Obesity and associated metabolic disorders have been implicated in liver carcinogenesis; however, there are little data on the role of obesity‐related biomarkers on liver cancer risk. We studied ...prospectively the association of inflammatory and metabolic biomarkers with risks of hepatocellular carcinoma (HCC), intrahepatic bile duct (IBD), and gallbladder and biliary tract cancers outside of the liver (GBTC) in a nested case‐control study within the European Prospective Investigation into Cancer and Nutrition. Over an average of 7.7 years, 296 participants developed HCC (n = 125), GBTC (n = 137), or IBD (n = 34). Using risk‐set sampling, controls were selected in a 2:1 ratio and matched for recruitment center, age, sex, fasting status, and time of blood collection. Baseline serum concentrations of C‐reactive protein (CRP), interleukin‐6 (IL‐6), C‐peptide, total high‐molecular‐weight (HMW) adiponectin, leptin, fetuin‐a, and glutamatdehydrogenase (GLDH) were measured, and incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. After adjustment for lifestyle factors, diabetes, hepatitis infection, and adiposity measures, higher concentrations of CRP, IL‐6, C‐peptide, and non‐HMW adiponectin were associated with higher risk of HCC (IRR per doubling of concentrations = 1.22; 95% CI = 1.02‐1.46; P = 0.03; 1.90; 95% CI = 1.30‐2.77; P = 0.001; 2.25; 95% CI = 1.43‐3.54; P = 0.0005; and 2.09; 95% CI = 1.19‐3.67; P = 0.01, respectively). CRP was associated also with risk of GBTC (IRR = 1.22; 95% CI = 1.05‐1.42; P = 0.01). GLDH was associated with risks of HCC (IRR = 1.62; 95% CI = 1.25‐2.11; P = 0.0003) and IBD (IRR = 10.5; 95% CI = 2.20‐50.90; P = 0.003). The continuous net reclassification index was 0.63 for CRP, IL‐6, C‐peptide, and non‐HMW adiponectin and 0.46 for GLDH, indicating good predictive ability of these biomarkers. Conclusion: Elevated levels of biomarkers of inflammation and hyperinsulinemia are associated with a higher risk of HCC, independent of obesity and established liver cancer risk factors. (Hepatology 2014;60:858–871)
Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically ...investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention.
The InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a cohort of 340,234 European participants with 3.99 million person-years of follow-up. We studied the combined effects of an additive genetic T2D risk score and modifiable and non-modifiable risk factors using Prentice-weighted Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly greater in younger individuals (p for interaction = 1.20×10-4). Relative genetic risk (per standard deviation 4.4 risk alleles) was also larger in participants who were leaner, both in terms of body mass index (p for interaction = 1.50×10-3) and waist circumference (p for interaction = 7.49×10-9). Examination of absolute risks by strata showed the importance of obesity for T2D risk. The 10-y cumulative incidence of T2D rose from 0.25% to 0.89% across extreme quartiles of the genetic score in normal weight individuals, compared to 4.22% to 7.99% in obese individuals. We detected no significant interactions between the genetic score and sex, diabetes family history, physical activity, or dietary habits assessed by a Mediterranean diet score.
The relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this sub-group is at low absolute risk and would not be a logical target for preventive interventions. The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention.
Tobacco smoking is a known cause of gastric cancer, but several aspects of the association remain imprecisely quantified. We examined the relation between cigarette smoking and the risk of gastric ...cancer using a uniquely large dataset of 23 epidemiological studies within the 'Stomach cancer Pooling (StoP) Project', including 10 290 cases and 26 145 controls. We estimated summary odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) by pooling study-specific ORs using random-effects models. Compared with never smokers, the ORs were 1.20 (95% CI: 1.09-1.32) for ever, 1.12 (95% CI: 0.99-1.27) for former, and 1.25 (95% CI: 1.11-1.40) for current cigarette smokers. Among current smokers, the risk increased with number of cigarettes per day to reach an OR of 1.32 (95% CI: 1.10-1.58) for smokers of more than 20 cigarettes per day. The risk increased with duration of smoking, to reach an OR of 1.33 (95% CI: 1.14-1.54) for more than 40 years of smoking and decreased with increasing time since stopping cigarette smoking (P for trend<0.01) and became similar to that of never smokers 10 years after stopping. Risks were somewhat higher for cardia than noncardia gastric cancer. Risks were similar when considering only studies with information on Helicobacter pylori infection and comparing all cases to H. pylori+ controls only. This study provides the most precise estimate of the detrimental effect of cigarette smoking on the risk of gastric cancer on the basis of individual data, including the relationship with dose and duration, and the decrease in risk following stopping smoking.
We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 ...diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp- and oral glucose tolerance test-based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs per allele 95% CI, -0.03 -0.04, -0.01; P = 0.004). This score was associated with lower BMI (-0.01 -0.01, -0.0; P = 0.02) and gluteofemoral fat mass (-0.03 -0.05, -0.02; P = 1.4 × 10(-6)) and with higher alanine transaminase (0.02 0.01, 0.03; P = 0.002) and γ-glutamyl transferase (0.02 0.01, 0.03; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (Pinteraction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (Pinteraction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.
Conflicting evidence exists regarding the association between saturated fatty acids (SFAs) and type 2 diabetes. In this longitudinal case-cohort study, we aimed to investigate the prospective ...associations between objectively measured individual plasma phospholipid SFAs and incident type 2 diabetes in EPIC-InterAct participants.
The EPIC-InterAct case-cohort study includes 12 403 people with incident type 2 diabetes and a representative subcohort of 16 154 individuals who were selected from a cohort of 340 234 European participants with 3·99 million person-years of follow-up (the EPIC study). Incident type 2 diabetes was ascertained until Dec 31, 2007, by a review of several sources of evidence. Gas chromatography was used to measure the distribution of fatty acids in plasma phospholipids (mol%); samples from people with type 2 diabetes and subcohort participants were processed in a random order by centre, and laboratory staff were masked to participant characteristics. We estimated country-specific hazard ratios (HRs) for associations per SD of each SFA with incident type 2 diabetes using Prentice-weighted Cox regression, which is weighted for case-cohort sampling, and pooled our findings using random-effects meta-analysis.
SFAs accounted for 46% of total plasma phospholipid fatty acids. In adjusted analyses, different individual SFAs were associated with incident type 2 diabetes in opposing directions. Even-chain SFAs that were measured (14:0 myristic acid, 16:0 palmitic acid, and 18:0 stearic acid) were positively associated with incident type 2 diabetes (HR 95% CI per SD difference: myristic acid 1·15 95% CI 1·09–1·22, palmitic acid 1·26 1·15–1·37, and stearic acid 1·06 1·00–1·13). By contrast, measured odd-chain SFAs (15:0 pentadecanoic acid and 17:0 heptadecanoic acid) were inversely associated with incident type 2 diabetes (HR 95% CI per 1 SD difference: 0·79 0·73–0·85 for pentadecanoic acid and 0·67 0·63–0·71 for heptadecanoic acid), as were measured longer-chain SFAs (20:0 arachidic acid, 22:0 behenic acid, 23:0 tricosanoic acid, and 24:0 lignoceric acid), with HRs ranging from 0·72 to 0·81 (95% CIs ranging between 0·61 and 0·92). Our findings were robust to a range of sensitivity analyses.
Different individual plasma phospholipid SFAs were associated with incident type 2 diabetes in opposite directions, which suggests that SFAs are not homogeneous in their effects. Our findings emphasise the importance of the recognition of subtypes of these fatty acids. An improved understanding of differences in sources of individual SFAs from dietary intake versus endogenous metabolism is needed.
EU FP6 programme, Medical Research Council Epidemiology Unit, Medical Research Council Human Nutrition Research, and Cambridge Lipidomics Biomarker Research Initiative.
The long-term association between dietary protein and type 2 diabetes incidence is uncertain. We aimed to investigate the association between total, animal, and plant protein intake and the incidence ...of type 2 diabetes.
The prospective European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study consists of 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,154 individuals from eight European countries, with an average follow-up time of 12.0 years. Pooled country-specific hazard ratios (HRs) and 95% CI of prentice-weighted Cox regression analyses were used to estimate type 2 diabetes incidence according to protein intake.
After adjustment for important diabetes risk factors and dietary factors, the incidence of type 2 diabetes was higher in those with high intake of total protein (per 10 g: HR 1.06 95% CI 1.02-1.09, P(trend) < 0.001) and animal protein (per 10 g: 1.05 1.02-1.08, P(trend) = 0.001). Effect modification by sex (P < 0.001) and BMI among women (P < 0.001) was observed. Compared with the overall analyses, associations were stronger in women, more specifically obese women with a BMI >30 kg/m(2) (per 10 g animal protein: 1.19 1.09-1.32), and nonsignificant in men. Plant protein intake was not associated with type 2 diabetes (per 10 g: 1.04 0.93-1.16, P(trend) = 0.098).
High total and animal protein intake was associated with a modest elevated risk of type 2 diabetes in a large cohort of European adults. In view of the rapidly increasing prevalence of type 2 diabetes, limiting iso-energetic diets high in dietary proteins, particularly from animal sources, should be considered.
Background
Previous studies suggest that dietary vitamin C is inversely associated with gastric cancer (GC), but most of them did not consider intake of fruit and vegetables. Thus, we aimed to ...evaluate this association within the Stomach cancer Pooling (StoP) Project, a consortium of epidemiological studies on GC.
Methods
Fourteen case–control studies were included in the analysis (5362 cases, 11,497 controls). We estimated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the association between dietary intake of vitamin C and GC, adjusted for relevant confounders and for intake of fruit and vegetables. The dose–response relationship was evaluated using mixed-effects logistic models with second-order fractional polynomials.
Results
Individuals in the highest quartile of dietary vitamin C intake had reduced odds of GC compared with those in the lowest quartile (OR: 0.64; 95% CI: 0.58, 0.72). Additional adjustment for fruit and vegetables intake led to an OR of 0.85 (95% CI: 0.73, 0.98). A significant inverse association was observed for noncardia GC, as well as for both intestinal and diffuse types of the disease. The results of the dose–response analysis showed decreasing ORs of GC up to 150–200 mg/day of vitamin C (OR: 0.54; 95% CI: 0.41, 0.71), whereas ORs for higher intakes were close to 1.0.
Conclusions
The findings of our pooled study suggest that vitamin C is inversely associated with GC, with a potentially beneficial effect also for intakes above the currently recommended daily intake (90 mg for men and 75 mg for women).
Other than the influence of ionizing radiation and benign thyroid disease, little is known about the risk factors for differentiated thyroid cancer (TC) which is an increasing common cancer ...worldwide. Consistent evidence shows that body mass is positively associated with TC risk. As excess weight is a state of chronic inflammation, we investigated the relationship between concentrations of leptin, adiponectin, C‐reactive protein, interleukin (IL)‐6, IL‐10 and tumor necrosis factor (TNF)‐α and the risk of TC. A case‐control study was nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study and included 475 first primary incident TC cases (399 women and 76 men) and 1,016 matched cancer‐free cohort participants. Biomarkers were measured in serum samples using validated and highly sensitive commercially available immunoassays. Odds ratios (ORs) of TC by levels of each biomarker were estimated using conditional logistic regression models, adjusting for BMI and alcohol consumption. Adiponectin was inversely associated with TC risk among women (ORT3vs.T1 = 0.69, 95% CI: 0.49–0.98, Ptrend = 0.04) but not among men (ORT3vs.T1 = 1.36, 95% CI: 0.67–2.76, Ptrend = 0.37). Increasing levels of IL‐10 were positively associated with TC risk in both genders and significantly so in women (ORT3vs.T1 = 1.59, 95% CI: 1.13–2.25, Ptrend = 0.01) but not in men (ORT3vs.T1 = 1.78, 95% CI: 0.80–3.98, Ptrend = 0.17). Leptin, CRP, IL‐6 and TNF‐α were not associated with TC risk in either gender. These results indicate a positive association of TC risk with IL‐10 and a negative association with adiponectin that is probably restricted to women. Inflammation may play a role in TC in combination with or independently of excess weight.
What's new?
How does being overweight lead to thyroid cancer? These authors investigated, using data from the EPIC cohort. Considering obesity as a state of chronic inflammation, they looked at levels of various proteins associated with inflammation, including C‐reactive protein, IL‐10, adiponectin, and others, and compared these with TC risk. Women with high adiponectin levels were less likely to develop thyroid cancer, while those with high IL‐10 levels had increased TC risk. No significant association was seen in men.
Dairy product intake may be inversely associated with risk of type 2 diabetes, but the evidence is inconclusive for total dairy products and sparse for types of dairy products.
The objective was to ...investigate the prospective association of total dairy products and different dairy subtypes with incidence of diabetes in populations with marked variation of intake of these food groups.
A nested case-cohort within 8 European countries of the European Prospective Investigation into Cancer and Nutrition Study (n = 340,234; 3.99 million person-years of follow-up) included a random subcohort (n = 16,835) and incident diabetes cases (n = 12,403). Baseline dairy product intake was assessed by using dietary questionnaires. Country-specific Prentice-weighted Cox regression HRs were calculated and pooled by using a random-effects meta-analysis.
Intake of total dairy products was not associated with diabetes (HR for the comparison of the highest with the lowest quintile of total dairy products: 1.01; 95% CI: 0.83, 1.34; P-trend = 0.92) in an analysis adjusted for age, sex, BMI, diabetes risk factors, education, and dietary factors. Of the dairy subtypes, cheese intake tended to have an inverse association with diabetes (HR: 0.88; 95% CI: 0.76, 1.02; P-trend = 0.01), and a higher combined intake of fermented dairy products (cheese, yogurt, and thick fermented milk) was inversely associated with diabetes (HR: 0.88; 95% CI: 0.78, 0.99; P-trend = 0.02) in adjusted analyses that compared extreme quintiles.
This large prospective study found no association between total dairy product intake and diabetes risk. An inverse association of cheese intake and combined fermented dairy product intake with diabetes is suggested, which merits further study.
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