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Bergen, Norway

Meyer K.,Bevital AS | Ueland P.M.,University of Bergen
Analytical Chemistry | Year: 2014

The most common technologies for quantitative determination of protein biomarkers are immunoassays, which exist in various formats. Immunoassays offer sensitive and fast protein quantification, but can hardly discriminate between protein variants. Post-translational modifications and genetic variants increase protein microheterogeneity and may play important roles in biological processes. Mass spectrometry combined with immunoaffinity enrichment detects protein microheterogeneity and can quantify different isoforms. We here present an immuno-MALDI-MS approach for the combined quantification of two important biomarkers of inflammation and renal function, C-reactive protein (CRP) and cystatin C, respectively. Antibodies were immobilized onto reversed-phase tips, which allows easy and flexible sample processing. Quantification was performed in singleplex and duplex assays, and characteristics were evaluated for different internal standards, i.e., PEGylated and polyhistidine-tagged proteins. The best performances were obtained for polyhistidine-tagged standards with respect to limits of detection (CRP, 0.10 μg/mL; cystatin C, 0.003 μg/mL) and coefficients of variation (CRP, 2.4-7.0%; cystatin C, 3.0-8.9%). The methods were benchmarked against immunoturbidimetry and nephelometry and demonstrated good between-assay agreement (R2 = 0.989 for CRP; R2 = 0.939 for cystatin C). Several variants of cystatin C were identified and quantified, while none were observed for CRP. This immuno-MALDI method describes a novel approach for targeted quantitative investigation of protein microheterogeneity and is well suited for assessment of biomarker status in precious samples from biobanks due to its low sample consumption. © 2014 American Chemical Society.

Oyen J.,University of Bergen | Nygard O.K.,University of Bergen | Gjesdal C.G.,University of Bergen | Ueland P.M.,University of Bergen | And 5 more authors.
Journal of Bone and Mineral Research | Year: 2014

Choline, obtained from diet and formed by biosynthesis, is the immediate precursor of betaine. Animal studies suggest an impact of choline on bone metabolism. We examined the associations of plasma choline and betaine with bone mineral density (BMD), the risk of hip fractures, and possible effect-modification by nicotine exposure. The Hordaland Health Study (1998 to 2000) included 7074 women and men (ages 46 to 49 or 71 to 74 years). In 5315, BMD was measured. The oldest (n = 3311) were followed for hip fractures through 2009. Risk associations were studied by logistic and Cox regression by comparing the lowest and middle tertiles with the highest, as well as trends across tertiles of plasma choline and betaine. In analyses adjusted for sex and age, participants in the lowest (odds ratio [OR] = 2.00, 95% confidence interval [CI] 1.69-2.37) and middle (OR = 1.39, CI 1.17-1.66) tertiles of plasma choline had an increased risk of low BMD (lowest quintile) (p trend < 0.001). Separate analyses for sex and age groups revealed the strongest relations in elderly women (lowest tertile: OR = 2.84, CI 1.95-4.14; middle tertile: OR = 1.80, CI 1.22-2.67, p trend < 0.001), and highest OR among those in the lowest tertile who were exposed to nicotine (OR = 4.56, CI 1.87-11.11). Low plasma choline was also associated with an increased risk of hip fracture in elderly women and men (lowest tertile: hazard ratio [HR] = 1.45, CI 1.08-1.94; middle tertile: HR = 1.13, CI 0.83-1.54, p trend = 0.012). In elderly women, the HR for hip fracture was 1.90 (CI 1.32-2.73) and 1.36 (CI 0.92-1.99) (p trend < 0.001) for lowest and middle tertiles of choline, and the highest HR was found among women in the lowest tertile exposed to nicotine (HR = 2.68, CI 1.16-6.19). Plasma betaine was not related to BMD or hip fracture. Low plasma choline was associated with low BMD in both sexes and increased the risk of hip fracture in elderly women. These results should motivate further studies on choline, nicotine exposure, and bone metabolism. © 2014 American Society for Bone and Mineral Research.

Oyen J.,University of Bergen | Gram Gjesdal C.,University of Bergen | Nygard O.K.,University of Bergen | Lie S.A.,University of Bergen | And 8 more authors.
PLoS ONE | Year: 2014

Lower bone mineral density (BMD) in smokers may be attributable to lower body weight or fat mass, rather than to a direct effect of smoking. We analyzed the effects of smoking exposure, assessed by plasma cotinine, and body fat on BMD and the risk of subsequent hip fracture. In the community-based Hordaland Health Study (HUSK), 3003 participants 46-49 years and 2091 subjects 71-74 years were included. Cotinine was measured in plasma and information on health behaviors was obtained from self-administered questionnaires. BMD and total body soft tissue composition were measured by dual X-ray absorptiometry. Information on hip fracture was obtained from computerized records containing discharge diagnoses for hospitalizations between baseline examinations 1997-2000 through December 31st, 2009. In the whole cohort, moderate and heavy smokers had stronger positive associations between fat mass and BMD compared to never smokers (differences in regression coefficient (95% CI) per % change in fat mass = 1.38 (0.24, 2.52) and 1.29 (0.17, 2.4), respectively). In moderate and heavy smokers there was a nonlinear association between BMD and fat mass with a stronger positive association at low compared to high levels of fat mass (Davies segmented test, p<0.001). In elderly women and men, heavy smokers had an increased risk of hip fracture compared to never smokers (hazard ratio = 3.31, 95% CI: 2.05, 5.35; p<0.001). In heavy smokers there was a tendency of a lower risk of hip fracture with higher percentage of fat mass. The deleterious effect of smoking on bone health is stronger in lean smokers than in smokers with high fat mass. © 2014 Øyen et al.

Sulo G.,Primary Health Care | Vollset S.E.,Primary Health Care | Vollset S.E.,Norwegian Institute of Public Health | Nygard O.,University of Bergen | And 6 more authors.
International Journal of Cardiology | Year: 2013

Background: Immune system activation is involved in atherosclerosis. Neopterin production and tryptophan catabolismthrough the kynurenine pathway, measured by the kynurenine-tryptophan ratio (KTR), are induced by interferon gamma, thus both are consideredmarkers of cell mediated immune activation. This study prospectively investigated their predictive value on acute coronary events among Norwegian community-dwelling older adults without previous coronary heart disease. Methods: 1112 men and 1631 women, 71-74 years old were examined during 1997-99 as part of the Hordaland Health Study. They were followed until an acute coronary event (defined as unstable angina, non-fatal or fatal acute myocardial infarction or sudden death) or December 31, 2006. Kaplan-Meier hazard curves were constructed for quartiles of plasma neopterin and KTR. Cox proportional hazards models adjusted for sex, body mass index, smoking, hypertension, renal function and cholesterol were used to examine the relation between neopterin and KTR quartiles and the study endpoint. Results:Median (interquartile range) valueswere 8.6 (7.2-10.4) nmol/L for neopterin and 25.8 (25.3-31.1) nmol/ μmol for KTR. During the follow up, 265 participants had at least one acute coronary event. Increased baseline levels of plasma neopterin and KTR were associated with continuous increased risk of developing the study endpoint (P-values for trend b0.001 and 0.019, respectively). Adjusted hazard ratios comparing the fourth quartile to the first were 1.65 (95% CI; 1.11-2.47; P=0.013) for neopterin and 1.57 (95% CI 1.03-2.39; P=0.036) for KTR. Conclusion: Plasma neopterin and KTR levels predict acute coronary events in older adults without previous coronary heart disease. © 2013 Elsevier Ireland Ltd. All rights reserved.

De Vogel S.,University of Bergen | Meyer K.,Bevital AS | Fredriksen A.,Bevital AS | Ulvik A.,Bevital AS | And 8 more authors.
International Journal of Epidemiology | Year: 2013

Background Although individual studies have been inconsistent, meta-analyses of epidemiological data suggest that high folate and vitamin B12 levels may be associated with increased prostate cancer risk. Methods Within JANUS, a prospective cohort in Norway (n=317 000) with baseline serum samples, we conducted a nested case-control study among 3000 prostate cancer cases and 3000 controls, matched on age and time at serum sampling, and county of residence. Using conditional logistic regression, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer risk were estimated according to quintiles of serum folate, vitamin B12, methylmalonic acid (MMA), total homocysteine (tHcy) and methionine, and according to MTHFR 677C→T genotypes. To correct for degradation during sample storage, folate concentration was measured as p-aminobenzoylglutamate (pABG) equivalents following oxidation and acid hydrolysis. Results We observed a weak positive association between folate concentration and prostate cancer risk [OR highest vs lowest quintile=1.15 (0.97-1.37), P-trend=0.04], which was more pronounced among individuals ≥50 years at inclusion [OR 1.40 (1.07-1.84), P-trend=0.02]. tHcy showed an inverse trend with risk [OR 0.92 (0.77-1.10), P-trend=0.03]. Vitamin B12, MMA and methionine concentrations were not associated with prostate cancer risk. Compared with the MTHFR 677CC genotype, the CT and TT variants, both of which were related to lower folate concentrations, were associated with reduced prostate cancer risk [OR 0.82 (0.72-0.94) and OR 0.78 (0.64-0.94), respectively]. Conclusion This large-scale population-based study suggests that high serum folate concentration may be associated with modestly increased prostate cancer risk. We did not observe an association between vitamin B12 status and prostate cancer risk. © The Author 2013; All rights reserved.

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