Search

Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genomewide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods: GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results: Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions: These data suggest several plausible genetic links between DLBCL and SLE. © 2017 BMJ Publishing Group. All rights reserved.

A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r2 ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09–1.27, P = 4.67 × 10−5] versus OR = 1.01 (95% CI, 0.93–1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (Ptrend = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models. Cancer Res; 74(20); 5808–18. ©2014 AACR.

Background: Recent data suggest the possible benefits of α-tocopherol and β-carotene supplementation on liver cancer and chronic liver disease (CLD), but the long-term trial data are limited. Methods: We evaluated the efficacy of supplemental 50 mg day−1 α-tocopherol and 20 mg day−1 β-carotene on incident liver cancer and CLD mortality in a randomised trial of 29 105 Finnish male smokers, who received supplementation for 5–8 years and were followed for 16 additional years for outcomes. Results: Supplemental α-tocopherol, β-carotene, or both, relative to placebo, did not reduce the risk of liver cancer or CLD, either overall, during the intervention or during the post-intervention period. Conclusions: Long-term supplemental α-tocopherol or β-carotene had no effect on liver cancer or CLD mortality over 24 years of follow-up.

We investigated the relationship between telomere length and lung cancer in a pooled analysis from three prospective cohort studies: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, conducted among men and women in the United States, and previously published data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Trial conducted among male smokers in Finland, and the Shanghai Women's Health Study (SWHS), which is comprised primarily of never-smokers. The pooled population included 847 cases and 847 controls matched by study, age, and sex. Leukocyte telomere length was measured by a monochrome multiplex qPCR assay. We used conditional logistic regression models to calculate ORs and their 95% confidence intervals (CI) for the association between telomere length and lung cancer risk, adjusted for age and pack-years of smoking. Longer telomere length was associated with increased lung cancer risk in the pooled analysis [OR (95% CI) by quartile: 1.00; 1.24 (0.90–1.71); 1.27 (0.91–1.78); and 1.86 (1.33–2.62); P trend = 0.000022]. Findings were consistent across the three cohorts and strongest for subjects with very long telomere length, i.e., lung cancer risks for telomere length [OR (95% CI)] in the upper half of the fourth quartile were 2.41 (1.28–4.52), 2.16 (1.11–4.23), and 3.02(1.39–6.58) for the PLCO trial, the ATBC trial, and the SWHS, respectively. In addition, the association persisted among cases diagnosed more than 6 years after blood collection and was particularly evident for female adenocarcinoma cases. Telomere length in white blood cell DNA may be a biomarker of future increased risk of lung cancer in diverse populations. Cancer Res; 74(15); 4090–8. ©2014 AACR.

Background: In an effort to understand the molecular mechanism behind the association between circulating vitamin D and prostate cancer, we measured relative telomere length and 25(OH)D levels in a cohort of older Finnish men. Methods: Using a nested study design, we examined quantitative PCR measured telomere length, season-adjusted serum 25-hydroxyvitamin D [25(OH)D], and subsequent prostate cancer risk in 1000 men (n=500 cases, 500 matched controls) participating in the extension study of the Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) Trial. Conditional regression models were used to explore mediation and effect modification of telomere length on the relation between serum 25(OH)D and prostate cancer risk. Results: An increased risk of prostate cancer was observed among men with longer (>median) relative telomere length (OR = 1.41, 95% CI: 1.06 to 1.90; continuous: OR = 2.36, 95%CI: 0.96 to 5.83) as well as men with higher 25(OH)D concentrations (OR = 1.67, 95% CI: 1.08 to 2.57 for highest vs. lowest quintile, P-trend = 0.03). No significant association between 25(OH)D levels and telomere length was observed. A suggested joint effect of 25(OH)D and telomere length on prostate cancer risk was observed. Conclusion: Serum 25(OH)D and relative telomere length are independent predictors of prostate cancer risk in this sample of older male Finnish smokers. No evidence of mediation between circulating vitamin D concentrations and telomere length was observed. Future studies are needed to further clarify the underlying biologic mechanisms of the 25(OH)D-prostate cancer association. Citation Format: Jacqueline M. Major, Barry I. Graubard, Stephanie J. Weinstein, Jeeyun Kim, Immaculata De Vivo, Jarmo Virtamo, Sharon A. Savage, Demetrius Albanes. Understanding the mechanism underlying vitamin D and prostate cancer: Exploring telomere length [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-172.

Objectives. We investigated associations of smoking and coronary heart disease (CHD) by age. Methods. Data came from the Pooling Project on Diet and Coronary Heart Disease (8 prospective studies, 1974–1996; n = 192 067 women and 74 720 men, aged 40–89 years). Results. During follow-up, 4326 cases of CHD were reported. Relative to never smokers, CHD risk among current smokers was highest in the youngest and lowest in the oldest participants. For example, among women aged 40 to 49 years the hazard ratio was 8.5 (95% confidence interval [CI] = 5.0, 14) and 3.1 (95% CI = 2.0, 4.9) among those aged 70 years or older. The largest absolute risk differences between current smokers and never smokers were observed among the oldest participants. Finally, the majority of CHD cases among smokers were attributable to smoking. For example, attributable proportions of CHD by age group were 88% (40-49 years), 81% (50-59 years), 71% for (60-69 years), and 68% (≥ 70 years) among women who smoked. Conclusions. Among smokers, the majority of CHD cases are attributable to smoking in all age groups. Smoking prevention is important, irrespective of age.

Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

Background: Two chemoprevention trials found that supplementation with b-carotene increased the risk of lung cancer and overall mortality. The biologic basis of these findings remains poorly understood. Objective: The objective was to compare the on-study change in metabolomic profiles of men randomly assigned to receive or not receive b-carotene supplements in the Alpha-Tocopherol, BetaCarotene Cancer Prevention (ATBC) Study. Design: The ATBC Study was a randomized, double-blind, placebo-controlled, primary cancer prevention trial; participants were Finnish male smokers assigned to 1 of 4 intervention groups: 1) a-tocopherol, 2) b-carotene, 3) both, or 4) placebo. Fifty participants with both baseline and follow-up fasting serum samples were randomly selected from each of these groups. Metabolomic profiling was conducted by mass spectrometry. The association between change in each metabolite over time and trial assignment (b-carotene or no b-carotene) was estimated by linear regression. Results: We measured 489 metabolites, and 17 changed significantly (P , 0.05) in response to b-carotene supplementation. More of these 17 metabolites were of xenobiotic origin than would be expected by chance (9 of 60, or 15%; P = 0.00004). We also found a suggestive association with 1,5-anhydroglucitol—a marker of glycemic control (b = 20.379, P = 0.0071). Conclusions: Male smokers supplemented with b-carotene developed metabolomic profiles consistent with the induction of cytochrome P450 enzymes, the primary metabolizers of xenobiotics in humans. These findings may shed light on the increased mortality associated with b-carotene supplementation in the ATBC Study and suggest the need to explore potential interactions between medication use and dietary supplements, particularly among smokers. This trial was registered at clinicaltrials.gov as NCT00342992. Am J Clin Nutr 2013;98:488‐93.

Background: Coffee intake is associated with reduced risk of liver cancer and chronic liver disease as reported in previous studies, including prospective ones conducted in Asian populations where hepatitis B viruses (HBVs) and hepatitis C viruses (HCVs) are the dominant risk factors. Yet, prospective studies in Western populations with lower HBV and HCV prevalence are sparse. Also, although preparation methods affect coffee constituents, it is unknown whether different methods affect disease associations. Methods: We evaluated the association of coffee intake with incident liver cancer and chronic liver disease mortality in 27 037 Finnish male smokers, aged 50–69, in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, who recorded their coffee consumption and were followed up to 24 years for incident liver cancer or chronic liver disease mortality. Multivariate relative risks (RRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazard models. Results: Coffee intake was inversely associated with incident liver cancer (RR per cup per day=0.82, 95% CI: 0.73–0.93; P-trend across categories=0.0007) and mortality from chronic liver disease (RR=0.55, 95% CI: 0.48–0.63; P-trend

Background: Solar ultraviolet radiation exposure has been inversely related to prostate cancer incidence and mortality, possibly mediated through vitamin D status. Pigmentation-related traits influence endogenous vitamin D synthesis and may alter risk of prostate cancer. Methods: We examined prostate cancer in relation to hair and eye colour, and skin phototype in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Incident cancer was diagnosed in 1982 out of 20 863 men. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazards models. Results: Prostate cancer risk did not differ by eye colour or skin phototype. Men with naturally red hair were significantly less likely to develop prostate cancer (HR=0.46, 95% CI 0.24–0.89) than men with light brown hair (reference). Conclusion: The red hair phenotype, which results from polymorphisms in the melanocortin-1-receptor (MC1R) gene, is associated with lower risk of prostate cancer. This pigmentation-related trait may influence prostate cancer development either directly, through genetic effects or regulatory mechanisms related to MC1R, another nearby gene, or other pigmentation genes, or indirectly, through associations with other exposures such as sunlight or vitamin D status.

Background Fruit and vegetables is a heterogeneous food group with different content of dietary fiber, vitamins, minerals, carotenoids, and bioactive phytochemicals. Our objective was to examine the relation between specific consumption of fruit and vegetable subgroups and stroke risk in a cohort of Swedish women and men. Methods and results We prospectively followed 74,961 participants (34,670 women and 40,291 men) who had completed a food frequency questionnaire in the autumn of 1997 and were free from stroke, coronary heart disease, and cancer at baseline. Diagnoses of stroke in the cohort during follow-up were ascertained from the Swedish Hospital Discharge Registry. A total of 4089 stroke cases, including 3159 cerebral infarctions, 435 intracerebral hemorrhages, 148 subarachnoid hemorrhages, and 347 unspecified strokes, were ascertained during 10.2 years of follow-up. The multivariable relative risk (RR) of total stroke for the highest vs. lowest category of total fruit and vegetable consumption was 0.87 (95% confidence interval [CI] 0.78–0.97; P for trend = 0.01). The association was confined to individuals without hypertension (corresponding RR, 0.81; 95% CI, 0.71–0.93; P for trend = 0.01). Among individual fruits and vegetable subgroups, inverse associations with total stroke were observed for apples/pears (RR, 0.89; 95% CI, 0.80–0.98; P for trend = 0.02) and green leafy vegetables (RR, 0.92; 95% CI, 0.81–1.04; P for trend = 0.03). Conclusion This study shows an inverse association of fruit and vegetable consumption with stroke risk. Particularly consumption of apples and pears and green leafy vegetables was inversely associated with stroke.

Purpose Our aim was examine the association between black tea consumption and risk of total stroke and stroke types in a prospective study. Methods A total of 74,961 Swedish women and men who were free of cardiovascular disease and cancer at baseline in 1997 were followed up through December 2008. Tea consumption was assessed with a questionnaire at baseline. Stroke cases were ascertained from the Swedish Hospital Discharge Registry. Results During a mean follow-up of 10.2 years, we ascertained 4089 cases of first stroke, including 3159 cerebral infarctions, 435 intracerebral hemorrhages, 148 subarachnoid hemorrhages, and 347 unspecified strokes. After adjustment for other risk factors, high tea consumption was associated with a significantly lower risk of total stroke; however, there was no dose–response relation (P for trend = .36). Compared with no tea consumption, the multivariable relative risk for four or more cups per day (median, 5) was 0.79 (95% confidence interval [CI], 0.62–0.998). The corresponding relative risks were 0.80 (95% CI, 0.61–1.04) for cerebral infarction and 0.68 (95% CI, 0.35–1.30) for hemorrhagic stroke. Conclusions These findings suggest that daily consumption of four or more cups of black tea is inversely associated with risk of stroke.

It has been hypothesized that a high intake of dairy protein may increase prostate cancer risk by increasing the production of insulin-like growth factor 1 (IGF-1). Several single nucleotide polymo ...

We screened DNA sequence variants on an exome-focused genotyping array in >300,000 participants with replication in >280,000 participants and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice revealed lipid changes consistent with the human data. We utilized mapped variants to address four clinically relevant questions and found the following: (1) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease; (2) outside of the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (3) only some mechanisms of lowering LDL-C seemed to increase risk for type 2 diabetes; and (4) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (e.g., TM6SF2, PNPLA3) tracked with higher liver fat, higher risk for type 2 diabetes, and lower risk for coronary artery disease whereas TG-lowering alleles involved in peripheral lipolysis (e.g., LPL, ANGPTL4) had no effect on liver fat but lowered risks for both type 2 diabetes and coronary artery disease.

There are no observational studies or controlled trials of amyotrophic lateral sclerosis (ALS) and circulating α-tocopherol (vitamin E) for prevention of ALS. This study addresses that gap. The study population comprised 29,127 Finnish male smokers, aged 50-69 years, who participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, which is both a prospective cohort and a randomized, double-blind, placebo-controlled trial of α-tocopherol (50 mg/day) and β-carotene (20 mg/day). Serum α-tocopherol and β-carotene was assayed at baseline (1985 - 1988). Follow-up (median 16.7 years) continued through 2004. ALS cases were identified through the national Hospital Discharge Register with diagnostic verification by hospital records and death certificates. During 407,260 person-years of follow-up, 50 men were identified with ALS. For males with serum α-tocopherol concentration above the median (≥ 11.6 mg/l), the age-adjusted relative risk (RR) compared to α-tocopherol below the median, was 0.56 (95% confidence interval 0.32 - 0.99), p = 0.046. The RR among α-tocopherol supplement recipients was 0.75 (95% CI 0.32 - 1.79), p = 0.52. Neither serum β-carotene level nor β-carotene supplementation was associated with ALS. In conclusion, the results are consistent with a hypothesized protective effect of α-tocopherol on ALS risk. However, pooled analyses of cohorts with serum and controlled trials are needed to clarify the role of α-tocopherol in ALS risk.

We report a genome-wide association study in 10,286 cases and 9,135 controls of European ancestry, in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative, identifying a new association with prostate cancer risk on chromosome 8q24 (rs620861, p=1.3×10-10, heterozygote OR = 1.17, 95% CI 1.10 – 1.24; homozygote OR = 1.33; 95% CI 1.21 – 1.45). This defines a new prostate locus on 8q24, Region 4, previously associated with breast cancer.

Background: One of the goals of personalized medicine is to generate individual risk profiles that could identify individuals in the population that exhibit high risk. The discovery of more than two-dozen independent single-nucleotide polymorphism markers in prostate cancer has raised the possibility for such risk stratification. In this study, we evaluated the discriminative and predictive ability for prostate cancer risk models incorporating 25 common prostate cancer genetic markers, family history of prostate cancer, and age. Methods: We fit a series of risk models and estimated their performance in 7,509 prostate cancer cases and 7,652 controls within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). We also calculated absolute risks based on SEER incidence data. Results: The best risk model (C-statistic = 0.642) included individual genetic markers and family history of prostate cancer. We observed a decreasing trend in discriminative ability with advancing age (P = 0.009), with highest accuracy in men younger than 60 years (C-statistic = 0.679). The absolute ten-year risk for 50-year-old men with a family history ranged from 1.6% (10th percentile of genetic risk) to 6.7% (90th percentile of genetic risk). For men without family history, the risk ranged from 0.8% (10th percentile) to 3.4% (90th percentile). Conclusions: Our results indicate that incorporating genetic information and family history in prostate cancer risk models can be particularly useful for identifying younger men that might benefit from prostate-specific antigen screening. Impact: Although adding genetic risk markers improves model performance, the clinical utility of these genetic risk models is limited. Cancer Epidemiol Biomarkers Prev; 21(3); 437–44. ©2012 AACR.

Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10 -20) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10 -11) near ETS1; 3q28 (rs6444305, p = 1.10 × 10 -10) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10 -10) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10 -8) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRß1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10 -67 to 2.67 × 10 -70). Additional independent signals included rs17203612 in HLA class II (odds ratio [ORper-allele] = 1.44; p = 4.59 × 10 -16) and rs3130437 in HLA class I (ORper-allele = 1.23; p = 8.23 × 10 -9). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk. © 2014 by The American Society of Human Genetics. All rights reserved.

Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.

International audience; Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 x 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 x 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk

Insulin-like growth factor-1 (IGF-1), insulin, and IL-6 are dysregulated in multiple myeloma pathogenesis and may also contribute to multiple myeloma etiology. To examine their etiologic role, we prospectively analyzed concentrations of serologic markers in 493 multiple myeloma cases and 978 controls from 8 cohorts in the Multiple Myeloma Cohort Consortium. We computed odds ratios (ORs) and 95% confidence intervals (CIs) for multiple myeloma per 1-SD increase in biomarker concentration using conditional logistic regression. We examined heterogeneity by time since blood collection (≤ 3, 4- ≤ 6, and > 6 years) in stratified models. Fasting IGF binding protein-1 concentration was associated with multiple myeloma risk within 3 years (OR, 95% CI per 1-SD increase: 2.3, 1.4-3.8, P = .001) and soluble IL-6 receptor level was associated within 6 years after blood draw (OR ≤ 3 years, 95% CI, 1.4, 1.1-1.9, P = .01; OR4- ≤ 6 years, 95% CI, 1.4, 1.1-1.7, P = .002). No biomarker was associated with longer-term multiple myeloma risk (ie, > 6 years). Interactions with time were statistically significant (IGF binding protein-1, P-heterogeneity = .0016; sIL6R, P-heterogeneity = .016). The time-restricted associations probably reflect the bioactivity of tumor and microenvironment cells in transformation from monoclonal gammopathy of undetermined significance or smoldering multiple myeloma to clinically manifest multiple myeloma.

Background: There is little research investigating the role of vitamin D binding protein (DBP) in the association between 25-hydroxyvitamin D (25(OH)D) and disease risk. Methods: Within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, 250 bladder cancer cases were randomly sampled and matched 1:1 to controls on age and date of blood collection. Odds ratios (OR) and 95% confidence intervals (CI) of bladder cancer were estimated by quartiles of DBP (measured by ELISA), 25(OH)D and the molar ratio of 25(OH)D:DBP, a proxy for free circulating 25(OH)D. Analyses were also conducted stratifying 25(OH)D by DBP (median split) and vice versa. Results: We found no direct association between circulating DBP levels and bladder cancer risk (P-trend=0.83). The inverse association between 25(OH)D and bladder cancer risk was unchanged after adjustment for DBP (Q4 vs Q1 OR=0.61, 95% CI=0.36–1.05; P-trend=0.04), and was stronger among men with lower DBP (low DBP: 25(OH)D Q4 vs Q1 OR=0.47, 95% CI=0.23–1.00; high DBP: 25(OH)D Q4 vs Q1 OR=0.83, 95% CI=0.40–1.75; P for interaction=0.11). Conclusion: Our findings provide additional support for an aetiologic role for vitamin D in bladder cancer and suggest that free, rather than total, circulating vitamin D may be a more relevant exposure when examining bladder and, perhaps, other cancers.

Background A high protein intake may reduce the risk of stroke but epidemiologic data on protein intake in relation to stroke risk are limited and inconsistent. Our objective was to test the hypothesis that protein intake would be inversely associated with risk of stroke. Methods and results We conducted a population-based prospective cohort study consisting of 34,670 Swedish women who were free of cardiovascular disease and cancer in 1997. Diet was assessed with a food-frequency questionnaire. Incident cases of stroke were ascertained from the Swedish Hospital Discharge Registry. We estimated relative risks (RR) with 95% confidence intervals (CI) using Cox proportional hazard regression model. During 10.4 years of follow-up, 1680 stroke events were identified, including 1310 cerebral infarctions, 154 intracerebral hemorrhages, 79 subarachnoid hemorrhages, and 137 unspecified strokes. Intake of total and animal protein, but not vegetable protein, was statistically significantly inversely associated with risk of total stroke and cerebral infarction after adjustment for other risk factors for stroke. The multivariable RRs of total stroke for the highest versus lowest quintile of intake were 0.74 (95% CI: 0.61, 0.91; P for trend = 0.006) for total protein and 0.71 (95% CI: 0.57, 0.88; P for trend = 0.01) for animal protein. The associations were stronger in women with a history of hypertension (RR of total stroke = 0.56; 95% CI: 0.40, 0.78 for highest versus lowest quintile of total protein). Conclusion These findings suggest that dietary protein intake is inversely associated with risk of stroke in women with hypertension.

Objective: To investigate the association between chocolate consumption and risk of stroke in men and conduct a meta-analysis to summarize available evidence from prospective studies of chocolate consumption and stroke. Methods: We prospectively followed 37,103 men in the Cohort of Swedish Men. Chocolate consumption was assessed at baseline using a food-frequency questionnaire. Cases of first stroke were ascertained from the Swedish Hospital Discharge Registry. For the meta-analysis, pertinent studies were identified by searching the PubMed and EMBASE databases through January 13, 2012. Study-specific results were combined using a random-effects model. Results: During 10.2 years of follow-up, we ascertained 1,995 incident stroke cases, including 1,511 cerebral infarctions, 321 hemorrhagic strokes, and 163 unspecified strokes. High chocolate consumption was associated with a lower risk of stroke. The multivariable relative risk of stroke comparing the highest quartile of chocolate consumption (median 62.9 g/week) with the lowest quartile (median 0 g/week) was 0.83 (95 % CI 0.70–0.99). The association did not differ by stroke subtypes. In a meta-analysis of 5 studies, with a total of 4,260 stroke cases, the overall relative risk of stroke for the highest vs lowest category of chocolate consumption was 0.81 (95% CI 0.73–0.90), without heterogeneity among studies ( p = 0.47). Conclusion: These findings suggest that moderate chocolate consumption may lower the risk of stroke.

Background: Moderate alcohol consumption associates with lower risk of type 2 diabetes, but in postprandial studies, alcohol induced impaired insulin sensitivity. The measurement of the glycemic index (GI) for beer has been considered challenging because of its low carbohydrate content. Therefore, imputed GI values from 36 to 95 on the basis of carbohydrate-rich beverages have been used for beer in epidemiologic studies. Objectives: We investigated the acute effects of alcohol on glucose and insulin responses and measured GIs and insulinemic indexes (IIs) of nonalcoholic and alcoholic beers. Design: In a crossover design, 10 healthy volunteers were served beer with 4.5% alcohol by volume, nonalcoholic beer, and a glucose solution with alcohol once and the reference glucose solution twice. Each portion contained 25 g available carbohydrate, and the beer and glucose solution with alcohol contained 21 g alcohol. Capillary blood samples were collected up to 2 h postprandial, and the incremental AUCs (IAUCs), GIs, and IIs were calculated. Results: Compared with the reference glucose solution, the glucose solution with alcohol produced an 18% higher postprandial glucose IAUC (P = 0.03) and had no significant effect on the insulin IAUC. Compared with the reference glucose solution, beer had no significant effect on glucose or insulin IAUCs, and nonalcoholic beer tended to reduce the glucose IAUC (P = 0.06) but not the insulin IAUC. GIs of beer and nonalcoholic beer were 119 and 80, and IIs were 130 and 88, respectively. Conclusions: Alcohol increases the postprandial glucose response, probably through impaired insulin sensitivity. GI values published for alcohol-containing beers have underestimated the true glycemic effects. This trial was registered at clinicaltrials.gov as NCT01477216. Am J Clin Nutr doi: 10.3945/ajcn.111.031682.

Vitamin E inhibits lipid peroxidation in cell membranes, prevents oxidative damage to DNA by scavenging free radicals, and reduces carcinogen production. No study to our knowledge, however, has examined the association between genetic variants and response to long-term vitamin E supplementation. We conducted a genome-wide association study (GWAS) of common variants associated with circulating α-tocopherol concentrations following 3 y of controlled supplementation. The study population included 2112 middle-aged, male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort who received a trial supplementation of α-tocopherol (50 mg/d) and had fasting serum α-tocopherol concentrations measured after 3 y. Serum concentrations were log-transformed for statistical analysis and general linear models adjusted for age, BMI, serum total cholesterol, and cancer case status. Associations with serum response to α-tocopherol supplementation achieved genome-wide significance for 2 single nucleotide polymorphisms (SNP): rs964184 on 11q23.3 (P = 2.6 × 10(-12)) and rs2108622 on 19pter-p13.11 (P = 2.2 × 10(-7)), and approached genome-wide significance for one SNP, rs7834588 on 8q12.3 (P = 6.2 × 10(-7)). Combined, these SNP explain 3.4% of the residual variance in serum α-tocopherol concentrations during controlled vitamin E supplementation. A GWAS has identified 3 genetic variants at different loci that appear associated with serum concentrations after vitamin E supplementation in men. Identifying genetic variants that influence serum nutrient biochemical status (e.g., α-tocopherol) under supplementation conditions improves our understanding of the biological determinants of these nutritional exposures and their associations with cancer etiology.

Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic cancer cases and 3934 control participants pooled from 12 cohort studies and 8 case-control studies (PanScan). We compiled 23 biological pathways hypothesized to be relevant to pancreatic cancer and observed a nominal association between pancreatic cancer and five pathways (P < 0.05), i.e. pancreatic development, Helicobacter pylori lacto/neolacto, hedgehog, Th1/Th2 immune response and apoptosis (P = 2.0 × 10(-6), 1.6 × 10(-5), 0.0019, 0.019 and 0.023, respectively). After excluding previously identified genes from the original GWAS in three pathways (NR5A2, ABO and SHH), the pancreatic development pathway remained significant (P = 8.3 × 10(-5)), whereas the others did not. The most significant genes (P < 0.01) in the five pathways were NR5A2, HNF1A, HNF4G and PDX1 for pancreatic development; ABO for H.pylori lacto/neolacto; SHH for hedgehog; TGFBR2 and CCL18 for Th1/Th2 immune response and MAPK8 and BCL2L11 for apoptosis. Our results provide a link between inherited variation in genes important for pancreatic development and cancer and show that pathway-based approaches to analysis of GWAS data can yield important insights into the collective role of genetic risk variants in cancer.

Background Whether intakes of dietary fat and cholesterol are associated with risk of stroke remain unclear. We examined the associations between intakes of total fat, specific types of fat, and cholesterol and risk of stroke in a prospective cohort of women. Methods The study population consisted of 34,670 women, aged 49–83 years, in the Swedish Mammography Cohort who were free of cardiovascular disease and completed a food-frequency questionnaire in 1997. Cox proportional hazard regression models were used to estimate relative risks (RR) with 95% confidence intervals (CI). Results During a mean follow-up of 10.4 years, we ascertained 1680 stroke events, including 1310 cerebral infarctions, 233 hemorrhagic strokes, and 137 unspecified strokes. After adjustment for other stroke risk factors, intake of long-chain omega-3 polyunsaturated fatty acids (PUFA) was inversely associated with risk of total stroke. The multivariable RR of total stroke for the highest compared with the lowest quintile of long-chain omega-3 PUFA intake was 0.84 (95% CI, 0.72–0.99; P for trend=0.04). Dietary cholesterol was positively associated with risk of total stroke (highest versus lowest quintile: RR=1.20; 95% CI, 1.00–1.44; P for trend=0.01) and cerebral infarction (corresponding RR=1.29; 95% CI, 1.05–1.58; P for trend=0.004). Total fat, saturated fat, monounsaturated fat, polyunsaturated fat, α-linolenic acid, and omega-6 PUFA intakes were not associated with stroke. Conclusions These findings suggest that intake of long-chain omega-3 PUFAs is inversely associated with risk of stroke, whereas dietary cholesterol is positively associated with risk.

Background and Purpose— Consumption of antioxidant-rich foods may reduce the risk of stroke by inhibition of oxidative stress and inflammation. Total antioxidant capacity (TAC) takes into account all antioxidants and the synergistic effects between them. We examined the association between dietary TAC and stroke incidence in cardiovascular disease (CVD)-free women and in women with CVD history at baseline. Methods— The study included women (31 035 CVD-free and 5680 with CVD history at baseline), aged 49 to 83 years, from the Swedish Mammography Cohort. Diet was assessed with a food frequency questionnaire. Dietary TAC was calculated using oxygen radical absorbance capacity values. Stroke cases were ascertained by linkage with the Swedish Hospital Discharge Registry. Results— During follow-up (September 1997 to December 2009), we identified 1322 stroke cases (988 cerebral infarctions, 226 hemorrhagic strokes, and 108 unspecified strokes) among CVD-free women and 1007 stroke cases (796 cerebral infarctions, 100 hemorrhagic strokes, and 111 unspecified strokes) among women with a CVD history. The multivariable hazard ratio of total stroke comparing the highest with the lowest quintile of dietary TAC was 0.83 (95% CI, 0.70–0.99; P for trend=0.04) in CVD-free women. Among women with a CVD history, the hazard ratios for the highest versus lowest quartile of TAC were 0.90 (95% CI, 0.75–1.07; P for trend=0.30) for total stroke and 0.55 (95% CI, 0.32–0.95; P for trend=0.03) for hemorrhagic stroke. Conclusions— These findings suggest that dietary TAC is inversely associated with total stroke among CVD-free women and hemorrhagic stroke among women with CVD history.

Genetic variation on the Y chromosome has not been convincingly implicated in prostate cancer risk. To comprehensively analyze the role of inherited Y chromosome variation in prostate cancer risk in individuals of European ancestry, we genotyped 34 binary Y chromosome markers in 3,995 prostate cancer cases and 3,815 control subjects drawn from four studies. In this set, we identified nominally significant association between a rare haplogroup, E1b1b1c, and prostate cancer in stage I (P = 0.012, OR = 0.51; 95% confidence interval 0.30–0.87). Population substructure of E1b1b1c carriers suggested Ashkenazi Jewish ancestry, prompting a replication phase in individuals of both European and Ashkenazi Jewish ancestry. The association was not significant for prostate cancer overall in studies of either Ashkenazi Jewish (1,686 cases and 1,597 control subjects) or European (686 cases and 734 control subjects) ancestry (Pmeta = 0.078), but a meta-analysis of stage I and II studies revealed a nominally significant association with prostate cancer risk (Pmeta = 0.010, OR = 0.77; 95% confidence interval 0.62–0.94). Comparing haplogroup frequencies between studies, we noted strong similarities between those conducted in the US and France, in which the majority of men carried R1 haplogroups, resembling Northwestern European populations. On the other hand, Finns had a remarkably different haplogroup distribution with a preponderance of N1c and I1 haplogroups. In summary, our results suggest that inherited Y chromosome variation plays a limited role in prostate cancer etiology in European populations but warrant follow-up in additional large and well characterized studies of multiple ethnic backgrounds. Electronic supplementary material The online version of this article (doi:10.1007/s00439-012-1139-5) contains supplementary material, which is available to authorized users.

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r 2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways. © 2013 Nature America, Inc. All rights reserved.

Background Gastric atrophy, as determined by a low serum pepsinogen I:II ratio, may be associated with an increased risk of oesophageal squamous cell carcinoma (OSCC). Ghrelin, a hormone which, is also produced in the gastric fundic glands may be a marker of gastric atrophy, but its association with OSCC is not known. Methods To examine the relationship between baseline serum ghrelin concentration and subsequent risk of OSCC, the authors conducted a nested case–control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study. 82 cases of OSCC were matched (1:1) by age and date of blood draw to controls from the ATBC study. Serum ghrelin was measured by radioimmunoassay. ORs and 95% CIs were calculated using conditional logistic regression with adjustment for potential confounders. Results For individuals in the lowest quartile of serum ghrelin, compared to those in the highest, the multivariate OR of subsequent OSCC was 6.83 (95% CI 1.46 to 31.84). These associations were dose dependent (p value for trend =0.005 for both), and independent of the effects of low pepsinogen I:II ratio and Helicobacter pylori infection. The significance of these associations remained even for individuals developing OSCC up to 10 years after baseline ghrelin measurement, although they become attenuated after 10 years. Conclusion Lower baseline concentrations of serum ghrelin were associated with an increase in risk of OSCC. Further studies are needed to confirm this finding in other populations and to explore the role of ghrelin in the aetiology of OSCC.

In follow-up of a recent genome-wide association study (GWAS) that identified a locus in chromosome 2p21 associated with risk for renal cell carcinoma (RCC), we conducted a fine mapping analysis of a 120 kb region that includes EPAS1. We genotyped 59 tagged common single-nucleotide polymorphisms (SNPs) in 2278 RCC and 3719 controls of European background and observed a novel signal for rs9679290 [P=5 5.75× 3 10 -8, per-allele odds ratio (OR) = 1.27, 95% confidence interval (CI): 1.17-1.39]. Imputation of common SNPs surrounding rs9679290 using HapMap 3 and 1000 Genomes data yielded two additional signals, rs4953346 (P = 4.09 × 10 -14) and rs12617313 (P = 7.48 × 10 -12), both highly correlated withrs9679290 (r 2 > 0.95), but interestingly not correlated with the two SNPs reported in the GWAS: rs11894252 and rs7579899 (r 2 < 0.1 with rs9679290). Genotype analysis of rs12617313 confirmed an association with RCC risk (P = 1.72 × 10 -9, per-allele OR = 1.28, 95% CI: 1.18-1.39) In conclusion, we report that chromosome 2p21 harbors a complex genetic architecture for common RCC risk variants. Published by Oxford University Press 2011.

Background: Vitamin D compounds inhibit prostate tumorigenesis experimentally, but epidemiologic data are inconsistent with respect to prostate cancer risk, with some studies suggesting nonsignificant positive associations. Methods: The 25-hydroxy vitamin D [25(OH)D]–prostate cancer relation was examined in a nested case–control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of 50- to 69-year-old Finnish men. We matched 1,000 controls to 1,000 cases diagnosed during up to 20 years of follow-up on the basis of age (±1 year) and fasting blood collection date (±30 days). Conditional multivariate logistic regression models estimated ORs and 95% CIs. All statistical significance testing was 2-sided. Results: Cases had nonsignificantly 3% higher serum 25(OH)D levels (P = 0.19). ORs (95% CIs) for increasing season-specific quintiles of 25(OH)D concentrations were 1.00 (reference), 1.29 (0.95–1.74), 1.34 (1.00–1.80), 1.26 (0.93–1.72), and 1.56 (1.15–2.12), with Ptrend = 0.01. Analyses based on prespecified clinical categories and season-adjusted values yielded similar results. These findings seemed stronger for aggressive disease [OR (95% CI) for fifth quintile of serum 25(OH)D [1.70 (1.05–2.76), Ptrend = 0.02], among men with greater physical activity [1.85 (1.26–2.72), Ptrend = 0.002], higher concentrations of serum total cholesterol [2.09 (1.36–3.21), Ptrend = 0.003] or α-tocopherol [2.00 (1.30–3.07), Ptrend = 0.01] and higher intakes of total calcium [1.82 (1.20–2.76), Ptrend = 0.01] or vitamin D [1.69 (1.04–2.75), Ptrend = 0.08], or among those who had received the trial α-tocopherol supplements [1.74 (1.15–2.64), Ptrend = 0.006]. Conclusion: Our findings indicate that men with higher vitamin D blood levels are at increased risk of developing prostate cancer. Impact: Greater caution is warranted with respect to recommendations for high-dose vitamin D supplementation and higher population target blood levels. Cancer Epidemiol Biomarkers Prev; 20(9); 1850–60. ©2011 AACR.

Retinol is one of the most biologically active forms of vitamin A and is hypothesized to influence a wide range of human diseases including asthma, cardiovascular disease, infectious diseases and cancer. We conducted a genome-wide association study of 5006 Caucasian individuals drawn from two cohorts of men: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We identified two independent single-nucleotide polymorphisms associated with circulating retinol levels, which are located near the transthyretin (TTR) and retinol binding protein 4 (RBP4) genes which encode major carrier proteins of retinol: rs1667255 (P =2.30× 10(-17)) and rs10882272 (P =6.04× 10(-12)). We replicated the association with rs10882272 in RBP4 in independent samples from the Nurses' Health Study and the Invecchiare in Chianti Study (InCHIANTI) that included 3792 women and 504 men (P =9.49× 10(-5)), but found no association for retinol with rs1667255 in TTR among women, thus suggesting evidence for gender dimorphism (P-interaction=1.31× 10(-5)). Discovery of common genetic variants associated with serum retinol levels may provide further insight into the contribution of retinol and other vitamin A compounds to the development of cancer and other complex diseases.

Genome-wide and candidate-gene association studies of bladder cancer have identified 10 susceptibility loci thus far. We conducted a meta-analysis of two previously published genome-wide scans (4501 cases and 6076 controls of European background) and followed up the most significant association signals [17 single nucleotide polymorphisms (SNPs) in 10 genomic regions] in 1382 cases and 2201 controls from four studies. A combined analysis adjusted for study center, age, sex, and smoking status identified a novel susceptibility locus that mapped to a region of 18q12.3, marked by rs7238033 (P = 8.7 x 10(-9); allelic odds ratio 1.20 with 95% CI: 1.13-1.28) and two highly correlated SNPs, rs10775480/rs10853535 (r(2) = 1.00; P = 8.9 x 10(-9); allelic odds ratio 1.16 with 95% CI: 1.10-1.22). The signal localizes to the solute carrier family 14 member 1 gene, SLC14A1, a urea transporter that regulates cellular osmotic pressure. In the kidney, SLC14A1 regulates urine volume and concentration whereas in erythrocytes it determines the Kidd blood groups. Our findings suggest that genetic variation in SLC14A1 could provide new etiological insights into bladder carcinogenesis.

Telomere length plays an important role in chromosomal stability and tumorigenesis, and its measurement in peripheral white blood cell DNA may be a predictor of the development of lung cancer.Using a new method - monochrome multiplex quantitative PCR - which reduces measurement variability, we compared telomere length relative to standard DNA in white blood cell DNA in 229 incident male lung cancer cases and 229 matched controls within the prospective Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of male smokers.Median (10th, 90th percentile) telomere length was 1.13 (0.86, 1.45) in cases and 1.08 (0.85, 1.38) in controls (P=0.038). Telomere length was inversely associated with pack-years of smoking (Spearman's correlation r=-0.16, P=0.02) among controls. Compared to subjects with shorter telomere length (≤median), subjects with greater telomere length (median) had a 1.6-fold (95% CI, 1.06-2.36) increased risk of lung cancer. There was a significant linear relationship between quartiles of telomere length and risk of lung cancer (odds ratios (95% confidence intervals) by quartile: 1.00, 0.98 (0.55-1.73), 1.62 (0.95-2.77), and 1.50 (0.84-2.68); P(trend)=0.05). In addition, subgroup analysis showed that greater telomere length was associated with an increased risk of lung cancer among longer-term smokers (38 years) (OR, 1.90; 95% CI, 1.00-3.59) but not among shorter-term smokers (≤38 years) (OR, 1.08; 95% CI, 0.56-2.11) (P(interaction)=0.01).Our results suggest that greater telomere length may be associated with higher risk of lung cancer among male smokers.

In genome-wide association studies (GWAS) of common genetic variants associated with circulating alpha- and gamma-tocopherol concentrations in two adult cohorts comprising 5006 men of European descent, we observed three loci associated with alpha-tocopherol levels, two novel single-nucleotide polymorphisms (SNPs), rs2108622 on 19pter-p13.11 (P= 1.7 × 10(-8)) and rs11057830 on 12q24.31 (P= 2.0 × 10(-8)) and confirmed a previously reported locus marked by rs964184 on 11q23.3 (P= 2.7 × 10(-10)). The three SNPs have been reported to be associated with lipid metabolism and/or regulation. We replicated these findings in a combined meta-analysis with two independent samples, P= 7.8 × 10(-12) (rs964184 on 11q23.3 near BUD13, ZNF259 and APOA1/C3/A4/A5), P= 1.4 × 10(-10) (rs2108622 on 19pter-p13.11 near CYP4F2) and P= 8.2 × 10(-9) (rs11057830 on 12q24.31 near SCARB1). Combined, these SNPs explain 1.7% of the residual variance in log alpha-tocopherol levels. In one of the two male GWAS cohorts (n= 992), no SNPs were significantly associated with gamma-tocopherol concentrations after including data from the replication sample for 71 independent SNPs with P1 × 10(-4) identified.

Background: Advanced glycation end products (AGE) accumulate in human tissue proteins during aging, particularly under hyperglycemia conditions. AGEs induce oxidative stress and inflammation via the receptor for AGEs (RAGE) and soluble RAGE (sRAGE) can neutralize the effects mediated by RAGE–ligand engagement. Methods: We examined the association between Nϵ-(carboxymethyl)lysine (CML), a prominent AGE, and sRAGE and colorectal cancer risk in a prospective case–cohort study nested within a cancer prevention trial among 29,133 Finnish male smokers. Among study subjects who were alive without cancer 5 years after baseline (1985–1988), we identified 483 incident colorectal cancer cases and randomly sampled 485 subcohort participants as the comparison group with the follow-up to April 2006. Baseline serum levels of CML-AGE, sRAGE, glucose and insulin were determined. Weighted Cox proportional hazard regression models were used to calculate relative risks (RR) and 95% CI. Results: Comparing highest with lowest quintile of sRAGE, the RR for incident colorectal cancer was 0.65 (95% CI, 0.39–1.07; Ptrend = 0.03), adjusting for age, years of smoking, body mass index, and CML-AGE. Further adjustment for serum glucose strengthened the association (RR = 0.52; 95% CI, 0.30–0.89; Ptrend = 0.009). Highest quintile of CML-AGE was not associated with an increased risk of colorectal cancer (multivariate RR = 1.20; 95% CI, 0.64–2.26). Conclusions: Higher prediagnostic levels of serum sRAGE were associated with lower risk of colorectal cancer in male smokers. Impact: This is the first epidemiologic study to implicate the receptor for AGEs in colorectal cancer development. Cancer Epidemiol Biomarkers Prev; 20(7); 1430–8. ©2011 AACR.

Cigarette smoking, obesity, type 2 diabetes, and, to a lesser extent, meat cooked at high temperatures are associated with pancreatic cancer. Cigarette smoke and foods cooked at higher temperatures are major environmental sources of advanced glycation end products (AGE). AGEs accumulate during hyperglycemia and elicit oxidative stress and inflammation through interaction with the receptor for AGEs (RAGE). Soluble RAGE (sRAGE) acts as an anti-inflammatory factor to neutralize AGEs and block the effects mediated by RAGE. In this study, we investigated the associations of prediagnostic measures of Nϵ-(carboxymethyl)-lysine (CML)-AGE and sRAGE with pancreatic cancer in a case–cohort study within a cohort of 29,133 Finnish male smokers. Serum samples and exposure information were collected at baseline (1985–1988). We measured CML-AGE, sRAGE, glucose, and insulin concentrations in fasting serum from 255 incident pancreatic cancer cases that arose through April 2005 and from 485 randomly sampled subcohort participants. Weighted Cox proportional hazard regression models were used to calculate relative risks (RR) and 95% CI, adjusted for age, years of smoking, and body mass index. CML-AGE and sRAGE were mutually adjusted. CML-AGE levels were not associated with pancreatic cancer [fifth compared with first quintile, RR (95% CI): 0.68 (0.38–1.22), Ptrend = 0.27]. In contrast, sRAGE levels were inversely associated with pancreatic cancer [fifth compared with first quintile, RR (95% CI): 0.46 (0.23–0.73), Ptrend = 0.002]. Further adjustment for glucose or insulin levels did not change the observed associations. Our findings suggest that sRAGE is inversely associated with pancreatic cancer risk among Finnish male smokers. Cancer Res; 71(10); 3582–9. ©2011 AACR.

International audience; Genome-wide association studies have identified prostate cancer susceptibility alleles on chromosome 11q13. As part of the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, the region flanking the most significant marker, rs10896449, was fine mapped in 10 272 cases and 9123 controls of European origin (10 studies) using 120 common single nucleotide polymorphisms (SNPs) selected by a two-staged tagging strategy using HapMap SNPs. Single-locus analysis identified 18 SNPs below genome-wide significance (P< 10(-8)) with rs10896449 the most significant (P= 7.94 × 10(-19)). Multi-locus models that included significant SNPs sequentially identified a second association at rs12793759 [odds ratio (OR) = 1.14, P= 4.76 × 10(-5), adjusted P= 0.004] that is independent of rs10896449 and remained significant after adjustment for multiple testing within the region. rs10896438, a proxy of previously reported rs12418451 (r(2)= 0.96), independent of both rs10896449 and rs12793759 was detected (OR = 1.07, P= 5.92 × 10(-3), adjusted P= 0.054). Our observation of a recombination hotspot that separates rs10896438 from rs10896449 and rs12793759, and low linkage disequilibrium (rs10896449-rs12793759, r(2)= 0.17; rs10896449-rs10896438, r(2)= 0.10; rs12793759-rs10896438, r(2)= 0.12) corroborate our finding of three independent signals. By analysis of tagged SNPs across ∼123 kb using next generation sequencing of 63 controls of European origin, 1000 Genome and HapMap data, we observed multiple surrogates for the three independent signals marked by rs10896449 (n= 31), rs10896438 (n= 24) and rs12793759 (n= 8). Our results indicate that a complex architecture underlying the common variants contributing to prostate cancer risk at 11q13. We estimate that at least 63 common variants should be considered in future studies designed to investigate the biological basis of the multiple association signals.

Background and Purpose— Coffee consumption has been inconsistently associated with stroke incidence and mortality in previous studies. We investigated the association between coffee consumption and stroke incidence in the Swedish Mammography Cohort. Methods— We prospectively followed of 34 670 women without a history of cardiovascular disease or cancer at baseline in 1997. Coffee consumption was assessed in 1997 using a self-administered questionnaire. Incident stroke cases were ascertained from the Swedish Hospital Discharge Registry. Results— During a mean follow-up of 10.4 years, we ascertained 1680 stroke events, including 1310 cerebral infarctions, 154 intracerebral hemorrhages, 79 subarachnoid hemorrhages, and 137 unspecified strokes. After adjustment for other risk factors, coffee consumption was associated with a statistically significant lower risk of total stroke, cerebral infarction, and subarachnoid hemorrhage but not intracerebral hemorrhage. The multivariable relative risks of total stroke across categories of coffee consumption (P for trend=0.02). The association between coffee consumption and cerebral infarction was not modified by smoking status, body mass index, history of diabetes or hypertension, or alcohol consumption. Conclusions— These findings suggest that low or no coffee consumption is associated with an increased risk of stroke in women.

Background: Lung cancer and tuberculosis cause significant morbidity and mortality worldwide. Tuberculosis may increase lung cancer risk through substantial and prolonged pulmonary inflammation. However, prospective data on tuberculosis and lung cancer risk are limited. Methods: Our study included 29,133 Finnish male smokers followed prospectively in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (1985–2005). Lung cancers were identified through linkage with the Finnish Cancer Registry, and hospital-treated tuberculosis cases were ascertained from the National Hospital Discharge Register. We assessed the association between tuberculosis and lung cancer risk with proportional hazards regression models, adjusting for age and cigarette smoking. Results: Forty-four lung cancer cases occurred among 273 men with tuberculosis (incidence rate = 1,786 per 100,000 person-years). Tuberculosis was associated with a two-fold elevation in lung cancer risk (HR = 1.97; 95% CI = 1.46–2.65) with significant associations observed for both incident (HR = 2.05; 95% CI = 1.42–2.96) and prevalent tuberculosis (HR = 1.82; 95% CI = 1.09–3.02). Lung cancer risk was greatest in the 2-year window after tuberculosis diagnosis (HR = 5.01; 95% CI = 2.96–8.48) but remained elevated at longer latencies (HR = 1.53; 95% CI = 1.07–2.20). Though tuberculosis was associated with an increased risk of squamous cell carcinoma (HR = 3.71), adenocarcinoma (HR = 1.71), small cell carcinoma (HR = 1.72), and lung cancer of other (HR = 1.23) and unknown histologies (HR = 1.35), only the association for squamous cell carcinoma was statistically significant. Conclusions: Tuberculosis is associated with increased lung cancer risk in male smokers. Impact: Our results add to the growing body of evidence implicating chronic inflammation and pulmonary scarring in the etiology of lung cancer. Cancer Epidemiol Biomarkers Prev; 20(4); 672–8. ©2011 AACR.

Greater exposure to retinol (vitamin A) may prevent prostate cancer, although under some conditions it could promote cell growth and de-differentiation. The authors prospectively examined prostate cancer risk and serum retinol levels, measured by using high-performance liquid chromatography, at baseline (n = 29,104) and after 3 years (n = 22,843) in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Cox proportional hazards models were used to estimate the relative risk of total (n = 2,041) and aggressive (n = 461) prostate cancer by quintiles of baseline and 3-year serum retinol concentrations and by change in serum retinol levels from baseline to 3 years. Men with higher retinol concentrations at baseline were more likely to develop prostate cancer (quintile 5 vs. quintile 1 hazard ratio = 1.19, 95% confidence interval: 1.03, 1.36; P(trend) = 0.009). The results were similar for aggressive disease. Joint categorization based on baseline and 3-year retinol levels showed that men who were in the highest quintile at both time points had the greatest increased risk (baseline/3-year quintile 5/quintile 5 vs. quintile 1/quintile 1 hazard ratio = 1.31, 95% confidence interval: 1.08, 1.59). In this largest study to date of vitamin A status and subsequent risk of prostate cancer, higher serum retinol was associated with elevated risk, with sustained high exposure conferring the greatest risk. Future studies may clarify the underlying biologic mechanisms of the retinol-prostate cancer association.

Epidemiologic studies of pancreatic cancer risk have reported null or nonsignificant positive associations for obesity, while associations for height have been null. Waist and hip circumference have been evaluated infrequently. A pooled analysis of 14 cohort studies on 846,340 individuals was conducted; 2,135 individuals were diagnosed with pancreatic cancer during follow-up. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were calculated by Cox proportional hazards models, and then pooled using a random effects model. Compared to individuals with a body mass index (BMI) at baseline between 21-22.9 kg/m(2), pancreatic cancer risk was 47% higher (95% CI:23-75%) among obese (BMI >= 30 kg/m(2)) individuals. A positive association was observed for BMI in early adulthood (pooled multivariate [MV]RR = 1.30, 95%CI = 1.09-1.56 comparing BMI >= 25 kg/m(2) to a BMI between 21 and 22.9 kg/m(2)). Compared to individuals who were not overweight in early adulthood (BMI = 10 kg/m(2) between BMI at baseline and younger ages compared to individuals whose BMI remained stable. Results were either similar or slightly stronger among never smokers. A positive association was observed between waist to hip ratio (WHR) and pancreatic cancer risk (pooled MVRR = 1.35 comparing the highest versus lowest quartile, 95%CI = 1.03-1.78). BMI and WHR were positively associated with pancreatic cancer risk. Maintaining normal body weight may offer a feasible approach to reducing morbidity and mortality from pancreatic cancer.

Background: Epidemiologic studies of fish consumption in relation to risk of stroke have yielded inconsistent results. Objective: In this study, we examined the association between fish consumption and stroke incidence in women. Design: We analyzed data from a population-based prospective cohort of 34,670 women in the Swedish Mammography Cohort who were free of cardiovascular disease and cancer at baseline. Information on fish consumption was obtained by a self-administered questionnaire in 1997. Incident cases of stroke were ascertained from the Swedish Hospital Discharge Registry. We used Cox proportional hazards regression to estimate relative risks (RRs) and 95% CIs. Results: Over a mean follow-up of 10.4 y, we ascertained 1680 incident cases of stroke, including 1310 cerebral infarctions, 233 hemorrhagic strokes, and 137 unspecified strokes. Fish consumption was significantly inversely associated with risk of total stroke but not with cerebral infarction or hemorrhagic stroke. Compared with women in the lowest quintile of fish consumption (,1.0 serving of fish/wk), the multivariable RR of total stroke for women in the highest quintile (.3.0 servings of fish/wk) was 0.84 (95% CI: 0.71, 0.98; P for trend = 0.049). Consumption of lean fish but not of other fish types was inversely associated with risk of stroke. The multivariable RR of total stroke was 0.67 (95% CI: 0.49, 0.93; P for trend = 0.07) for 3 servings of lean fish/wk compared with that for no consumption. Conclusion: These results suggest that the consumption of fish, especially of lean fish, may reduce risk of stroke in women. This trial was registered at clinicaltrials.gov as NCT01127698. Am J Clin Nutr 2011;93:487‐93.

Potatoes, especially mashed potatoes, are known to result in high glycaemic and insulinaemic responses. However, in most meals, potatoes are accompanied by other foods. The objective of the present study was to investigate how glycaemic and insulinaemic responses to a mashed potato meal changed when a high-fat food (rapeseed oil), a high-protein food (chicken breast) and/or salad were added to the meal. Healthy subjects (n11) ingested the test meals once and the reference food (glucose solution) twice in a random order at 1-week intervals. Capillary blood samples were then drawn for 2 h, and glucose and insulin were analysed. The 2 h glycaemic responses to six mashed potato-containing meals varied more than twofold. The glycaemic index (GI) of pure mashed potato was 108, whereas combined with chicken breast, rapeseed oil and salad, it was only 54. The latter GI also differed considerably from its predicted value of 103, which was based on the individual GI of the components of the meal. The insulinaemic indices of the mashed potato-based meals varied between 94 and 148. Chicken breast in the meal increased the insulinaemic response, and rapeseed oil diminished it. However, the insulinaemic response to mashed potato with chicken breast and rapeseed oil was lower than that to mashed potato alone. In conclusion, the protein, fat and salad contents of a meal exert considerable influence on the glycaemic and insulinaemic responses to mashed potatoes. Furthermore, the estimation of the GI of a mixed meal by calculation is imprecise.

Measurements of serum prostate-specific antigen (PSA) protein levels form the basis for a widely used test to screen men for prostate cancer. Germline variants in the gene that encodes the PSA protein (KLK3) have been shown to be associated with both serum PSA levels and prostate cancer. Based on a resequencing analysis of a 56 kb region on chromosome 19q13.33, centered on the KLK3 gene, we fine mapped this locus by genotyping tag SNPs in 3,522 prostate cancer cases and 3,338 controls from five case–control studies. We did not observe a strong association with the KLK3 variant, reported in previous studies to confer risk for prostate cancer (rs2735839; P = 0.20) but did observe three highly correlated SNPs (rs17632542, rs62113212 and rs62113214) associated with prostate cancer [P = 3.41 × 10−4, per-allele trend odds ratio (OR) = 0.77, 95% CI = 0.67–0.89]. The signal was apparent only for nonaggressive prostate cancer cases with Gleason score 8 or stage ≥III (P = 0.31, per-allele trend OR = 1.12, 95% CI = 0.90–1.40). One of the three highly correlated SNPs, rs17632542, introduces a non-synonymous amino acid change in the KLK3 protein with a predicted benign or neutral functional impact. Baseline PSA levels were 43.7% higher in control subjects with no minor alleles (1.61 ng/ml, 95% CI = 1.49–1.72) than in those with one or more minor alleles at any one of the three SNPs (1.12 ng/ml, 95% CI = 0.96–1.28) (P = 9.70 × 10−5). Together our results suggest that germline KLK3 variants could influence the diagnosis of nonaggressive prostate cancer by influencing the likelihood of biopsy. Electronic supplementary material The online version of this article (doi:10.1007/s00439-011-0953-5) contains supplementary material, which is available to authorized users.

Background: Many epidemiologic studies have examined the association between C-reactive protein (CRP) and risk of cancer with inconsistent results. Methods: We conducted two nested, case–control studies in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC) and Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) to test whether prediagnostic circulating CRP concentrations were associated with pancreatic adenocarcinoma. Between 1985 and 2004, 311 cases occurred in ATBC and between 1994 and 2006, 182 cases occurred in PLCO. Controls (n = 510 in ATBC, n = 374 in PLCO) were alive at the time the case was diagnosed and were matched by age, date of blood draw, sex, and race. We used conditional logistic regression adjusted for smoking to calculate OR and 95% CI for pancreatic cancer. Results: CRP concentrations (ng/mL) tended to be inversely or not associated with pancreatic cancer risk in ATBC, PLCO, and combined analyses [per standardized quintile increase in CRP, continuous OR = 0.94 (95% CI, 0.89–0.99), OR = 0.99 (95% CI, 0.95–1.04), OR = 0.98 (95% CI, 0.95–1.01), respectively]. In combined analyses, we observed a significant interaction (Pinteraction = 0.02) such that inverse associations were suggestive in younger (OR = 0.95; 95% CI, 0.90–1.01), but not older, participants. Conclusion: Our results do not support the hypothesis that higher CRP concentrations are associated with incident pancreatic cancer. Impact: Our results highlight the importance of investigating more specific biomarkers for inflammation that may reflect the biological mechanisms underlying pancreatic cancer in prospective cohort studies. Cancer Epidemiol Biomarkers Prev; 20(2); 359–69. ©2010 AACR.

Background and Purpose— High red meat consumption has been associated with increased risk of some cancers and may also be a risk factor for cardiovascular diseases. However, epidemiological studies of red meat consumption in relation to risk of stroke are very limited. Our objective was to examine the association between red meat consumption and stroke incidence in the Swedish Mammography Cohort. Methods— We prospectively followed 34 670 women without cardiovascular disease and cancer at baseline. Participants completed a self-administered questionnaire on diet and other risk factors for cardiovascular diseases in 1997. Cox proportional hazards models were used to estimate multivariable-adjusted relative risks (RR) and 95% CI. Results— During a mean follow-up of 10.4 years, we ascertained 1680 incident cases of stroke, comprising 1310 cerebral infarction, 154 intracerebral hemorrhage, 79 subarachnoid hemorrhage, and 137 unspecified stroke. Total red meat and processed meat consumption was associated with a statistically significant increased risk of cerebral infarction, but not of total stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. The multivariable RR of cerebral infarction for the highest versus the lowest quintile of consumption were 1.22 (95% CI, 1.01–1.46) for red meat and 1.24 (95% CI, 1.04–1.49) for processed meat. Fresh (unprocessed) meat consumption was not associated with total stroke or with any stroke subtype. Conclusion— Findings from this study suggest that red and processed meat consumption may increase the risk of cerebral infarction in women.