Circulating Isovalerylcarnitine and Lung Cancer Risk: Evidence from Mendelian Randomization and Prediagnostic Blood Measurements.

BACKGROUND: Tobacco exposure causes 8 of 10 lung cancers, and identifying additional risk factors is challenging due to confounding introduced by smoking in traditional observational studies. MATERIALS AND METHODS: We used Mendelian randomization (MR) to screen 207 metabolites for their role in lung cancer predisposition using independent genome-wide association studies (GWAS) of blood metabolite levels (n = 7,824) and lung cancer risk (n = 29,266 cases/56,450 controls). A nested case-control study (656 cases and 1,296 matched controls) was subsequently performed using prediagnostic blood samples to validate MR association with lung cancer incidence data from population-based cohorts (EPIC and NSHDS). RESULTS: An MR-based scan of 207 circulating metabolites for lung cancer risk identified that blood isovalerylcarnitine (IVC) was associated with a decreased odds of lung cancer after accounting for multiple testing (log10-OR = 0.43; 95% CI, 0.29-0.63). Molar measurement of IVC in prediagnostic blood found similar results (log10-OR = 0.39; 95% CI, 0.21-0.72). Results were consistent across lung cancer subtypes. CONCLUSIONS: Independent lines of evidence support an inverse association of elevated circulating IVC with lung cancer risk through a novel methodologic approach that integrates genetic and traditional epidemiology to efficiently identify novel cancer biomarkers. IMPACT: Our results find compelling evidence in favor of a protective role for a circulating metabolite, IVC, in lung cancer etiology. From the treatment of a Mendelian disease, isovaleric acidemia, we know that circulating IVC is modifiable through a restricted protein diet or glycine and L-carnatine supplementation. IVC may represent a modifiable and inversely associated biomarker for lung cancer.

Coffee consumption and colorectal cancer risk: a multicentre case-control study from Italy and Spain.

BACKGROUND: Coffee contains many bioactive substances that can play a role on colorectal cancer. Epidemiological evidence of coffee intake and colorectal cancer is, however, inconsistent. AIM: To provide further information on the risk of colorectal cancer in relation to coffee consumption. METHODS: Data derive from two companion case-control studies conducted in Italy and Spain within the European Union Project on Health Impacts of long-term exposure to disinfection by-products in Drinking Water and the Spanish Multi-Case Control study on Cancer. These included a total of 2289 incident cases with colorectal cancer and 3995 controls with information on coffee intake. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were derived from unconditional logistic regression models, adjusted for study centre, sex, age, education, smoking, and other covariates. RESULTS: Compared with never coffee drinkers, the OR was 0.99 (95% CI 0.95-1.02) for total coffee consumption. There was no significant trend in risk with dose or duration, the ORs being 0.95 (95% CI 0.72-1.25) for an amount of five or more cups per day of coffee and 0.95 (95% CI 0.75-1.19) for a duration of consumption of 50 years or longer. The OR was 1.04 (95% CI 0.87-1.25) for two or more cups per day of decaffeinated coffee. There were no heterogeneity across strata of various covariates, as well as no apparent differences between various anatomical subsites. CONCLUSION: This large pooled analysis of two studies shows no association of coffee and decaffeinated coffee with colorectal cancer risk.

Interaction Between GAD65 Antibodies and Dietary Fish Intake or Plasma Phospholipid n-3 Polyunsaturated Fatty Acids on Incident Adult-Onset Diabetes: The EPIC-InterAct Study.

OBJECTIVE: Islet autoimmunity is associated with diabetes incidence. We investigated whether there was an interaction between dietary fish intake or plasma phospholipid n-3 polyunsaturated fatty acid (PUFA) concentration with the 65-kDa isoform of GAD (GAD65) antibody positivity on the risk of developing adult-onset diabetes. RESEARCH DESIGN AND METHODS: We used prospective data on 11,247 incident cases of adult-onset diabetes and 14,288 noncases from the EPIC-InterAct case-cohort study conducted in eight European countries. Baseline plasma samples were analyzed for GAD65 antibodies and phospholipid n-3 PUFAs. Adjusted hazard ratios (HRs) for incident diabetes in relation to GAD65 antibody status and tertiles of plasma phospholipid n-3 PUFA or fish intake were estimated using Prentice-weighted Cox regression. Additive (proportion attributable to interaction [AP]) and multiplicative interactions between GAD65 antibody positivity (≥65 units/mL) and low fish/n-3 PUFA were assessed. RESULTS: The hazard of diabetes in antibody-positive individuals with low intake of total and fatty fish, respectively, was significantly elevated (HR 2.52 [95% CI 1.76-3.63] and 2.48 [1.79-3.45]) compared with people who were GAD65 antibody negative and had high fish intake, with evidence of additive (AP 0.44 [95% CI 0.16-0.72] and 0.48 [0.24-0.72]) and multiplicative (P = 0.0465 and 0.0103) interactions. Individuals with high GAD65 antibody levels (≥167.5 units/mL) and low total plasma phospholipid n-3 PUFAs had a more than fourfold higher hazard of diabetes (HR 4.26 [2.70-6.72]) and an AP of 0.46 (0.12-0.80) compared with antibody-negative individuals with high n-3 PUFAs. CONCLUSIONS: High fish intake or relative plasma phospholipid n-3 PUFA concentrations may partially counteract the increased diabetes risk conferred by GAD65 antibody positivity.