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.

Dietary intake of total polyphenol and polyphenol classes and the risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Polyphenols may play a chemopreventive role in colorectal cancer (CRC); however, epidemiological evidence supporting a role for intake of individual polyphenol classes, other than flavonoids is insufficient. We evaluated the association between dietary intakes of total and individual classes and subclasses of polyphenols and CRC risk and its main subsites, colon and rectum, within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The cohort included 476,160 men and women from 10 European countries. During a mean follow-up of 14 years, there were 5991 incident CRC cases, of which 3897 were in the colon and 2094 were in the rectum. Polyphenol intake was estimated using validated centre/country specific dietary questionnaires and the Phenol-Explorer database. In multivariable-adjusted Cox regression models, a doubling in total dietary polyphenol intake was not associated with CRC risk in women (HRlog2 = 1.06, 95% CI 0.99-1.14) or in men (HRlog2 = 0.97, 95% CI 0.90-1.05), respectively. Phenolic acid intake, highly correlated with coffee consumption, was inversely associated with colon cancer in men (HRlog2 = 0.91, 95% CI 0.85-0.97) and positively associated with rectal cancer in women (HRlog2 = 1.10, 95% CI 1.02-1.19); although associations did not exceed the Bonferroni threshold for significance. Intake of other polyphenol classes was not related to colorectal, colon or rectal cancer risks. Our study suggests a possible inverse association between phenolic acid intake and colon cancer risk in men and positive with rectal cancer risk in women.

Assessing the relationship between perfluoroalkyl substances, thyroid hormones and binding proteins in pregnant women; a longitudinal mixed effects approach.

The mechanisms involved in thyroid homeostasis are complex, and perfluoroalkyl substances (PFASs) have been indicated to interfere at several levels in this endocrine system. Disruption of the maternal thyroid homeostasis during early pregnancy is of particular concern, where subclinical changes in maternal thyroid hormones (THs) may affect embryonic and foetal development. The present study investigated associations between THs, thyroid binding proteins (TH-BPs) and PFAS concentrations in pregnant women from Northern Norway. Women participating in The Northern Norway Mother-and-Child contaminant Cohort Study (MISA) donated a blood sample at three visits related to their pregnancy and postpartum period (during the second trimester, 3 days and 6 weeks after delivery) in the period 2007-2009. Participants were assigned to quartiles according to PFAS concentrations during the second trimester and mixed effects linear models were used to investigate potential associations between PFASs and repeated measurements of THs, TH-BPs, thyroxin binding capacity and thyroid peroxidase antibodies (anti-TPOs). Women within the highest perfluorooctane sulfonate (PFOS) quartile had 24% higher mean concentrations of thyroid stimulating hormone (TSH) compared to the first quartile at all sampling points. Women within the highest quartiles of perfluorodecanoate (PFDA) had 4% lower mean concentrations of triiodothyronine (T3) and women within the highest quartile of perfluoroundecanoate (PFUnDA) had 3% lower mean concentrations of free triiodothyronine (FT3). Further, the difference in concentrations and the changes between three time points were the same for the PFAS quartiles. Thyroxin binding capacity was associated with all the THs and TH-BPs, and was selected as a holistic adjustment for individual changes in TH homeostasis during pregnancy. Finally, adjusting for maternal iodine status did not influence the model predictions. Findings in the present study suggest modifications of TH homeostasis by PFASs in a background exposed maternal population. The variation in levels of THs between PFAS quartiles was within normal reference ranges and may not be of clinical significance in the pregnant woman. However, subtle individual changes in maternal THs may have significant consequences for foetal health.

The Northern Norway Mother-and-Child Contaminant Cohort (MISA) Study: PCA analyses of environmental contaminants in maternal sera and dietary intake in early pregnancy.

BACKGROUND: Although predictors of contaminants in serum or whole blood are usually examined by chemical groups (e.g., POPs, toxic and/or essential elements; dietary sources), principal component analysis (PCA) permits consideration of both individual substances and combined variables. OBJECTIVES: Our study had two primary objectives: (i) Characterize the sources and predictors of a suite of eight PCBs, four organochlorine (OC) pesticides, five essential and five toxic elements in serum and/or whole blood of pregnant women recruited as part of the Mother-and-Child Contaminant Cohort Study conducted in Northern Norway (The MISA study); and (ii) determine the influence of personal and social characteristics on both dietary and contaminant factors. METHODS: Recruitment and sampling started in May 2007 and continued for the next 31 months until December 2009. Blood/serum samples were collected during the 2nd trimester (mean: 18.2 weeks, range 9.0-36.0). A validated questionnaire was administered to obtain personal information. The samples were analysed by established laboratories employing verified methods and reference standards. PCA involved Varimax rotation, and significant predictors (p≤0.05) in linear regression models were included in the multivariable linear regression analysis. RESULTS: When considering all the contaminants, three prominent PCA axes stood out with prominent loadings of: all POPs; arsenic, selenium and mercury; and cadmium and lead. Respectively, in the multivariate models the following were predictors: maternal age, parity and consumption of freshwater fish and land-based wild animals; marine fish; cigarette smoking, dietary PCA axes reflecting consumption of grains and cereals, and food items involving hunting. PCA of only the POPs separated them into two axes that, in terms of recently published findings, could be understood to reflect longitudinal trends and their relative contributions to summed POPs. CONCLUSIONS: The linear combinations of variables generated by PCA identified prominent dietary sources of OC groups and of prominent toxic elements and highlighted the importance of maternal characteristics.

Consumption of lean fish reduces the risk of type 2 diabetes mellitus: a prospective population based cohort study of Norwegian women.

BACKGROUND: The effects of fish consumption and n-3 fatty acids on type 2 diabetes mellitus (T2DM) have recently been debated. OBJECTIVE: We explored the risk of T2DM in relation to consumption of lean fish, fatty fish, fish products and total fish as well as cod liver oil supplements in a representative sample of Norwegian women. DESIGN: This was a prospective population based cohort study in 33740 women free of T2DM, stroke, angina or heart attack and with detailed information on important co-variates and dietary intake at baseline. Risk ratios and corresponding 95% CI were estimated using Poisson regression with log-person time as offset. RESULTS: Lean fish consumption was inversely associated with T2DM compared to zero intake. Risk ratios and 95% CI for intake of 75 and 100 g lean fish per day were 0.71 (0.51, 0.98) and 0.67 (0.46, 0.98), respectively. There was no effect of intake of fatty fish, fish products, total fish or use of cod liver oil supplements on the risk of T2DM. CONCLUSION: Lean fish consumption of 75-100 g/d had a beneficial effect on T2DM. It remains unclear whether lean fish in itself has a protective effect on T2DM or that lean fish consumers have a protective life-style that we were not able to take into account in this study. Unfavorable effects of fatty fish consumption or use of cod liver oil supplements on T2DM were not observed.

Selected vitamins and essential elements in meat from semi-domesticated reindeer (Rangifer tarandus tarandus L.) in mid- and northern Norway: geographical variations and effect of animal population density.

Meat samples (n = 100) were collected from semi-domesticated reindeer originating from 10 grazing districts in Norway. We aimed at studying concentrations, correlations, geographical variations and the effect of animal population density on vitamins A, B3, B7, B12 and E, and calcium, iron, zinc, selenium, chromium and cobalt. Mean concentrations of vitamins A, B3, B7; B12 and E were <5 µg, 6.6 mg, <0.5 µg, 4.7 µg and 0.5 mg/100 g wet weight, respectively. Concentrations of calcium, iron, zinc, selenium, chromium and cobalt were 4.7 mg, 2.8 mg, 6.4 mg, 19.4 µg, 1.7 µg and 0.5 µg/100 g wet weight, respectively. Vitamin E and selenium were the nutrients that exhibited the largest geographical variations (p < 0.05), although no geographical gradient was observed for any of the studied nutrients. Age had a significant effect on zinc and selenium concentrations. Iron was significantly positive correlated with calcium (r = 0.3416, p < 0.01) and vitamin B12 with zinc (r = 0.35, p < 0.05). Reindeer from districts with low animal population density had significantly higher selenium concentration than those from districts with medium and high population densities (p < 0.01). Reindeer meat contained higher vitamin B12, iron, zinc and selenium concentrations when compared to Norwegian beef, lamb, mutton, pork and chicken meat.

Change in plasma levels of vitamin D after consumption of cod-liver and fresh cod-liver oil as part of the traditional north Norwegian fish dish "Mølje".

OBJECTIVE: To assess changes in plasma 25-hydroxy vitamin D (25(OH)D) concentrations after ingestion of <>, a traditional north Norwegian fish dish rich in vitamin D. METHODS: Thirty-three volunteers all living in the city of Tromsø, located in northern Norway (latitude 690), were served a "Mølje" meal consisting of cod, hard roe, cod liver, and fresh cod-liver oil. The amounts of liver, and cod-liver oil consumed were weighed and recorded. Blood samples were collected before the meal, and at 4 hours, 12 hours and 5 days after it. The cod liver and cod-liver oil were analysed for vitamin D content and the plasma samples for the metabolite 25(OH)D. Trends in plasma 25(OH)D levels during the five-day observation period were analysed. The study was conducted at the beginning of April of 2000. RESULTS: Among the 33 participating subjects, 69.7% had baseline plasma 25(OH)D concentrations below 50 nmol/l and for one-quarter of the subjects, they were < 37.5 nmol/l The participants who acknowledged taking cod-liver oil supplements had significantly higher baseline 25(OH)D plasma levels at the outset of the study compared to those reporting not doing so (p = 0.02). Changes in plasma 25(OH)D levels relative to baseline concentrations were significantly associated with the body mass index (p < 0.01). CONCLUSION: Vitamin D status in populations living in circumpolar areas needs more research to investigate to what degree people living in the Arctic areas are at increased risk for vitamin D insufficiency and to determine the role of the traditional diet in preventing such deficiency.

Change in levels of persistent organic pollutants in human plasma after consumption of a traditional northern Norwegian fish dish-mølje (cod, cod liver, cod liver oil and hard roe).

The traditional northern Norwegian fish dish "mølje", consisting of boiled cod, cod liver, cod liver oil and hard roe, is still consumed frequently during the winter months January to March. The liver of the cod is rich in lipids and the levels of persistent organic pollutants (POPs) are relatively high. To better understand the short-term consequences of this traditional meal on the plasma levels of PCBs and p,p'-DDE, individual intake of liver and cod liver oil during one meal was measured. Blood samples were collected from 33 participants before the meal, and then 4 h, 12 h and 5 days after it. Lipid-weight and wet-weight levels of 10 PCB congeners and p,p'-DDE were determined in the plasma samples and the food. The plasma levels of p,p'-DDE was found to increase significantly from 0 to 4 h, both when expressed as wet-weight (35% change) and lipid-weight (20% change). The corresponding changes (0-4 h) in wet-weight levels of the most prevalent PCB congeners were non significant. By contrast, PCB congeners with low levels in the food showed a significant drop in lipid-weight levels during the first 4 h. The observed changes were independent of amount consumed. Significant differences in fasting and non-fasting samples were found for most PCBs and p,p'-DDE. For the lipid weight levels of sum PCBs there was a significant decrease of 16% from non-fasting to fasting samples. To obtain reliable data on human levels of POPs it is, on the basis of these findings, recommended that blood samples should be collected from fasting individuals and both wet-weight and lipid-weight levels should be reported.