Meta-analysis of case-control genome-wide association studies (GWAS) for early onset and morbid obesity identified four variants in/near the PRL, PTER, MAF and NPC1 genes.
We aimed to validate ...association of these variants with obesity-related traits in population-based samples.
Genotypes and anthropometric traits were available in up to 31 083 adults from the Fenland, EPIC-Norfolk, Whitehall II, Ely and Hertfordshire studies and in 2042 children and adolescents from the European Youth Heart Study. In each study, we tested associations of rs4712652 (near-PRL), rs10508503 (near-PTER), rs1424233 (near-MAF) and rs1805081 (NPC1), or proxy variants (r (2)>0.8), with the odds of being overweight and obese, as well as with body mass index (BMI), percentage body fat (%BF) and waist circumference (WC). Associations were adjusted for sex, age and age(2) in adults and for sex, age, age group, country and maturity in children and adolescents. Summary statistics were combined using fixed effects meta-analysis methods.
We had 80% power to detect odds ratios of 1.046 to 1.092 for overweight and 1.067 to 1.136 for obesity. Variants near PRL, PTER and MAF were not associated with the odds of being overweight or obese, or with BMI, %BF or WC after meta-analysis (P>0.15). The NPC1 variant rs1805081 showed some evidence of association with %BF (β=0.013 s.d./allele, P=0.040), but not with any of the remaining obesity-related traits (P>0.3).
Overall, these variants, which were identified in a GWAS for early onset and morbid obesity, do not seem to influence obesity-related traits in the general population.
Higher coffee intake has been purportedly related to a lower risk of liver cancer. However, it remains unclear whether this association may be accounted for by specific biological mechanisms.
We ...aimed to evaluate the potential mediating roles of inflammatory, metabolic, liver injury, and iron metabolism biomarkers on the association between coffee intake and the primary form of liver cancer-hepatocellular carcinoma (HCC).
We conducted a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition among 125 incident HCC cases matched to 250 controls using an incidence-density sampling procedure. The association of coffee intake with HCC risk was evaluated by using multivariable-adjusted conditional logistic regression that accounted for smoking, alcohol consumption, hepatitis infection, and other established liver cancer risk factors. The mediating effects of 21 biomarkers were evaluated on the basis of percentage changes and associated 95% CIs in the estimated regression coefficients of models with and without adjustment for biomarkers individually and in combination.
The multivariable-adjusted RR of having ≥4 cups (600 mL) coffee/d compared with <2 cups (300 mL)/d was 0.25 (95% CI: 0.11, 0.62; P-trend = 0.006). A statistically significant attenuation of the association between coffee intake and HCC risk and thereby suspected mediation was confirmed for the inflammatory biomarker IL-6 and for the biomarkers of hepatocellular injury glutamate dehydrogenase, alanine aminotransferase, aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), and total bilirubin, which-in combination-attenuated the regression coefficients by 72% (95% CI: 7%, 239%). Of the investigated biomarkers, IL-6, AST, and GGT produced the highest change in the regression coefficients: 40%, 56%, and 60%, respectively.
These data suggest that the inverse association of coffee intake with HCC risk was partly accounted for by biomarkers of inflammation and hepatocellular injury.
The Systematic COronary Risk Evaluation – Older Persons (SCORE-OP) algorithm is developed to assess 10-year risk of death due to cardiovascular disease (CVD) in individuals aged ≥65 years. We studied ...the performance of SCORE-OP in the European Prospective Investigation of Cancer Norfolk (EPIC-Norfolk) prospective population cohort.
10-year CVD mortality as predicted by SCORE-OP was compared with observed CVD mortality among individuals in the EPIC-Norfolk cohort. Persons aged 65–79 years without known CVD were included in the analysis. CVD mortality was defined as death due to ischemic heart disease, cardiac failure, cerebrovascular disease, peripheral-artery disease or aortic aneurysm. Predicted 10-year CVD mortality was calculated by the SCORE-OP algorithm, and compared to observed mortality rates. The area under the receiver operator characteristics curve (AUROC) was calculated to evaluate discriminative power. Calibration was evaluated by calculating ratios of predicted vs observed mortality and by Hosmer-Lemeshow tests.
A total of 6590 individuals (45.8% men), mean age 70.2 years (standard deviation 3.3) were included. The predicted mortality by SCORE-OP was 9.84% (95% confidence interval (CI) 9.76–9.92) and observed mortality was 10.2% (95% CI 9.52–11.04), ratio 0.96. AUROC was 0.63 (95% CI 0.60–0.65), and X2 was 3.3 (p = 0.92).
SCORE-OP overall accurately estimates the rate of CVD mortality in a general population aged 65–79 years. However, while calibration is excellent, the discriminative power of the SCORE-OP is limited, and as such cannot be readily implemented in clinical practice for this population.
•SCORE-OP overall accurately estimates the rate of CVD mortality in individuals aged 65–79 years in the general population.•SCORE-OP overestimates the rate of CVD mortality in younger (65–69 years) individuals.•SCORE-OP underestimates the rate of CVD mortality in older (70–79 years) individuals.•Discriminative performance of SCORE-OP was limited and warrants attention before SCORE-OP is implemented in daily practice.
Hepcidin is the main regulator of iron homeostasis and dysregulation of proteins involved in iron metabolism has been associated with tumorogenesis. However, to date, no epidemiological study has ...researched the association between hepcidin levels and gastric cancer risk. To further investigate the relationship between hepcidin levels and gastric cancer risk, we conducted a nested case‐control study (EURGAST) within the multicentric European Prospective Investigation into Cancer and Nutrition study. The study included 456 primary incident gastric adenocarcinoma cases and 900 matched controls that occurred during an average of 11 years of follow‐up. We measured serum levels of hepcidin‐25, iron, ferritin, transferrin and C‐reactive protein. Odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of gastric cancer by hepcidin levels were estimated from multivariable conditional logistic regression models. Mediation effect of the ferritin levels on the hepcidin‐gastric cancer pathway was also evaluated. After adjusting for relevant confounders, we observed a statistically significant inverse association between gastric cancer and hepcidin levels (OR 5 ng/l = 0.96, 95% CI = 0.93–0.99). No differences were found by tumor localization or histological type. In mediation analysis, we found that the direct effect of hepcidin only represents a nonsignificant 38% (95% CI: −69%, 91%). In summary, these data suggest that the inverse association of hepcidin levels and gastric cancer risk was mostly accounted by ferritin levels. Further investigation including repeated measures of hepcidin is needed to clarify their role in gastric carcinogenesis.
What's new?
New results link gastric cancer risk to iron metabolism. Disruptions in iron metabolism can lead to cancer, and these authors investigate for the first time a link between gastric cancer risk and levels of the iron‐regulating protein hepcidin. Stomach cells produce hepcidin, and low hepcidin can allow bacterial overgrowth that causes ulcers. The authors conducted a case‐control study and measured pre‐diagnostic levels of both hepcidin and ferritin. Higher hepcidin levels correlated with lower cancer risk; further analysis revealed that the relationship between the two relies on ferritin, consistent with previous findings that higher levels of stored iron stimulates hepcidin production.
The purpose of this study was to examine the relationship between breast arterial calcification (BAC), commonly found on mammography, and cardiovascular disease and its risk factors.
The study ...population, nested within the European Prospective Investigation of Cancer-Norfolk (EPIC-Norfolk) cohort study, consisted of 1,590 women older than 55 years, not taking hormone replacement therapy, and with available screening mammograms. Mammograms were coded by three radiologists for presence or absence of BAC. History of coronary heart disease (CHD), stroke, and diabetes and risk factors for cardiovascular disease (including smoking status, body mass index BMI, blood pressure, diabetes, and glycosylated hemoglobin HbA1c) were independently measured from health examinations in the EPIC study.
The prevalence of BAC was 16.0%. Women with BAC were significantly older than those without it. BAC was associated with prevalent CHD, but not stroke. The odds ratio of having CHD was 2.54 (95% confidence interval, 1.03-6.30). The sensitivity and specificity were 32.4% and 85.5%, respectively. Except for smoking, which showed an inverse association, there was no consistent significant association of BAC with cardiovascular disease risk factors including BMI, diabetes, HbA1c, or lipids.
BAC found on mammograms was associated with prevalent CHD after adjustment for age, but with low sensitivity. BAC may provide additional information toward identifying cardiovascular disease risk among otherwise healthy women.
CA125 is the best ovarian cancer early detection marker to date; however, sensitivity is limited and complementary markers are required to improve discrimination between ovarian cancer cases and ...non‐cases. Anti‐CA125 autoantibodies are observed in circulation. Our objective was to evaluate whether these antibodies (1) can serve as early detection markers, providing evidence of an immune response to a developing tumor, and (2) modify the discriminatory capacity of CA125 by either masking CA125 levels (resulting in lower discrimination) or acting synergistically to improve discrimination between cases and non‐cases. We investigated these objectives using a nested case–control study within the European Prospective Investigation into Cancer and Nutrition cohort (EPIC) including 250 cases diagnosed within 4 years of blood collection and up to four matched controls. Circulating CA125 antigen and antibody levels were quantified using an electrochemiluminescence assay. Adjusted areas under the curve (aAUCs) by 2‐year lag‐time intervals were calculated using conditional logistic regression calibrated toward the absolute risk estimates from a pre‐existing epidemiological risk model as an offset‐variable. Anti‐CA125 levels alone did not discriminate cases from controls. For cases diagnosed <2 years after blood collection, discrimination by CA125 antigen was suggestively higher with higher anti‐CA125 levels (aAUC, highest antibody tertile: 0.84 0.76–0.92; lowest tertile: 0.76 0.67–0.86; phet = 0.06). We provide the first evidence of potentially synergistic discrimination effects of CA125 and anti‐CA125 antibodies in ovarian early detection. If these findings are replicated, evaluating CA125 in the context of its antibody may improve ovarian cancer early detection.
What's new?
Although CA125, a mucin produced in epithelial cells, is a known marker for ovarian cancer, complementary biomarkers are necessary for reliable early cancer detection. Here, the authors examined autoantibodies against CA125 as potential pre‐diagnosis markers. Although anti‐CA125 levels did not discriminate between ovarian cases and controls, discrimination of CA125 differed by levels of its antibody, with the highest discrimination among women with the highest antibody levels. The authors propose that CA125 and anti‐CA125 may act synergistically for ovarian cancer early detection.
Although genome-wide association studies (GWAS) for prostate cancer (PrCa) have identified more than 100 risk regions, most of the risk genes at these regions remain largely unknown. Here we ...integrate the largest PrCa GWAS (N = 142,392) with gene expression measured in 45 tissues (N = 4458), including normal and tumor prostate, to perform a multi-tissue transcriptome-wide association study (TWAS) for PrCa. We identify 217 genes at 84 independent 1 Mb regions associated with PrCa risk, 9 of which are regions with no genome-wide significant SNP within 2 Mb. 23 genes are significant in TWAS only for alternative splicing models in prostate tumor thus supporting the hypothesis of splicing driving risk for continued oncogenesis. Finally, we use a Bayesian probabilistic approach to estimate credible sets of genes containing the causal gene at a pre-defined level; this reduced the list of 217 associations to 109 genes in the 90% credible set. Overall, our findings highlight the power of integrating expression with PrCa GWAS to identify novel risk loci and prioritize putative causal genes at known risk loci.
Abstract Background Serum C-reactive protein (CRP) is a marker of general systemic inflammation. It has been suggested that inflammation may have a role in osteoporosis and subsequent fracture risk. ...We examined the prospective relationship between CRP and fracture risk in a large cohort study. Methods The study populations were 18,586 men and women aged 40–79 enrolled between 1993 and 1997 in the European Prospective Investigation into Cancer in Norfolk study (EPIC-Norfolk), who had high sensitivity serum CRP measured in frozen serum from baseline. After 261,563 person-years of follow up (Median (inter-quartile range) follow-up time was 14.8 (13.6–16.1) years), 792 incident fractures (291 hip fractures) were ascertained by hospital record linkage. All multivariate regression models were adjusted for age, sex, body mass index, smoking, alcohol intake, physical activity, past history of fractures, history of osteoporosis, use of NSAIDs and corticosteroid medication, medical history of arthritis, cancer, myocardial infarction, stroke and diabetes, and in women only menopausal status and postmenopausal Hormone Replacement Therapy. Results We found a U-shaped association for CRP and fracture risk. The lowest risk of fracture was observed for men and women with baseline CRP levels in the range of 1.1–2 mg/L in fractional polynomial Cox-proportional hazards regression analysis. Hazard ratios of all-fractures for participants with CRP levels 0.1–0.5; 0.6–1; 1.1–2; 2.1–3; 3.1–10; and above 10 mg/L were 1.31 (1.03, 1.66); 1.21 (0.98, 1.51); 1.00 (referent category); 1.06 (0.82, 1.35); 1.22 (1.00, 1.51); and 1.29 (0.91, 1.81) respectively. Although a similar U-shaped association was observed for hip fractures, the corresponding hazard ratios were not statistically significant. Conclusion A U-shaped association was observed between CRP and fracture risk. The increased risk of fracture observed at lower end of CRP compared to intermediate levels require further exploration, confirmation in other populations, and investigation into potential biological mechanisms.
Abstract We present the main findings observed to date from the European Prospective Investigation into Cancer and Nutrition (EPIC) on dietary factors associated with the most frequent cancer sites. ...Methods EPIC is a multicentre prospective study carried out in 23 centres in 10 European countries: Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden and the United Kingdom, including 519,978 participants (366,521 women and 153,457 men), most aged 35–70 years. Results We observed the following significant associations: gastric cancer risk was inversely associated with high plasma vitamin C, some carotenoids, retinol and α-tocopherol, high intake of cereal fibre and high adhesion to Mediterranean diet, while red and processed meat were associated with increased risk. High intake of dietary fibre, fish, calcium, and plasma vitamin D were associated with a decreased risk of colorectal cancer, while red and processed meat intake, alcohol intake, body mass index (BMI) and abdominal obesity were associated with an increased risk. High intake of fruit and vegetables in current smokers were associated with a decreased risk of lung cancer. An increased risk of breast cancer was associated with high saturated fat intake and alcohol intake. In postmenopausal women, BMI was positively and physical activity negatively associated with breast cancer risk. High intake of dairy protein and calcium from dairy products and high serum concentration of IGF-I were associated with an increased risk of prostate cancer. These results contribute to scientific evidence for appropriate public health strategies and prevention activities aimed at reducing the global cancer burden.
Abstract Aim Weight change during adult life may reflect metabolic changes and influence colorectal cancer (CRC) development, but such role is not well established. We aimed to explore the ...association between adult weight change (from age 20 to 50) and CRC risk. In particular, we investigated differences according to colon and rectal cancer, sex and measures of attained adiposity. Methods We included 201,696 participants from six participating countries in the European Prospective Investigation into Cancer and Nutrition (1992–2010). During a mean follow-up of 11.2 years 2384 (1194 in men and 1190 in women) incident CRC cases occurred. Cox proportional hazard models adjusted for body mass index at age 20 and lifestyle factors at study recruitment were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results After multivariable adjustment, each kg of weight gained annually from age 20 to 50 was associated with a 60% higher risk of colon cancer (95% CI 1.20–2.09), but not rectal cancer (HR 1.13, 95% CI 0.79–1.62, Pinteraction = 0.04). The higher risk of colon cancer was restricted to people with high attained waist circumference at age 50 (HR 1.82, 95% CI 1.14–2.91, Pinteraction = 0.02). Results were not different in men and women ( Pinteraction = 0.81). Conclusion(s) Adult weight gain, as reflected by attained abdominal obesity at age 50, increases colon cancer risk in both men and women. These data underline the importance of weight management and metabolic health maintenance in early adult life years for colon cancer prevention.
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