectional analysis of serum alpha-tocopherol and sex hormone concentrations was conducted within a subset of the ATBC Study. Serum was collected in the morning after an overnight fast at baseline from 204 men ages 50-69 years participating in the ATBC Study and free of prostate cancer. Hormones were measured by radioimmunoassay, and alpha-tocopherol was measured by high-performance liquid chromatography by standard procedures. Multivariate linear regression was used to evaluate the association of serum alpha-tocopherol with nine androgens and estrogens after controlling for age, body mass index, hormone assay batch, and serum cholesterol. Serum alpha-tocopherol was significantly inversely associated with serum androstenedione, testosterone, sex hormone-binding globulin, and estrone. The difference in hormone concentration per milligram of alpha-tocopherol was 1.8-2.6% for these four hormones. These results indicated that alpha-tocopherol is related to concentrations of several sex hormones in older men and may have implications for the observed protective effect of supplemental vitamin E in relation to prostate cancer in the ATBC Study.

High intakes of calcium, potassium, and fluids have been shown to be associated with lowered risk of kidney stones. The authors studied the associations between diet and risk of kidney stones in a cohort of 27,001 Finnish male smokers aged 50-69 years who were initially free of kidney stones. All men participated in the Alpha-Tocopherol, Beta-Carotene Lung Cancer Prevention Study and completed a validated dietary questionnaire at baseline. After 5 years of follow-up (1985-1988), 329 men had been diagnosed with kidney stones. After data were controlled for possible confounders, the relative risk of kidney stones for men in the highest quartile of magnesium intake was 0.52 (95% confidence interval (CI) 0.32-0.85) as compared with men in the lowest quartile. Intake of fiber was directly associated with risk (relative risk (RR) = 2.06, 95% CI 1.39-3.03). Calcium intake was not associated with the risk of kidney stones. Beer consumption was inversely associated with risk of kidney stones; each bottle of beer consumed per day was estimated to reduce risk by 40% (RR = 0.60, 95% CI 0.47-0.76). In conclusion, the authors observed that magnesium intake and beer consumption were inversely associated and fiber intake was directly associated with risk of kidney stones.

Lung cancer is the most common cancer in the world, and smoking is the major risk factor, accounting for about 90% of the cases. Diet has also been implicated in the development of lung cancer, although the specific nutrients remain to be elucidated. Vitamins with antioxidant activity have received much attention. β-Carotene, the most efficient provitamin A, was found to be inversely related to the risk of lung cancer in many prospective epidemiological studies, especially in studies measuring serum concentrations of β-carotene. The findings from controlled trials, however, contradict the hypothesis that β-carotene could prevent lung cancer, but rather suggest increased risk of lung cancer with supplementary β-carotene. Data from both prospective studies and a controlled trial suggest no role for vitamin E in lung carcinogenesis. Some prospective epidemiological studies suggest an inverse relationship between dietary vitamin C and the risk of lung cancer, but due to the high correlation between dietary vitamin C and vegetable and fruit intake the independent role of dietary vitamin C is difficult to estimate. Studies using prediagnostic plasma concentrations of ascorbic acid do not support the involvement of vitamin C in lung carcinogenesis, and no controlled trials of vitamin C on lung cancer have been published. Thus, supplementation with antioxidant vitamins cannot be recommended for the prevention of lung cancer. Non-smoking is the most important target in the prevention of lung cancer. High i ntakes of vegetables and fruits may provide additional protection and are unlikely to be harmful.

The validity of stroke diagnosis in the National Hospital Discharge Register and the Register of Causes of Death was examined among 546 middle-aged men in Finland. The subjects were cases of cerebrovascular diseases of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study and identified by record linkage to the registers. In all, 375 events with cerebrovascular disease as hospital discharge diagnosis and 218 events with cerebrovascular disease as the underlying cause of death were reviewed using specific criteria modified from the classifications of the National Survey of Stroke and the WHO MONICA Study. For hospital stroke diagnoses, there was agreement on diagnosis for all strokes in 90%, for subarachnoid hemorrhage in 79%, intracerebral hemorrhage in 82%, and cerebral infarction in 90%. The respective agreement rates for stroke as the underlying cause of death were 97%, 95%, 91%, and 92%. The data were insufficient for review in 1% and 3% of the stroke events, respectively. Age, observation year and trial supplementation with alphatocopherol or beta-carotene had no effect on validity. In conclusion, the validity of stroke diagnosis was good in registers of hospital diagnoses and causes of death justifying their use for endpoint assessment in epidemiological studies.

Objectives: We evaluated the association between alcohol intake and lung cancer in a trial-based cohort in Finland, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study). Methods: During an average of 7.7 years of follow-up, 1059 lung cancer cases were diagnosed among the 27,111 male smokers with complete alcohol and dietary information. The relationship between alcohol and lung cancer was assessed in multivariate Cox regression models that adjusted for age, smoking, body mass index and intervention group. Results: Nondrinkers, 11% of the study population, were at increased lung cancer risk compared to drinkers (RR = 1.2, 95% CI: 1.0–1.4), possibly due to the inclusion of ex-drinkers who had stopped drinking for health reasons. Among drinkers only, we observed no association between lung cancer and total ethanol or specific beverage (beer, wine, spirits) intake. We found no significant effect modification by level of smoking, dietary micronutrients or trial intervention group; however, for men in the highest quartile of alcohol intake, we observed a slight increase in risk for lighter smokers (>1 pack/day) and reduced risk among the heaviest smokers (

Objectives: Based on previous epidemiological studies, high fat and meat consumption may increase and fiber, calcium, and vegetable consumption may decrease the risk of colorectal cancer. We sought to address these hypotheses in a male Finnish cohort.

Ecologic studies support an inverse association between sunlight exposure and incidence of prostate cancer ([1][1]-[3][2]). Because sun exposure is the major source of human vitamin D production, several authors have hypothesized that the link between reduced prostate cancer incidence and increased

Insulin resistance and hyperinsulinemia have been hypothesized to increase the risk of prostate cancer ([1][1]-[3][2]). Insulin has mitogenic and antiapoptotic activity and may exert these properties directly on prostate epithelial cells ([4][3]). In addition, hyperinsulinemia may affect prostate

Background The prognosis of patients with lung cancer is better when the diagnosis is made early; the disease is localized, and radical surgery is possible. Screening for lung cancer with mass radiography or sputum cytology should contribute to a more favorable prognosis. Large-scale screening studies have improved the survival rates for lung cancer but have yielded no reduction in mortality rates. Methods The histologic types, stages, treatments, and survival rates were studied in 93 men who were found to have lung cancer in a single chest radiograph screening of more than 33,000 men who smoked and were 50 to 69 years old ("screened cases"), and in 239 men of the same age range whose lung cancer was detected through ordinary health care system ("other cases") during the screening period. Results The distribution of the histology was similar in the two groups, but screening detected more instances of early-stage disease that were resectable more often than in the other group (37 vs 19%). The 5-year survival rate for men in the screened cases was 19%, and that of men in the other cases was 10% (relative risk, 0.65; 95% confidence interval [CI], 0.50 to 0.84). The survival rate of men in the screened cases remained significantly higher than that of men in the other cases even after adjustments for age, smoking status, histology, stage of the disease, and resectability of the disease (relative risk, 0.74; 95% CI, 0.55 to 1.00). Conclusions According to this study, chest radiograph screening might improve the prognosis of lung cancer. Our results are, however, subject to many factors that were only partially controlled for, and they should be interpreted cautiously.

OBJECTIVE: To examine the effect of alpha tocopherol and beta carotene supplementation on the incidence of age related cataract extraction. SETTING: The Alpha-tocopherol Beta-carotene (ATBC) Study was a randomised, double blind, placebo controlled, 2 x 2 factorial trial conducted in south western Finland. The cataract surgery study population of 28,934 male smokers 50-69 years of age at the start. INTERVENTION: Random assignment to one of four regimens: alpha tocopherol 50 mg per day, beta carotene 20 mg per day, both alpha tocopherol and beta carotene, or placebo. Follow up continued for five to eight years (median 5.7 years) with a total of 159,199 person years. OUTCOME MEASURE: Cataract extraction, ascertained from the National Hospital Discharge Registry. RESULTS: 425 men had cataract surgery because of senile or presenile cataract during the follow up. Of these, 112 men were in the alpha tocopherol alone group, 112 men in the beta carotene alone group, 96 men in the alpha tocopherol and beta carotene group, and 105 men in the placebo group. When supplementation with alpha tocopherol and with beta carotene were introduced to a Cox proportional hazards model with baseline characteristics (age, education, history of diabetes, body mass index, alcohol consumption, number of cigarettes smoked daily, smoking duration, visual acuity, and total cholesterol), neither alpha tocopherol (relative risk, RR, 0.91, 95% confidence intervals, CI, 0.74, 1.11) nor beta carotene (RR 0.97, 95% CI 0.79, 1.19) supplementation affected the incidence of cataract surgery. CONCLUSION: Supplementation with alpha tocopherol or beta carotene does not affect the incidence of cataract extractions among male smokers.

PURPOSE Animal research and observational studies in man suggest a protective effect of antioxidant vitamins in the development of age-related maculopathy (ARM). METHODS The ATBC study, a population-based, controlled clinical trial of alpha-tocopherol and beta carotene to prevent lung cancer, took place in Finland between 1984 and 1993. Over 29,000 smoking males aged 50 to 69 years were randomly assigned to alpha-tocopherol (AT; 50 mg/day), beta-carotene (BC; 20 mg/day), both of these, or placebo. We performed an end-of-trial ophthalmological examination on a random sample of 941 participants aged 65 years or more from two of the fourteen study areas, to discover if the five to eight-year intervention with alpha-tocopherol and/or beta-carotene had been associated with a difference in ARM prevalence. Age-related maculopathy was assessed using colour photographs of the macula. RESULTS Altogether, 269 cases of ARM were found; there were more cases in the AT group (32%; 75/237), BC group (29%; 68/234), and combined antioxidant group (28%; 73/257) than in the placebo group (25%; 53/213). However, neither substance was significantly associated with the risk of ARM in a logistic regression analysis controlling for possible risk factors. CONCLUSIONS No beneficial effect of long-term supplementation with alpha-tocopherol or beta-carotene on the occurrence of ARM was detected among smoking males.

Abstract —In an attempt to identify genetic factors underlying extreme alterations of serum HDL cholesterol (HDL-C) concentrations, we examined two probands with HDL-C levels 230 Arg (LCAT Fin ) mutation, and the second was homozygous for an Arg 399 Cys mutation we described previously. Transient expression of the mutant LCAT Fin cDNA in COS cells disclosed markedly diminished LCAT enzyme activity. In the low–HDL-C group of men (n=156), 8 carriers of LCAT Fin and 1 carrier of the LCAT Arg 399 Cys were identified. In addition, the frequency of the lipoprotein lipase (LPL) Asn 291 Ser mutation was significantly ( P 230 Arg mutation (LCAT Fin ), which, together with the LPL Asn 291 Ser mutation, represents a relatively common genetic cause of diminishing HDL-C levels, at least among Finns. This article also reports occurrence of a CETP mutation in subjects having non-Japanese roots.

Purpose: To examine if long-term supplementation with alpha-tocopherol (AT) or beta-carotene (BC) was associated with the prevalence of vascular changes in retinal arterioles. Methods: An end-of-trial subsample from a double-blind, placebo-controlled clinical trial designed to study the effects of alpha-tocopherol and beta-carotene on lung cancer incidence (ATBC Study). Setting: Source population of Helsinki and the surrounding province. Participants: 1072 men 50-69 years old and smoking at least 5 cigarettes per day at study entry. Interventions: Random allocation to one of four supplementation regimens: 50 mg per day alpha-tocopherol, 20 mg per day beta-carotene, both alpha-tocopherol and beta-carotene, or placebo. Median follow-up time was 6.6 years (range 5.2-8.0 years). Main outcome measure: Presence of vascular changes in retinal arterioles as determined from end-of-trial retinal color photographs. Results: Retinal vascular changes were most prevalent in the AT (161 men, 62%), and in the BC (163 men, 62%) groups. The prevalence rate was lowest in the AT plus BC group (161 men, 55%), and slightly higher in the placebo group (145 men, 57%). There was no statistically significant association of either AT (OR 0.9, 95% CI 0.7-1.2) or BC (OR 1.0, 95% CI 0.8-1.3) supplementation with the prevalence of retinal vascular changes after adjusting for major risk factors. Conclusions: Supplementation with alpha-tocopherol or beta-carotene for a median of 6.6 years does not protect against retinal vascular changes among smoking males.

Background: Vitamin E and beta-carotene are considered to decrease the risk of gastric cancer both in humans and in laboratory animals. We studied the effect of dietary supplementation with alpha-tocopherol and beta-carotene on the end-of-trial prevalence of premalignant and malignant lesions of the stomach in older men with atrophic gastritis. Methods: The study was carried out within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC study) in Finland, in which 29,133 male smokers aged 50-69 years were randomly assigned to receive daily 50 mg alpha-tocopherol, 20 mg beta-carotene, both of these agents, or placebo, for 5-8 years. Serum pepsinogen was determined at base line and after 3 years' supplementation to find men with atrophic gastritis. A low serum pepsinogen I level, indicating atrophic gastritis of the corpus area of the stomach, was found in 2132 men. These men were invited to have upper gastrointestinal endoscopy (gastroscopy), which was performed on 1344 subjects after a media...

The association between physical activity and prostate cancer was evaluated in the trial-based cohort of the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study (n = 29,133). During up to nine years of follow-up, 317 men developed incident prostate cancer. The relationship between occupational, leisure, and combined activity and prostate cancer was assessed in multivariate Cox regression models that adjusted for intervention group, benign prostatic hyperplasia, age, smoking, and urban residence. Compared with sedentary workers, relative risks (RR) and 95 percent confidence intervals (CI) for occupational walkers, walker/lifters, and heavy laborers were 0.6 (CI = 0.4-1.0), 0.8 (CI = 0.5-1.3), and 1.2 (CI = 0.7-2.0), respectively. Among working men, leisure activity (active cf sedentary) was associated inversely with risk (RR = 0.7, CI = 0.5-0.9). This inverse association for leisure activity was observed, with the exception of heavy laborers, for all occupational activity levels, and was strongest among walkers compared with men sedentary at work and leisure, and to a lesser degree among walker/lifters. These results are consistent with a protective effect of physical activity on prostate cancer.

Dietary factors are widely studied as risk factors for colorectal cancer, with much information from case-control studies. We evaluated the validity of dietary data from a retrospective case-control study of diet and colorectal cancer. As part of the alpha-Tocopherol, beta-Carotene Cancer Prevention Study, diet was assessed at baseline and after diagnosis for colorectal cancer cases and at baseline and regularly during the trial for a random control group. The dietary assessment referred to the previous 12 months (in cases before diagnosis). In the two dietary assessments, the cases reported a greater increase in consumption of fruits and dairy products and a decrease in consumption of potatoes. Accordingly, relative risks for colorectal cancer by baseline dietary data differed markedly from odds ratios from case-control data; e.g., relative risk for a 652-mg increase in calcium intake was 0.79 (95% confidence interval = 0.48-1.30) in case-cohort analysis vs. an odds ratio of 1.57 (95% confidence interval = 1.06-2.33) for case-control analysis. The most likely explanation is the influence of current diet on recall of prediagnosis diet and effects of occult cancer on diet in the year before cancer diagnosis, which have implications for interpretation of case-control studies in evaluating associations between diet and colorectal cancer.

The intake of the mainly plant-derived n-3 PUFA α-linolenic acid (ALA) has been reported to be associated with a lower risk of CHD. However, the results have been inconsistent. Therefore, the objective of the present study was to examine the association between the intake of ALA and the risk of CHD. Potential effect modification by the intake of long-chain n-3 PUFA (n-3 LCPUFA) was also investigated. Data from eight American and European prospective cohort studies including 148 675 women and 80 368 men were used. The outcome measure was incident CHD (CHD event and death). During 4–10 years of follow-up, 4493 CHD events and 1751 CHD deaths occurred. Among men, an inverse association (not significant) between the intake of ALA and the risk of CHD events and deaths was observed. For each additional gram of ALA consumed, a 15 % lower risk of CHD events (hazard ratios (HR) 0·85, 95 % CI 0·72, 1·01) and a 23 % lower risk of CHD deaths (HR 0·77, 95 % CI 0·58, 1·01) were observed. No consistent association was observed among women. No effect modification by the intake of n-3 LCPUFA was observed.

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10 '21), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10 '10), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10 '8) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10 '13 and 3.63 × 10 '11, respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL. © 2014 Nature America, Inc. All rights reserved.

We determined whether serum carotenoid or retinol concentrations were altered by beta-carotene supplementation in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study and whether such effects were modified by alcohol consumption or cigarette use. Participants in this substudy were 491 randomly selected men aged 58-76 y from the metropolitan Helsinki study center [237 receiving supplemental beta-carotene (20 mg/d) and 254 not receiving such supplementation]. Dietary carotenoids, retinol, and alcohol, and serum beta-carotene, alpha-tocopherol, retinol, and cholesterol were assessed at baseline. After an average of 6.7 y of supplementation, serum was collected and carotenoid, retinol, and alpha-tocopherol concentrations were determined by HPLC. Serum carotenoid fractions were highly correlated with each other (Por = 0.0001). Compared with the unsupplemented group, the beta-carotene group had significantly higher serum concentrations of beta-carotene (1483%), alpha-carotene (145%), and beta-cryptoxanthin (67%) (Por = 0.0001). Retinol concentrations were 6% higher (P = 0.03) and lutein was 11% lower (P = 0.02) in the supplemented group. Serum lycopene, zeaxanthin, and alpha-tocopherol did not differ according to beta-carotene-supplementation status. Although these beta-carotene-group differences were not significantly altered by amount of alcohol consumption, higher consumption (12.9 g/d, median) was related to lower (10-38%) concentrations of carotenoids, particularly beta-carotene, alpha-carotene, and beta-cryptoxanthin, in both the supplemented and unsupplemented groups. Smoking status did not significantly influence the supplementation-related differences in serum carotenoid and retinol values but concentrations of carotenoids were generally highest in participants who quit smoking while in the study and lowest in current smokers ofor = 20 cigarettes/d. This study showed that serum concentrations of non-beta-carotene carotenoids are altered by long-term beta-carotene supplementation and confirms the adverse effects of alcohol and cigarette smoking on serum carotenoids.

Summary Background Epidemiological data suggest that the intake of antioxidants such as α-tocopherol (vitamin E) and β-carotene has an inverse correlation with the incidence of coronary heart disease. The results from clinical trials of antioxidant supplementation in people with known coronary heart disease are inconclusive. Methods We studied the frequency of major coronary events in 1862 men enrolled in the Alpha-tocopherol Beta-carotene Cancer Prevention Study (smokers aged between 50 and 69 years) who had a previous myocardial infarction. In this randomised, double-blind, placebo-controlled study, men had received dietary supplements of α-tocopherol (50 mg/day), β-carotene (20 mg/day), both, or placebo. The median follow-up was 5·3 years. The endpoint of this substudy was the first major coronary event after randomisation. Analyses were by intention to treat. Findings 424 major coronary events (non-fatal myocardial infarction and fatal coronary heart disease) occurred during follow-up. There were no significant differences in the number of major coronary events between any supplementation group and the placebo group (α-tocopherol 94/466; β-carotene 113/461; α-tocopherol and β-carotene 123/497; placebo 94/438 [log-rank test, p=0·25]). There were significantly more deaths from fatal coronary heart disease in the β-carotene (74/461, multivariate-adjusted relative risk 1·75 [95% Cl 1·16–2·64], p=0·007) and combined α-tocopherol and β-carotene groups (67/497, relative risk 1·58 [1·05–2·40], p=0·03) than in the placebo group (39/438), but there was no significant increase in the α-tocopherol supplementation group (54/466, relative risk 1·33 [0·86–2·05], p=0·20). Interpretation The proportion of major coronary events in men with a previous myocardial infarction who smoke was not decreased with either α-tocopherol or β-carotene supplements. In fact, the risk of fatal coronary heart disease increased in the groups that received either β-carotene or the combination of α-tocopherol and β-carotene; there was a non-significant trend of increased deaths in the α-tocopherol group. We do not recommend the use of α-tocopherol or β-carotene supplements in this group of patients.

Epidemiological evidence suggests that airway obstruction is an independent risk factor for lung cancer and that this cannot be explained by active or passive smoking alone. Chlamydia pneumoniae infection has been associated with chronic bronchitis and its exacerbates. Our aim was to evaluate the association between chronic C. pneumoniae infection and risk of lung cancer among male smokers. Smoking males with lung cancer (n = 230) and their age- and locality-matched controls were selected among participants of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The presence of C. pneumoniae infection was assessed by analyzing specific antibodies and immune complexes in 2 serum samples collected with a 3-year interval before the lung cancer diagnosis. The diagnosis of chronic infection was based on stable levels of positive specific IgA antibody (titer ≥ 16) and immune complex (titer ≥ 4). Relative risks were estimated by odds ratios (OR) adjusted for age, locality and smoking history by a conditional logistic regression model. Markers suggesting chronic C. pneumoniae infection were present in 52% of cases and 45% of controls and hence were positively associated with the incidence of lung cancer (OR 1.6; 95% confidence interval [CI] 1.0–2.3). The incidence was especially increased in men younger than 60 years (OR 2.9; 95% CI 1.5–5.4) but not in the older age group (OR 0.9; 95% CI 0.5–1.6). Before concluding that C. pneumoniae infection is a new independent risk factor for lung cancer, corroboration from other studies with larger number of cases and longer follow-up is needed. Int. J. Cancer 74:31–34. © 1997 Wiley-Liss, Inc.

SummaryAntibodies against phospholipid-binding plasma proteins, such as β2-glycoprotein I (β2-GPI) and prothrombin, are associated with thromboembolic events in patients with systemic lupus erythematosus and also in subjects with no evident underlying diseases. We wanted to examine whether increased levels of antibodies to negatively-charged phospholipids (cardiolipin), to phospholipid-binding plasma proteins β2-GPI and prothrombin and to oxidised low-density lipoprotein (LDL) were associated with risk of deep venous thrombosis or pulmonary embolism in subjects with no previous thrombosis. The antibodies were measured in stored serum samples from 265 cases of deep venous thrombosis of the lower extremity or pulmonary embolism occurring during a median follow-up of about 7 years and from 265 individually matched controls. The study subjects were middle-aged men participating in a cancer prevention trial of alpha-tocopherol and beta-carotene and the cases of thromboembolic events were identified from nationwide Hospital Discharge Register.The risk for thrombotic events was significantly increased only in relation to antiprothrombin antibodies. As adjusted for body mass index, number of daily cigarettes and history of chronic bronchitis, myocardial infarction and heart failure at baseline, the odds ratio per one unit of antibody was 6.56 (95% confidence interval 1.73-25.0). The seven highest individual optical density-unit values of antiprothrombin antibodies were all confined to subjects with thromboembolic episodes.In conclusion, the present nested case-control study showed that high autoantibody levels against prothrombin implied a risk of deep venous thrombosis and pulmonary embolism and could be involved in the development of the thrombotic processes.

We validated diagnoses of acute myocardial infarction (AMI) and death from coronary heart disease (CHD) found in the Finnish National Hospital Discharge Register and the Register of Causes of Death from a sample of the 29,133 men participating in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The cases were traced to hospitals and institutes performing medico-legal death cause examinations and all relevant information was collected. The cardiac events were re-evaluated according to the diagnostic criteria of the Finnish contribution to the WHO MONICA project, i.e. the FINMONICA criteria. Altogether 408 cases of non-fatal AMI (n = 217) and death from CHD (n = 191) were reviewed. In the re-evaluation 94% of them (95% confidence interval 92-96%) were diagnosed as either definite (57%) or possible (37%) AMI. Non-fatal cases were more often classified definite AMI in the review, whereas fatal cases were more often classified possible AMI. Age or trial supplementation group did not affect classification, and no secular trend was observed. In conclusion, the diagnoses of AMI and death from CHD in the registers were highly predictive of a true major coronary event defined by strict criteria, thus their use in endpoint assessment in epidemiological studies and clinical trials is justified.

Experimental and human epidemiologic data suggest a protective role for vitamin D in large bowel cancer. To investigate this association, we conducted a nested case-control study within a Finnish clinical trial cohort. Cases (n = 146) were participants diagnosed with primary adenocarcinoma of the large bowel. Controls were matched (2:1) to cases on age, date of baseline blood draw, and study clinic. Prediagnostic serum levels of the vitamin D metabolites, 25-hydroxyvitamin D (25-OH D), and 1,25-dihydroxyvitamin D (1,25-DIOH D) were used as primary exposure measures. The baseline geometric-mean serum level of 25-OH D was 11.6 percent lower in cases than in controls (12.2 cf 13.8 ug/l, P = 0.01) while serum levels of 1,25-DIOH D did not differ by case-control status. No association was seen between serum levels of 1,25-DIOH D and large bowel cancer risk. However, the estimated relative risk (RR) of large bowel cancer decreased with increasing level of serum 25-OH D and the association was more pronounced for rectal cancer (55 cases; RR by quartile = 1.00, 0.93, 0.77, 0.37; trend P = 0.06). Neither exclusion of early cases nor multivariate adjustment for potential confounders materially altered these estimates. There was no evidence of effect modification by level of 1,25-dihydroxyvitamin D or with other known risk-factors for large bowel cancer.

Global methylation in blood DNA has been associated with bladder cancer risk in case-control studies, but has not been examined prospectively. We examined the association between LINE1 total percent 5-methylcytosine and bladder cancer risk using pre-diagnostic blood DNA from the United States-based, Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial (PLCO) (299 cases/676 controls), and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) cohort of Finnish male smokers (391 cases/778 controls). Logistic regression adjusted for age at blood draw, study center, pack-years of smoking, and sex was used to estimate odd ratios (ORs) and 95% confidence intervals (CIs) using study- and sex-specific methylation quartiles. In PLCO, higher, although non-significant, bladder cancer risks were observed for participants in the highest three quartiles (Q2-Q4) compared with the lowest quartile (Q1) (OR = 1.36, 95% CI: 0.96 -1.92). The association was stronger in males (Q2-Q4 vs. Q1 OR = 1.48, 95% CI: 1.00-2.20) and statistically significant among male smokers (Q2-Q4 vs. Q1 OR = 1.83, 95% CI: 1.14-2.95). No association was found among females or female smokers. Findings for male smokers were validated in ATBC (Q2-Q4 vs. Q1: OR = 2.31, 95% CI: 1.62-3.30) and a highly significant trend was observed (P = 8.7 × 10(-7)). After determining that study data could be combined, pooled analysis of PLCO and ATBC male smokers (580 cases/1119 controls), ORs were significantly higher in Q2-Q4 compared with Q1 (OR = 2.03, 95% CI: 1.52-2.72), and a trend across quartiles was observed (P = 0.0001). These findings suggest that higher global methylation levels prior to diagnosis may increase bladder cancer risk, particularly among male smokers.

Helicobacter have been detected in human bile and hepatobiliary tissue. Despite evidence that Helicobacter species promote gallstone formation and hepatobiliary tumors in laboratory studies, it remains unclear whether Helicobacter species contribute to these cancers in humans. We used a multiplex panel to assess whether seropositivity to 15 Helicobacter pylori proteins was associated with subsequent incidence of hepatobiliary cancers in the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We included 64 biliary cancers, 122 liver cancers, and 224 age-matched controls which occurred over the course of 22 years. Helicobacter pylori seropositivity was defined as those positive to ≥4 antigens. Odds ratios (OR) and 95% confidence intervals were adjusted for major hepatobiliary cancer risk factors. Among the controls, 88% were seropositive to H. pylori at baseline. Among those who subsequently developed hepatobiliary cancer, the prevalence of seropositivity was higher: 100% for gallbladder cancer, 97% of extrahepatic bile duct cancer, 91% of ampula of Vater cancer, 96% of intrahepatic bile duct cancer, and 94% of hepatocellular carcinoma. Although the OR for gallbladder cancer could not be calculated, the OR for the other sites were 7.01 (95% confidence interval [CI]: 0.79-62.33), 2.21 (0.19-25.52), 10.67 (0.76-150.08), and 1.20 (0.42-3.45), respectively, with an OR of 5.47 (95% CI: 1.17-25.65) observed for the biliary tract cancers combined. ORs above 1 were observed for many of the investigated antigens, although most of these associations were not statistically significant. Conclusion: Seropositivity to H. pylori proteins was associated with an increased risk of biliary tract cancers in ATBC. Further studies are needed to confirm our findings and to determine how H. pylori might influence the risk of biliary tract cancer. (Hepatology 2014;60:1962–1970)

In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study among 29,133 Finnish male smokers aged 50–69 years, daily α-tocopherol (50 mg) for a median of 6.1 years decreased the risk of prostate cancer, whereas β-carotene (20 mg) increased risk of lung cancer and overall mortality. To determine the post-intervention effects of α-tocopherol and β-carotene, 25,563 men were followed 18 years for cancer incidence and all causes of mortality through national registers. Neither supplement had significant effects on post-trial cancer incidence. Relative risk (RR) for lung cancer (n=2,881) was 1.04 (95% confidence interval [CI], 0.96–1.11) among β-carotene recipients compared with nonrecipients. For prostate cancer (n=2,321) RR was 0.97 (95% CI, 0.89–1.05) among α-tocopherol recipients compared with nonrecipients with the preventive effect of α-tocopherol continuing approximately 8 years post-intervention. Body mass index significantly modified the effect of α-tocopherol on prostate cancer (P for interaction=0.01): RR 1.00 (95% CI, 0.88–1.14) in normal-weight men, 0.87 (95% CI, 0.77–0.98) in overweight men, and 1.25 (95% CI, 1.01–1.55) in obese men. The post-trial relative mortality (based on 16,686 deaths) was 1.02 (95% CI, 0.98–1.05) for α-tocopherol recipients compared with nonrecipients and 1.02 (95% CI, 0.99–1.05) for β-carotene recipients compared with nonrecipients. α-Tocopherol decreased post-trial prostate cancer mortality (RR, 0.84; 95% CI, 0.70–0.99), whereas β-carotene increased it (RR, 1.20; 95% CI, 1.01–1.42). In conclusion, supplementation with α-tocopherol and β-carotene appeared to have no late effects on cancer incidence. The preventive effect of moderate-dose α-tocopherol on prostate cancer continued several years post-trial and resulted in lower prostate cancer mortality.

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.

Vitamin D is a steroid prohormone either synthesized in the skin after UV exposure or achieved through supplemental or dietary intake. Although there is strong evidence for its role in maintaining bone and muscle health, there has been recent debate1 about the role of vitamin D deficiency in cardiovascular (CDV) conditions2 based on conflicting results. Cross-sectional studies have consistently shown associations of hypertension with lower 25-hydroxyvitamin D (25(OH)D) baseline levels, but recent findings in large cohorts with measured rather than self-reported blood pressure have not found this association to be persistent over time.3 To our knowledge, there have been no large, well-documented, prospective studies that have investigated measured hypertension and pulse rate (a measure of heart health) over time and compared this concurrently with coronary heart disease (CHD) and diabetes outcomes. As such, we investigated these relationships in a population of Finnish male middle-aged smokers with well-documented lifestyle, dietary, and medical data: the Alpha-Tocopherol and Beta-Carotene (ATBC) study cohort.4 Thus the aims of this study were to investigate the following: The association between baseline 25(OH)D levels and measured blood pressure (systolic blood pressure (SBP) and diastolic blood pressure (DBP)) and pulse rate as well as diabetes and CHD prevalence measured at baseline. These measures were adjusted for confounding by lifestyle, medical conditions, and diet (n = 2,271). The association between baseline 25(OH)D and measured blood pressure, pulse rate, diabetes, and CHD prevalence (n = 1,957) 4 years after baseline, with adjustment for confounding as above. The association between baseline 25(OH)D and change in measured blood pressure levels and pulse rates 4 years after baseline, with adjustment for confounding as above.

We have examined the associations between dietary glycaemic index (GI), substitutions of total, low-, medium- and high-GI carbohydrates for fat and the risk of CHD. The study consisted of 21 955 male smokers, aged 50–69 years, within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The diet was assessed at baseline using a validated FFQ. During a 19-year follow-up, 4379 CHD cases (2377 non-fatal myocardial infarctions and 2002 CHD deaths) were identified from national registers. Relative risks (RR) and CI for CHD were analysed using Cox proportional hazards modelling, and multivariate nutrient density models were applied to examine the associations between the substitutions of macronutrients and the risk of CHD. Dietary GI was inversely associated with CHD risk: multivariate RR in the highest v. lowest quintile was 0·89 (95 % CI 0·81, 0·99). Replacement of higher-GI carbohydrates with lower-GI carbohydrates did not associate with the risk. Replacing saturated and trans-fatty acids with carbohydrates was associated with decreased CHD risk: RR for substitution of 2 % of energy intake was 0·97 (95 % CI 0·94, 0·99). On the contrary, replacing MUFA with carbohydrates was associated with an increased risk: RR for substitution of 2 % of energy intake was 1·08 (95 % CI 1·01, 1·16). We conclude that in the present study population, contrary to the hypothesis, a lower GI does not associate with a decreased risk of CHD. The associations of carbohydrates with CHD risk depend on the fatty acid composition of the diet.

Bladder cancer results from the combined effects of environmental and genetic factors, smoking being the strongest risk factor. Evaluating absolute risks resulting from the joint effects of smoking and genetic factors is critical to assess the public health relevance of genetic information. Analyses included up to 3,942 cases and 5,680 controls of European background in seven studies. We tested for multiplicative and additive interactions between smoking and 12 susceptibility loci, individually and combined as a polygenic risk score (PRS). Thirty-year absolute risks and risk differences by levels of the PRS were estimated for U.S. males aged 50 years. Six of 12 variants showed significant additive gene–environment interactions, most notably NAT2 (P = 7 × 10−4) and UGT1A6 (P = 8 × 10−4). The 30-year absolute risk of bladder cancer in U.S. males was 6.2% for all current smokers. This risk ranged from 2.9% for current smokers in the lowest quartile of the PRS to 9.9% for current smokers in the upper quartile. Risk difference estimates indicated that 8,200 cases would be prevented if elimination of smoking occurred in 100,000 men in the upper PRS quartile compared with 2,000 cases prevented by a similar effort in the lowest PRS quartile (Padditive = 1 × 10−4). Thus, the potential impact of eliminating smoking on the number of bladder cancer cases prevented is larger for individuals at higher than lower genetic risk. Our findings could have implications for targeted prevention strategies. However, other smoking-related diseases, as well as practical and ethical considerations, need to be considered before any recommendations could be made. Cancer Res; 73(7); 2211–20. ©2012 AACR.

Background Even though dietary fiber has been hypothesized to reduce the risk of coronary heart disease, few large epidemiological studies have examined this relation with good methodology. Methods and Results The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study was a randomized, double-blind, placebo-controlled trial with daily supplementation of α-tocopherol and/or beta-carotene. Of the participants, 21 930 smoking men aged 50 to 69 years who were free of diagnosed cardiovascular disease and had completed a validated dietary questionnaire at baseline were followed for 6.1 years. We monitored the incidence of major coronary events (a combination of first nonfatal myocardial infarction and coronary heart disease death; n=1399) and mortality from coronary heart disease (n=635). Both entities had a significant inverse association with dietary fiber, but the association was stronger for coronary death. For men in the highest quintile of total dietary fiber intake (median, 34.8 g/d), the relative risk for coronary death was 0.69 (95% confidence interval, 0.54 to 0.88; P Conclusions These findings suggest that independent of other risk factors, greater intake of foods rich in fiber can substantially reduce the risk of coronary heart disease, and particularly coronary death, in middle-aged, smoking men.

Background Experimental and epidemiologic investigations suggest that alpha-tocopherol (the most prevalent chemical form of vitamin E found in vegetable oils, seeds, grains, nuts, and other foods) and beta-carotene (a plant pigment and major precursor of vitamin A found in many yellow, orange, and dark-green, leafy vegetables and some fruit) might reduce the risk of cancer, particularly lung cancer. The initial findings of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study) indicated, however, that lung cancer incidence was increased among participants who received beta-carotene as a supplement. Similar results were recently reported by the Beta-Carotene and Retinol Efficacy Trial (CARET), which tested a combination of beta-carotene and vitamin A. Purpose We examined the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of lung cancer across subgroups of participants in the ATBC Study defined by base-line characteristics (e.g., age, number of cigarettes smoked, dietary or serum vitamin status, and alcohol consumption), by study compliance, and in relation to clinical factors, such as disease stage and histologic type. Our primary purpose was to determine whether the pattern of intervention effects across subgroups could facilitate further interpretation of the main ATBC Study results and shed light on potential mechanisms of action and relevance to other populations. Methods A total of 29,133 men aged 50-69 years who smoked five or more cigarettes daily were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), alpha-tocopherol and beta-carotene, or a placebo daily for 5-8 years (median, 6.1 years). Data regarding smoking and other risk factors for lung cancer and dietary factors were obtained at study entry, along with measurements of serum levels of alpha-tocopherol and beta-carotene. Incident cases of lung cancer (n = 894) were identified through the Finnish Cancer Registry and death certificates. Each lung cancer diagnosis was independently confirmed, and histology or cytology was available for 94% of the cases. Intervention effects were evaluated by use of survival analysis and proportional hazards models. All P values were derived from two-sided statistical tests. Results No overall effect was observed for lung cancer from alpha-tocopherol supplementation (relative risk [RR] = 0.99; 95% confidence interval [CI] = 0.87-1.13; P = .86, logrank test). beta-Carotene supplementation was associated with increased lung cancer risk (RR = 1.16; 95% CI = 1.02-1.33; P = .02, logrank test). The beta-carotene effect appeared stronger, but not substantially different, in participants who smoked at least 20 cigarettes daily (RR = 1.25; 95% CI = 1.07-1.46) compared with those who smoked five to 19 cigarettes daily (RR = 0.97; 95% CI = 0.76-1.23) and in those with a higher alcohol intake (> or = 11 g of ethanol/day [just under one drink per day]; RR = 1.35; 95% CI = 1.01-1.81) compared with those with a lower intake (RR = 1.03; 95% CI = 0.85-1.24). Conclusions Supplementation with alpha-tocopherol or beta-carotene does not prevent lung cancer in older men who smoke. beta-Carotene supplementation at pharmacologic levels may modestly increase lung cancer incidence in cigarette smokers, and this effect may be associated with heavier smoking and higher alcohol intake. Implications While the most direct way to reduce lung cancer risk is not to smoke tobacco, smokers should avoid high-dose beta-carotene supplementation.

Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups. © 2013 Nature America, Inc. All rights reserved.

Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P = 1.22 × 10-14), 18q21.33 (BCL2, P = 7.76 × 10-11), 11p15.5 (C11orf21, P = 2.15 × 10 -10), 4q25 (LEF1, P = 4.24 × 10-10), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P = 2.50 × 10-9), 9p21.3 (CDKN2B-AS1, P = 1.27 × 10-8), 18q21.32 (PMAIP1, P = 2.51 × 10 -8), 15q15.1 (BMF, P = 2.71 × 10-10) and 2p22.2 (QPCT, P = 1.68 × 10-8), as well as an independent signal at an established locus (2q13, ACOXL, P = 2.08 × 10-18). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P = 5.40 × 10-8) and 5p15.33 (TERT, P = 1.92 × 10-7). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism. © 2013 Nature America, Inc. All rights reserved.

OBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186)), rs10665 with FVII (p = 2.4 × 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57)) and factor VIII (p = 1.2 × 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811). INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.

PurposeDiabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan).MethodsThe pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case-control study design. Subjects who were diagnosed with diabetes near the time (

Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.

Genome-wide association studies (GWASs) of renal cell cancer (RCC) have identified four susceptibility loci thus far. To identify an additional RCC common susceptibility locus, we conducted a GWAS and performed a meta-analysis with published GWASs (totalling 2215 cases and 8566 controls of European background) and followed up the most significant association signals [nine single nucleotide polymorphisms (SNPs) in eight genomic regions] in 3739 cases and 8786 controls. A combined analysis identified a novel susceptibility locus mapping to 2q22.3 marked by rs12105918 (P 5 1.80 3 10 28 ; odds ratio 1.29, 95% CI: 1.18‐1.41). The signal localizes to intron 2 of the ZEB2 gene (zinc finger E box-binding homeobox 2). Our findings suggest that genetic variation in ZEB2 influences the risk of RCC. This finding provides further insights into the genetic and biological basis of inherited genetic susceptibility to RCC.

Background: Iron is an essential micronutrient that can have carcinogenic effects when at high or low concentrations. Previous studies of iron in relation to gastric cancer have not assessed subtype-specific relationships. We used the prospective Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study to assess whether iron metrics were associated with gastric cardia cancer (GCC) and gastric noncardia cancer (GNCC). Methods: We selected 341 incident gastric cancer cases (86 cardia, 172 noncardia, and 83 nonspecified), accrued during 22 years of follow-up, and 341 individually matched controls. We measured prediagnostic serum iron, ferritin, unsaturated iron binding capacity, and C-reactive protein. Total iron-binding capacity (TIBC) and transferrin saturation were estimated from these metrics. Dietary iron exposures were estimated from a food frequency questionnaire. Multivariable logistic regression was used for analysis. Results: Serum iron metrics were not associated with GCC, except for a potential “n”-shaped relationship with TIBC (global P = 0.038). GNCC was inversely associated with serum ferritin (global P = 0.024), serum iron (global P = 0.060) and, possibly, transferrin saturation. TIBC appeared to share a “u”-shaped relationship with GNCC (global P = 0.033). Dietary iron exposures were not associated with either subsite. Adjustment for Helicobacter pylori and gastric atrophy had little effect on observed associations. Conclusions: We found little evidence for the involvement of iron exposure in the pathogenesis of GCC. GNCC was associated with an iron profile similar to that of iron deficiency. Impact: Our findings indicate that inverse associations between iron metrics and gastric cancer are driven by associations with GNCC. Further elucidation of potential mechanisms is warranted. Cancer Epidemiol Biomarkers Prev; 21(11); 2033–42. ©2012 AACR.

Binding of advanced glycation end products (AGEs) to their receptor (RAGE) increases oxidative stress and inflammation, and may be involved in liver injury and subsequent carcinogenesis. Soluble RAGE (sRAGE) may neutralize the effects mediated by AGEs/RAGE complex. Epidemiologic studies examining sRAGE or AGEs in association with liver cancer are lacking. We examined the associations between prediagnostic serum concentrations of sRAGE or Nε-(carboxymethyl)-lysine (CML)-AGE and hepatocellular carcinoma (HCC) in a case-cohort study within a cohort of 29,133 Finnish male smokers who completed questionnaires and provided a fasting blood sample in 1985–1988. During follow-up beginning 5 years after enrollment through April 2006, 145 liver cancers occurred. Serum concentrations of sRAGE, CML-AGE, glucose, and insulin were measured in cases and 485 randomly sampled cohort participants. Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) were available on most cases and a subset of the study population. Weighted Cox proportional hazards regression was used to calculate relative risks (RR) and 95% confidence intervals (CI), adjusted for age, years of smoking, and body mass index. sRAGE and CML-AGE concentrations were inversely associated with liver cancer (sRAGE: RR, highest versus lowest tertile, 0.77; 95% CI, 0.48–1.24; Ptrend=0.28; continuous RR, 0.86; 95% CI, 0.75–0.99; CML-AGE: RR, highest versus lowest tertile, 0.19; 95% CI, 0.10–0.35; Ptrend

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of > 2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 x 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 x 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.

Background and Purpose Epidemiological studies of the associations of low-fat dairy and specific dairy food consumption with risk of stroke are sparse. Our aim was to examine the association between consumption of total, low-fat, full-fat, and specific dairy foods and risk of stroke in a prospective cohort study. Methods We followed 74 961 Swedish women and men who were free from cardiovascular disease and cancer and who completed a 96-item food frequency questionnaire in 1997. Incident cases of stroke were ascertained from the Swedish Hospital Discharge Registry. Results During a mean follow-up of 10.2 years, we ascertained 4089 cases of stroke, including 3159 cerebral infarctions, 583 hemorrhagic strokes, and 347 unspecified strokes. Consumption of low-fat dairy foods was inversely associated with risk of total stroke ( P for trend=0.03) and cerebral infarction ( P for trend=0.03). The multivariable relative risks for the highest compared with the lowest quintile of low-fat dairy consumption were 0.88 (95% CI, 0.80–0.97) for total stroke and 0.87 (95% CI, 0.78–0.98) for cerebral infarction. Consumption of total dairy, full-fat dairy, milk, sour milk/yogurt, cheese, and cream/crème fraiche was not associated with stroke risk. Conclusions These results suggest that low-fat dairy consumption is inversely associated with the risk of stroke.

Purpose Various 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. Methods We 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. Results Overall 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. Conclusion Results 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.

Genome-wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. There is limited information on the mechanistic basis of these associations, particularly about whether they interact with circulating concentrations of growth factors and sex hormones, which may be important in prostate cancer etiology. Using conditional logistic regression, the authors compared per-allele odds ratios for prostate cancer for 39 GWAS-identified SNPs across thirds (tertile groups) of circulating concentrations of insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), testosterone, androstenedione, androstanediol glucuronide, estradiol, and sex hormone-binding globulin (SHBG) for 3,043 cases and 3,478 controls in the Breast and Prostate Cancer Cohort Consortium. After allowing for multiple testing, none of the SNPs examined were significantly associated with growth factor or hormone concentrations, and the SNP-prostate cancer associations did not differ by these concentrations, although 4 interactions were marginally significant (MSMB-rs10993994 with androstenedione (uncorrected P = 0.008); CTBP2-rs4962416 with IGFBP-3 (uncorrected P = 0.003); 11q13.2-rs12418451 with IGF-1 (uncorrected P = 0.006); and 11q13.2-rs10896449 with SHBG (uncorrected P = 0.005)). The authors found no strong evidence that associations between GWAS-identified SNPs and prostate cancer are modified by circulating concentrations of IGF-1, sex hormones, or their major binding proteins.

Genome-wide association studies have identified a SNP, rs2294008, on 8q24.3 within the prostate stem cell antigen ( PSCA ) gene, as a risk factor for bladder cancer. To fine-map this region, we imputed 642 SNPs within 100 Kb of rs2294008 in addition to 33 markers genotyped in one of the reported genome-wide association study in 8,652 subjects. A multivariable logistic regression model adjusted for rs2294008 revealed a unique signal, rs2978974 ( r 2 = 0.02, D′ = 0.19 with rs2294008). In the combined analysis of 5,393 cases and 7,324 controls, we detected a per-allele odds ratio (OR) = 1.11 [95% confidence interval (CI) = 1.06–1.17, P = 5.8 × 10 −5 ] for rs2294008 and OR = 1.07 (95% CI = 1.02–1.13, P = 9.7 × 10 −3 ) for rs2978974. The effect was stronger in carriers of both risk variants (OR = 1.24, 95% CI = 1.08–1.41, P = 1.8 × 10 −3 ) and there was a significant multiplicative interaction ( P = 0.035) between these two SNPs, which requires replication in future studies. The T risk allele of rs2294008 was associated with increased PSCA mRNA expression in two sets of bladder tumor samples ( n = 36, P = 0.0007 and n = 34, P = 0.0054) and in normal bladder samples ( n = 35, P = 0.0155), but rs2978974 was not associated with PSCA expression. SNP rs2978974 is located 10 Kb upstream of rs2294008, within an alternative untranslated first exon of PSCA . The non-risk allele G of rs2978974 showed strong interaction with nuclear proteins from five cell lines tested, implying a regulatory function. In conclusion, a joint effect of two PSCA SNPs, rs2294008 and rs2978974, suggests that both variants may be important for bladder cancer susceptibility, possibly through different mechanisms that influence the control of mRNA expression and interaction with regulatory factors.