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 = 1.80 × 10−8; 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.
Despite a well-established link between obesity and renal cell carcinoma (RCC), the mechanism through which obesity acts to increase cancer risk is unclear. Adiponectin, leptin and resistin are adipocyte-secreted peptide hormones that may influence RCC development through their demonstrated effects on inflammation, insulin resistance and cell growth and proliferation. We conducted a nested case–control study to evaluate whether prediagnostic serum adiponectin, leptin and resistin levels are associated with RCC risk. This case–control study (273 cases and 273 controls) was nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of Finnish male smokers. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using conditional logistic regression models, with analyte levels modeled continuously and categorically (defined using quartiles among controls). High adiponectin levels were significantly associated with reduced RCC risk (Quartile 4 versus Quartile 1: OR = 0.52, 95% CI = 0.30–0.88; P trend = 0.01). This association remained upon additional adjustment for body mass index at blood collection and exclusion of cases diagnosed within the first 2 years of follow-up. In addition, model adjustment for adiponectin resulted in a substantial attenuation of the association between BMI and RCC (OR per 5kg/m2 changed from 1.19 to 1.05). No clear associations with RCC were observed for leptin or resistin. Our results suggest that elevated levels of circulating adiponectin are associated with decreased subsequent risk of RCC. These findings provide the strongest evidence to date, suggesting that the association between obesity and RCC is mediated at least in part through the effects of low adiponectin.
End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischaemic 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.
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).
Stage 1 identified 524 SNPs from 23 LD blocks having significant association (p<5 ×10-8) with one or more coagulation/fibrin phenotypes. 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 (vWF 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/non-cases using MORGAM and WTCCC2 collections. SNP rs505922 was nominally associated with ischaemic stroke, odds ratio = 0.94 (95% confidence intervals, 0.88-0.99), p=0.023. Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta=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).
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.
GWAS; thrombosis; stroke; coagulation factor; stroke subtype
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 ATBC Cancer Prevention Study to assess whether iron metrics were associated with gastric cardia cancer (GCC) and gastric noncardia cancer (GNCC).
We selected 341 incident gastric cancer cases (86 cardia, 172 noncardia, and 83 non-specified), accrued during 22 years of follow-up, and 341 individually matched controls. We measured prediagnostic serum iron, ferritin, unsaturated iron binding capacity (UIBC), 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.
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.
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.
Helicobacter pylori; Iron; Nested Case-Control Studies; Prospective Studies; Stomach Neoplasms
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 men 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.
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.
Amyotrophic lateral sclerosis; vitamin E; cohort studies; risk factors in epidemiology
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.
gene-environment interaction; gonadal steroid hormones; insulin-like growth factor binding protein 3; insulin-like growth factor I; molecular epidemiology; prostatic neoplasms
A recent genome-wide association study of bladder cancer identified the UGT1A gene cluster on chromosome 2q37.1 as a novel susceptibility locus. The UGT1A cluster encodes a family of UDP-glucuronosyltransferases (UGTs), which facilitate cellular detoxification and removal of aromatic amines. Bioactivated forms of aromatic amines found in tobacco smoke and industrial chemicals are the main risk factors for bladder cancer. The association within the UGT1A locus was detected by a single nucleotide polymorphism (SNP) rs11892031. Now, we performed detailed resequencing, imputation and genotyping in this region. We clarified the original genetic association detected by rs11892031 and identified an uncommon SNP rs17863783 that explained and strengthened the association in this region (allele frequency 0.014 in 4035 cases and 0.025 in 5284 controls, OR = 0.55, 95%CI = 0.44–0.69, P = 3.3 × 10−7). Rs17863783 is a synonymous coding variant Val209Val within the functional UGT1A6.1 splicing form, strongly expressed in the liver, kidney and bladder. We found the protective T allele of rs17863783 to be associated with increased mRNA expression of UGT1A6.1 in in-vitro exontrap assays and in human liver tissue samples. We suggest that rs17863783 may protect from bladder cancer by increasing the removal of carcinogens from bladder epithelium by the UGT1A6.1 protein. Our study shows an example of genetic and functional role of an uncommon protective genetic variant in a complex human disease, such as bladder cancer.
Lead (Pb) is classified as a probable human carcinogen. However, its role in renal cell cancer (RCC) has not been established. Calcium and vitamin D may off-set toxicity in vivo.
In this nested case-control study, whole blood lead (Pb), total serum calcium, and serum 25-hydroxyvitamin D were measured in blood drawn prior to diagnosis among male smokers participating in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Single nucleotide polymorphisms (SNPs) in five genes (CALB1, TRPV5, TRPV6, VDR, and ALAD) related to lead toxicity or calcium transport were genotyped. Logistic and linear regression were used to determine RCC risk and time to diagnosis (respectively), adjusting for other risk factors.
Among 154 newly diagnosed cases and 308 matched controls, RCC was associated with higher whole blood lead (OR=2.0, 95% CI:1.0,3.9; quartile 4 (Q4) v. Q1, Ptrend=0.022) and CALB1 rs1800645 (Ptrend=0.025, minor ‘T’ allele frequency=0.34). Higher total serum calcium (Ptrend=<0.001) was associated with reduced RCC risk. Total serum calcium and 25-hydroxyvitamin D levels did not alter the association observed with lead. Time from enrollment to RCC diagnosis was positively associated with serum calcium (Ptrend=0.002) and 25-hydroxyvitamin D (Ptrend=0.054) among cases.
Higher blood lead concentrations, below the 10 ug/dL level of concern, were associated with RCC, independent from serum calcium and CALB1 promoter polymorphism.
Increased risk of RCC is associated with lower serum calcium and higher whole blood lead in smokers. The clinical prognostic value of serum calcium and vitamin D in RCC should be further investigated.
calcium; lead; vitamin D; renal cell carcinoma; polymorphism; CALB1
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 = 5.75 × 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 with rs9679290 (r2 > 0.95), but interestingly not correlated with the two SNPs reported in the GWAS: rs11894252 and rs7579899 (r2 < 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.
High concentrations of circulating 25-hydroxyvitamin D [25(OH)D] have been associated with elevated pancreatic cancer risk. As this is contrary to an expected inverse association between vitamin D status and cancer, we examined whether vitamin D binding protein (DBP), the primary carrier of vitamin D compounds in circulation, plays a role in this relationship. Prediagnostic serum DBP and 25(OH)D were studied in relation to risk of pancreatic cancer in a nested case-control study of 234 pancreatic cancer cases and 234 controls in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression, and statistical tests were two-sided. We found that DBP and 25(OH)D were correlated (r=0.27; p<0.0001), and DBP was inversely associated with pancreatic cancer risk (OR=0.66, 95% CI=0.39–1.12, for the highest vs. lowest quartile; p-trend=0.02). Importantly, this association appeared to have a threshold between quartiles 2–4 and quartile 1, and was primarily evident among men with concurrent high 25(OH)D concentrations (OR=0.33, 95% CI=0.16–0.70 for highest vs. lowest quartile; p-trend=0.002), with no association in men with lower serum 25(OH)D (OR=1.28, 95% CI=0.62–2.61 for highest vs. lowest quartile, p-trend 0.63, p-interaction= 0.01). Men with higher 25(OH)D concentrations and serum DBP below the median showed greatly elevated risk of pancreatic cancer (OR=5.01, 95% CI 2.33–10.78, for highest vs. lowest quartile; p-trend < 0.0001), while risk was weakly inversely associated with serum 25(OH)D when DBP concentrations were higher (p-interaction = 0.001). Taken together, our findings indicate that higher DBP concentrations may sequester more 25(OH)D and reduce free 25(OH)D bioavailability. Simultaneous examination of DBP and 25(OH)D may be important in determining the association of vitamin D with cancer risk.
Vitamin D Binding Protein; 25-Hydroxyvitamin D; Pancreatic Cancer; serum biomarkers; prospective study
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 SNP 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.
We fit a series of risk models and estimated their performance in 7,509 prostate cancer cases and 7,652 controls within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We also calculated absolute risks based on SEER incidence data.
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).
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 PSA screening.
Although adding genetic risk markers improves model performance, the clinical utility of these genetic risk models is limited.
Prostate cancer; polymorphism; risk prediction model
Circulating total cholesterol has been inversely associated with cancer risk; however, the role of reverse causation and the associations for high density lipoprotein (HDL) cholesterol have not been fully characterized. We examined the relationship between serum total and HDL cholesterol and risk of overall and site-specific cancers among 29,093 men in the ATBC Study cohort.
Fasting serum total and HDL cholesterol were assayed at baseline, and 7,545 incident cancers were identified during up to 18 years of follow-up. Multivariable proportional hazards models were conducted to estimate relative risks.
Higher serum total cholesterol concentration was associated with decreased risk of cancer overall (RR for comparing high versus low quintile=0.85, 95%CI=0.79–0.91; P trend < 0.001; >276.7 versus <203.9 mg/dL), and the inverse association was particularly evident for cancers of the lung and liver. These associations were no longer significant, however, when cases diagnosed during the first nine years of follow-up were excluded. Greater HDL cholesterol was also associated with decreased risk of cancer (RR for high versus low quintile=0.89, 95%CI=0.83–0.97; P trend=0.01; >55.3 versus <36.2 mg/dL). The inverse association of HDL cholesterol was evident for cancers of lung, prostate, liver, and the hematopoietic system, and the associations of HDL cholesterol with liver and lung cancers remained after excluding cases diagnosed within 12 years of study entry.
Our findings suggest that prior observations regarding serum total cholesterol and cancer are largely explained by reverse causation. Although chance and reverse causation may explain some of the inverse HDL associations, we cannot rule out some etiologic role for this lipid fraction.
serum; cholesterol; high density lipoprotein cholesterol; cancer; risk; prospective; cohort
A recent Genome-Wide Association Study (GWAS) of prostate cancer in a Japanese population identified five novel regions not previously discovered in other ethnicities. In this study, we attempt to replicate these five loci in a series of nested prostate cancer case-control studies of European ancestry.
We genotyped five SNPs: rs13385191 (chromosome 2p24), rs12653946 (5p15), rs1983891 (6p21), rs339331 (6p22) and rs9600079 (13q22), in 7,956 prostate cancer cases and 8,148 controls from a series of nested case-control studies within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We tested each SNP for association with prostate cancer risk and assessed if associations differed with respect to disease severity and age of onset.
Four SNPs (rs13385191, rs12653946, rs1983891 and rs339331) were significantly associated with prostate cancer risk (p-values ranging from 0.01 to 1.1×10-5). Allele frequencies and odds ratios were overall lower in our population of European descent compared to the discovery Asian population. SNP rs13385191 (C2orf43) was only associated with low-stage disease (p=0.009, case-only test). No other SNP showed association with disease severity or age of onset. We did not replicate the 13q22 SNP, rs9600079 (p=0.62).
Four SNPs associated with prostate cancer risk in an Asian population are also associated with prostate cancer risk in men of European descent.
This study illustrates the importance of evaluation of prostate cancer risk markers across ethnic groups.
Epidemiological studies evaluating the association between folate intake and risk of pancreatic cancer have produced inconsistent results. The statistical power to examine this association has been limited in previous studies partly because of small sample size and limited range of folate intake in some studies.
We analyzed primary data from 14 prospective cohort studies that included 319 716 men and 542 948 women to assess the association between folate intake and risk of pancreatic cancer. Folate intake was assessed through a validated food-frequency questionnaire at baseline in each study. Study-specific relative risks (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models and then pooled using a random effects model. All statistical tests were two-sided.
During 7–20 years of follow-up across studies, 2195 pancreatic cancers were identified. No association was observed between folate intake and risk of pancreatic cancer in men and women (highest vs lowest quintile: dietary folate intake, pooled multivariable RR = 1.06, 95% CI = 0.90 to 1.25, Ptrend = .47; total folate intake [dietary folate and supplemental folic acid], pooled multivariable RR = 0.96, 95% CI = 0.80 to 1.16, Ptrend = .90). No between-study heterogeneity was observed (for dietary folate, Pheterogeneity = .15; for total folate, Pheterogeneity = .22).
Folate intake was not associated with overall risk of pancreatic cancer in this large pooled analysis.
In an analysis of 31,717 cancer cases and 26,136 cancer-free controls drawn from 13 genome-wide association studies (GWAS), we observed large chromosomal abnormalities in a subset of clones from DNA obtained from blood or buccal samples. Mosaic chromosomal abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of size >2 Mb were observed in autosomes of 517 individuals (0.89%) with abnormal cell proportions between 7% and 95%. In cancer-free individuals, the frequency increased with age; 0.23% under 50 and 1.91% between 75 and 79 (p=4.8×10−8). Mosaic abnormalities were more frequent in individuals with solid-tumors (0.97% versus 0.74% in cancer-free individuals, OR=1.25, p=0.016), with a stronger association for cases who had DNA collected prior to diagnosis or treatment (OR=1.45, p=0.0005). Detectable clonal mosaicism was common in individuals for whom DNA was collected at least one year prior to diagnosis of leukemia compared to cancer-free individuals (OR=35.4, p=3.8×10−11). These findings underscore the importance of the role and time-dependent nature of somatic events in the etiology of cancer and other late-onset diseases.
Oesophageal cancers rank as the eighth most common cancer and the sixth most common cause of cancer death, worldwide. 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, like pepsinogen, is produced in the fundic glands of the stomach, may be a sensitive and specific marker of gastric atrophy, but its association with OSCC is not known.
To examine the relationship between baseline serum ghrelin concentration and subsequent risk of OSCC, we 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. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression with adjustment for potential confounders.
For those individuals in the lowest quartile of serum ghrelin, compared to those in the highest, the multivariate odds ratio of subsequent OSCC was 6.83 (95% CI: 1.46, 31.84). These associations were dose dependent (P for trend = 0.005 for both), and independent of the effects of low pepsinogen I/II ratio (a marker of gastric fundic atrophy) and Helicobacter pylori infection. The significance of these associations remained even for individuals developing OSCC up to 10 years after baseline ghrelin measurement, though they become attenuated after 10 years.
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.
ghrelin; oesophageal squamous cell carcinoma; atrophy
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 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); Ptrend = 0.05). In addition, subgroup analysis showed that greater telomere length was associated with increased risk of lung cancer among heavy smokers (> 38 years) (OR, 1.90; 95% CI, 1.00–3.59) but not among light smokers (≤ 38 years) (OR, 1.08; 95% CI, 0.56–2.11) (Pinteraction = 0.01).
Our results suggest that greater telomere length may be associated with higher risk of lung cancer among male smokers.
Telomere length; lung cancer; cohort study
Previous studies evaluating whether risk factors for gastric cancer are also associated with colorectal cancer (CRC) have shown inconsistent results. We prospectively examined the association of atrophic gastritis, a pre-malignant condition for gastric cancer and long-term sequelae common to many exposure factors, and the risk of incident CRC.
A total of 20,928 Finnish male smokers, aged 50–69, who were participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC) had serum pepsinogen I (SPGI) levels measured. Participants with low SPGI levels (<25 µg/l) (n=1,665) were invited for gastroscopy. Of these, 1,059 (63.6%) participants underwent gastroscopy and atrophic gastritis was histologically confirmed in 1,006 (95.0%) participants. We used Cox proportional hazards regression to evaluate the risk of incident CRC.
During a mean follow-up of 11.3 years (236,258 person-years), 425 incident CRC were diagnosed. The incidence rates were 1.82, 1.48, and 1.82 per 1,000 person-years of follow-up for participants with normal SPGI (≥25 µg/l), low SPGI, and histologically-confirmed atrophic gastritis, respectively. Compared to subjects with normal SPGI, there was no increased risk of CRC among subjects with low SPGI (Adjusted Hazard Ratio (HR) = 0.71; 95%CI: 0.47–1.05) and among those with histologically-confirmed atrophic gastritis (Adjusted HR = 0.86; 95%CI: 0.55–1.34).
Atrophic gastritis is not associated with an increased risk of colorectal cancer among male smokers.
Serum pepsinogen; atrophic gastritis; colorectal cancer
There is convincing evidence that a high dietary fiber intake may lower the risk of coronary heart disease. However, the role of fiber in the prevention of stroke is unclear. We examined the associations of dietary fiber and fiber-rich food intake with risk of stroke within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.
Between 1985 and 1988, 26 556 Finnish male smokers aged 50–69 years who had no history of stroke completed a dietary questionnaire. During a mean follow-up of 13.6 years, 2702 cerebral infarctions, 383 intracerebral hemorrhages, and 196 subarachnoid hemorrhages were ascertained.
After adjustment for cardiovascular risk factors and folate and magnesium intakes, there was no significant association between intake of total fiber, water-soluble fiber, water-insoluble fiber, or fiber derived from fruit or cereal sources and risk of any stroke subtype. Vegetable fiber intake as well as consumption of fruit, vegetables, and cereals were inversely associated with risk of cerebral infarction; the multivariate relative risks (RR) for the highest quintile of intake compared with the lowest were 0.86 (95% confidence interval (CI): 0.76–0.99) for vegetable fiber, 0.82 (95% CI: 0.73–0.93) for fruit, 0.75 (95% CI: 0.66–0.85) for vegetables, and 0.87 (95% CI: 0.74–1.03) for cereals. Vegetable consumption was inversely associated with risk of subarachnoid hemorrhage (RR for highest versus lowest quintile: 0.62; 95% CI: 0.40–0.98) and cereal consumption was inversely associated with risk of intracerebral hemorrhage (RR: 0.64; 95% CI: 0.41–1.01).
These findings suggest a beneficial effect of consumption of fruits, vegetables, and cereals on stroke risk.
cereals; dietary fiber; fruits; prospective studies; stroke; vegetables
Findings on dietary glycaemic index (GI) and glycaemic load (GL) as risk factors for type 2 diabetes have been controversial. We examined the associations of dietary GI and GL and the associations of substitution of lower GI carbohydrates for higher GI carbohydrates with diabetes risk in a cohort of Finnish men. The cohort consisted of 25 943 male smokers aged 50–69 years. Diet was assessed, at baseline, using a validated diet history questionnaire. During a 12-year follow-up, 1 098 incident diabetes cases were identified from a national register. Cox proportional hazard modelling was used to estimate the risk for diabetes and multivariate nutrient density models to examine the effects of substitution of different carbohydrates. Dietary GI and GL were not associated with diabetes risk; multivariate relative risk (RR) for highest versus lowest quintile for GI was 0.87 (95% CI: 0.71, 1.07) and for GL 0.88 (95% CI: 0.65, 1.17). Substitution of medium GI carbohydrates for high GI carbohydrates was inversely associated with diabetes risk (multivariate RR for highest versus lowest quintile 0.75, 95% CI: 0.59, 0.96), but substitution of low GI carbohydrates for medium or high GI carbohydrates was not associated with the risk. In conclusion, dietary GI and GL were not associated with diabetes risk and substitutions of lower GI carbohydrates for higher GI carbohydrates were not consistently associated with lower diabetes risk. The associations of dietary GI and GL with diabetes risk should be interpreted by considering nutritional correlates, as foods may have different properties that affect risk.
glycaemic index; glycaemic load; carbohydrates; type 2 diabetes; ATBC Study
Studies suggest a decreased risk of high-grade prostate cancer in men with lower circulating total cholesterol, and that statins may protect against aggressive disease. Confirmation in additional populations and examination of associations for lipoprotein subfractions are needed.
We examined prostate cancer risk and serum total and HDL cholesterol in the ATBC Study cohort (n=29,093). Cox proportional hazards models were used to estimate the relative risk of total (n=2,041), non –aggressive (n=829), aggressive (n=461), advanced (n=412), and high-grade (n=231) prostate cancer by categories of total and HDL cholesterol.
After excluding the first 10 years of follow-up, men with higher serum total cholesterol were at increased risk of overall (≥240 vs. <200 mg/dL: HR=1.22, 95% CI 1.03-1.44, p-trend=0.01) and advanced (≥240 vs. <200 mg/dL: HR=1.85, 95% CI 1.13–3.03, p-trend=0.05) prostate cancer. Higher HDL cholesterol was suggestively associated with a decreased risk of prostate cancer regardless of stage or grade.
In this population of smokers, high serum total cholesterol was associated with higher risk of advanced prostate cancer, and high HDL cholesterol suggestively reduced the risk of prostate cancer overall. These results support previous studies and, indirectly, support the hypothesis that statins may reduce the risk of advanced prostate cancer by lowering cholesterol.
Cholesterol; HDL; Prospective Studies; Prostatic Neoplasms; Epidemiology; Risk; Molecular; Biomarker
Consumption of milk and other dairy foods has been inconsistently associated with risk of stroke. We examined the association between dairy food intake and risk of stroke subtypes within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.
Between 1985 and 1988, 26,556 Finnish male smokers aged 50–69 years who had no history of stroke completed a food frequency questionnaire. We used Cox proportional hazards models to estimate relative risks (RR) and 95% confidence intervals (CI), adjusted for potential confounders.
During a mean follow-up of 13.6 years, 2702 cerebral infarctions, 383 intracerebral hemorrhages, and 196 subarachnoid hemorrhages were ascertained. We observed positive associations between whole milk intake and risk of intracerebral hemorrhage (RR = 1.41 for the highest versus lowest quintile of intake; 95% CI = 1.02–1.96) and between yogurt intake and subarachnoid hemorrhage (RR = 1.83 for the highest versus lowest quintile of intake; 95% CI = 1.20–2.80). Men in the highest quintile of cream intake had a modest decreased risk of cerebral infarction (RR = 0.81; 95% CI = 0.72–0.92) and intracerebral hemorrhage (RR = 0.72; 95% CI = 0.52–1.00). There were no strong associations between intakes of total dairy, low fat milk, sour milk, cheese, ice cream, or butter and risk of any stroke subtype.
These findings suggest that intake of certain dairy foods may be associated with risk of stroke.
dairy; diet; epidemiology; milk; prospective studies; stroke
Relatively small lifestyle modifications related to weight reduction, physical activity and diet has been shown to decrease the risk of type 2 diabetes. Connected with diet, low consumption of meat has been suggested as a protective factor of diabetes. The aim was to examine the association between the consumption of total meat or the specific types of meat and risk of type 2 diabetes. The ATBC cohort included middle aged male smokers. During up to 12 years of follow-up, 1098 incident cases of diabetes were diagnosed from 24,845 participants through the nationwide register. Food consumption was assessed by a validated food frequency questionnaire. In the age and intervention group adjusted model, high total meat consumption was a risk factor of type 2 diabetes (relative risk (RR) 1.50, 95% confidence interval (CI): 1.23, 1.82, highest vs. lowest quintile). The result was similar after adjustment for environmental factors and foods related to diabetes and meat consumption. The RR of type 2 diabetes was 1.37 for processed meat (95% CI: 1.11, 1.71) in the multivariate model. The results were explained more by intakes of sodium than intakes of saturated fatty acids, protein, cholesterol, heme iron, magnesium and nitrate, and were not modified by obesity. No association was found between red meat, poultry and the risk of type 2 diabetes. In conclusion, it may help to prevent the global epidemic of type 2 diabetes by reducing the consumption of processed meat. It seems that sodium of processed meat may explain the association.
cohort study; epidemiology; meat; processed meat; diabetes
Two primary prevention trials unexpectedly demonstrated adverse effects of supplemental β-carotene on lung cancer incidence in cigarette smokers. To elucidate the molecular mechanisms that might underlie these effects, we studied the immunohistochemical expression of cytochrome P450 (CYP) 1A1, 1A2, and 2E1, retinoic acid receptor-β (RAR-β), activated protein-1 (AP-1) elements, cyclin D1, and Ki67 in lung tumors and, when available, adjacent normal tissues obtained from incident cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Archival lung tissue was available from 52 men randomized to receive 20 mg of β-carotene per day and 30 men randomized to the placebo arm, all of whom were diagnosed with incident non-small cell lung carcinoma during the course of the trial and subsequently underwent radical pulmonary resection. In normal appearing bronchial epithelium, positive staining for cyclin D1 was observed in 23% of cases in the β-carotene group and 0% of cases in the placebo group (based on only 3 of 13 versus 0 of 11 cases staining positively, however; p=0.04), with no differences in expression noted in lung tumor tissue (p=0.48). There were no statistically significant differences in Ki67 expression in normal or cancerous lung tissue between intervention groups, although a small increase in staining was noted among cases in the β-carotene versus placebo group (88% versus 71% of cases stained positive, respectively; p=0.13). Contrary to expectation, β-carotene supplementation had no apparent effect on RAR-β expression. These findings suggest that male smokers supplemented with β-carotene may have had an increased risk of lung cancer due to aberrant cell growth, although our results are based on a relatively small number of cases and require confirmation in other completed trials of β-carotene supplementation.
β-carotene; immunohistochemistry; lung cancer; smoking; supplementation