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BACKGROUND AND PURPOSE: High levels of 25-hydroxyvitamin D3 (25[OH]D3 ) are associated with a lower risk for multiple sclerosis (MS). The bioavailability of 25(OH)D3 is regulated by its main plasma carrier, vitamin D-binding protein (DBP). Free 25(OH)D3 can be estimated by also measuring DBP concentration. In addition, DBP has immunomodulatory functions that may independently affect MS pathogenesis. No previous studies have assessed free 25(OH)D3 or DBP in presymptomatically collected samples. This study was undertaken to assess free 25(OH)D3 and DBP as risk factors for MS. METHODS: A nested case-control study was performed with presymptomatic serum samples identified through cross-linkage of MS registries and Swedish biobanks. Concentration of 25(OH)D3 was measured with liquid chromatography and DBP levels with sandwich immunoassay. Free 25(OH)D3 was approximated as free vitamin D3 index: (25[OH]D3 /DBP) × 103 . MS risk was analyzed by conditional logistic regression, calculating odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: Serum samples from 660 pairs of matched cases and controls were included. At

Supplementary Table 2: Multivariate odds ratios for colorectal cancer risk according to plasma vitamin B12 after stratification by baseline and tumor characteristics.

Background: A diet rich in folate is associated with a reduced colorectal cancer risk, whereas the role of circulating levels is less clear. The aim of this study was to relate prediagnostic plasma folate, vitamin B12, and homocysteine concentrations to the risk of colorectal cancer.Methods: This was a prospective case–control study of 331 cases and 662 matched controls nested within the population-based Northern Sweden Health and Disease Study. Median follow-up time from recruitment to diagnosis was 10.8 years.Results: Plasma folate concentrations were positively related to colorectal cancer risk; multivariate odds ratios were 1.62 [95% confidence intervals (CI), 1.08–2.42] and 1.42 (95% CI, 0.94–2.21) for the middle and highest versus lowest tertile, respectively. In subjects with follow-up Conclusions: In this population-based, nested case–control study, low plasma folate concentrations were associated with a reduced colorectal cancer risk. This protective role was mainly observed in subjects with higher tumor stage or shorter follow-up time between recruitment and diagnosis. Low circulating folate status may protect against colorectal cancer or suppress progression of preneoplastic or neoplastic lesions.Impact: These findings may have relevance for the ongoing debate about mandatory folic acid fortification of flour. Cancer Epidemiol Biomarkers Prev; 23(10); 2136–44. ©2014 AACR.

Peer reviewed: True, Funder: International Agency for Research on Cancer (IARC), Funder: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Funder: NIHR Imperial Biomedical Research Centre (BRC), Funder: Danish Cancer Society (Denmark), Funder: Ligue Contre le Cancer, Funder: Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Funder: Institut National de la Santé et de la Recherche Médicale (INSERM), Funder: German Cancer Aid, Funder: German Cancer Research Center (DKFZ), Funder: German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Funder: Federal Ministry of Education and Research (BMBF), Funder: Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Funder: Compagnia di San Paolo, Funder: National Research Council, Funder: Dutch Ministry of Public Health, Welfare and Sports (VWS), Funder: Netherlands Cancer Registry (NKR), Funder: LK Research Funds, Funder: Dutch Prevention Funds, Funder: Dutch ZON (Zorg Onderzoek Nederland), Funder: World Cancer Research Fund (WCRF), Funder: Statistics Netherlands, Funder: Health Research Fund (FIS)—Instituto de Salud Carlos III (ISCIII), Funder: Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, Funder: Catalan Institute of Oncology—ICO, Funder: Swedish Cancer Society, Funder: Swedish Research Council, Funder: County Councils of Skåne and Västerbotten, Polyphenols are bioactive compounds from plants with antioxidant properties that may have a protective role against body weight gain, with adipose tissue and systemic oxidative stress as potential targets. We aimed to investigate the dietary intake of individual polyphenols and their association with 5-year body weight change in a sub-cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC). This study included 349,165 adult participants from nine European countries. Polyphenol intake was estimated through country-specific validated dietary questionnaires and the Phenol-Explorer database. Body weight was obtained at recruitment and after a mean follow-up time of 5 years. Associations were estimated using multilevel mixed linear regression models. From 91 polyphenols included, the majority (n = 67) were inversely associated with 5-year body weight change after FDR-correction (q < 0.05). The greatest inverse associations were observed for quercetin 3-O-rhamnoside (change in weight for doubling in intake: -0.071 (95% CI: -0.085; -0.056) kg/5 years). Only 13 polyphenols showed positive associations with body weight gain, mainly from the subclass hydroxycinnamic acids (HCAs) with coffee as the main dietary source, such as 4-caffeoylquinic acid (0.029 (95% CI: 0.021; 0.038) kg/5 years). Individual polyphenols with fruit, tea, cocoa and whole grain cereals as the main dietary sources may contribute to body weight maintenance in adults. Individual HCAs may have different roles in body weight change depending on their dietary source.

Objectives Cystathionine-gamma-lyase (CSE) in the transsulfuration pathway generates hydrogen sulfide (H2S), suggested regulating cardiovascular function. The G1208T polymorphism in the CTH gene, rs1021737, has, in addition to MTHFR, been found to increase homocysteine, related to myocardial infarction (MI) risk. This study aimed, for the first time, to investigate the associations of the polymorphisms CTH G1208T, MTHFR C677T, and A1298C with the prospective risk of developing a fatal or non-fatal first MI. Methods This case-referent study included 545 cases later developing a first-ever MI and 1,054 referents from the Northern Sweden Health and Disease Study. Fatal MI was defined as death within 28 days after MI symptoms. Results Women, but not men, had a positive association between fatal MI and the CTH G1208T, odds ratio [95% confidence interval] 3.14 [1.16–8.54] for heterozygotes, and the dominant model 3.22 [1.22–8.51], and for the MTHFR A1298C heterozygotes 3.24 [1.26–8.34] and the dominant model 2.63 [1.06–6.50]. The MTHFR C677T polymorphism was not related to MI. Conclusions This study indicates that the minor alleles of CTH G1208T and MTHFR A1298C polymorphisms are associated with a higher risk for a fatal MI among women but not for non-fatal MI. No association was found in men.

Tobacco consumption is a renal risk factor, but the effects on the estimated glomerular filtration rate (eGFR) remain unclear. We aimed to evaluate the possible impact of using tobacco products (smoking and snus) on eGFR based on creatinine or cystatin C. We used a first cohort with 949 participants and a second cohort with 995 participants; none had pre-existing renal disease. All subjects donated a blood sample and completed a questionnaire, including questions about tobacco use. To assess the effect on eGFR, hierarchical multiple linear regression models were used. Active smoking associated independently with a higher eGFRcreatinine in all subjects (p < 0.001; β = 0.11). Further analyses stratified for sex, showed similar findings for men (p < 0.001; β = 0.14) and for women (p = 0.026; β = 0.10). eGFRcystatin C was significantly associated with active smoking in all subjects (p = 0.040; β = −0.05), but no association was seen after stratification for sex. Snus did not associate with eGFR. In conclusion, smoking associated significantly with a higher eGFRcreatinine. The mechanism may be renal hyperfiltration of smaller molecules such as creatinine. This is probably caused by substances from smoked tobacco other than nicotine, as no effect was seen for snus.

Objective: The aim of this study was to evaluate the associations among the intake of total polyphenols, polyphenol classes, and polyphenol subclasses and body weight change over 5years. Methods: A total of 349,165 men and women aged 25 to 70years were recruited in the Physical Activity, Nutrition, Alcohol, Cessation of Smoking, Eating Out of Home and Obesity (PANACEA) project of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort from nine European countries. Body weight was measured at baseline and at follow-up after a median time of 5years. Polyphenol intake, including four main polyphenol classes and eighteen subclasses, was estimated using validated dietary questionnaires and Phenol-Explorer. Multilevel mixed linear regression models were used to estimate the associations. Results: Participants gained, on average, 2.6 kg (5.0 kg) over 5years. Total flavonoids intake was inversely associated with body weight change (-0.195kg/5 years, 95% CI: -0.262 to -0.128). However, the intake of total polyphenols (0.205kg/5 years, 95% CI: 0.138 to 0.272) and intake of hydroxycinnamic acids (0.324kg/5 years, 95% CI: 0.267 to 0.381) were positively associated with body weight gain. In analyses stratified by coffee consumption, hydroxycinnamic acid intake was positively associated with body weight gain in coffee consumers (0.379kg/5 years, 95% CI: 0.319 to 0.440), but not in coffee nonconsumers (-0.179kg/5 years, 95% CI: -0.490 to 0.133). Conclusions: Higher intakes of flavonoids and their subclasses are inversely associated with a modest body weight change. Results regarding hydroxycinnamic acids in coffee consumers require further investigation., Consejo Nacional de Ciencia y Tecnologia (CONACyT) 693636, Instituto de Salud Carlos III CD20/ 00071 CPII20/00009 FI19/00185 PI18/ 00191

High levels of 25-hydroxyvitamin DA nested case-control study was performed with presymptomatic serum samples identified through cross-linkage of MS registries and Swedish biobanks. Concentration of 25(OH)DSerum samples from 660 pairs of matched cases and controls were included. At20 years of age, high levels of free vitamin DThese findings support the hypothesis that high levels of free 25(OH)D

Supplemental Digital Content is available in the text., Background Iron deficiency is common among inflammatory bowel disease (IBD) patients, generally reported without comparisons with controls. The aim of this study was to analyse if iron deficiency was more common among those later developing IBD compared to matched controls in a prospective setting. Methods We included 96 healthy subjects later developing IBD and 191 matched controls from the Northern Sweden Health and Disease Study. We analysed iron, ferritin, transferrin, and calculated transferrin saturation in plasma sampled at least 1 year prior to IBD diagnosis. Iron deficiency was defined as plasma ferritin 3 mg/L, iron deficiency could not be excluded if ferritin was

Background C-reactive protein (CRP) is a marker of systemic inflammation. Increased levels of CRP in young persons have been suggested to decrease the risk of multiple sclerosis (MS). Objectives To assess CRP as a risk factor for MS. Methods Levels of CRP were measured with a high-sensitive immunoassay in biobank samples from 837 individuals who later developed MS and 984 matched controls. The risk of developing MS was analysed by conditional logistic regression on z-scored CRP values. Results Levels of CRP were not associated with MS risk. Conclusions We found no association between CRP levels and risk of MS development.

Background & aims: Circulating levels of acylcarnitines (ACs) have been associated with the risk of various diseases such as cancer and type 2 diabetes. Diet and lifestyle factors have been shown to influence AC concentrations but a better understanding of their biological, lifestyle and metabolic determinants is needed. Methods: Circulating ACs were measured in blood by targeted (15 ACs) and untargeted metabolomics (50 ACs) in 7770 and 395 healthy participants of the European Prospective Investigation into Cancer and Nutrition (EPIC), respectively. Associations with biological and lifestyle characteristics, dietary patterns, self-reported intake of individual foods, estimated intake of carnitine and fatty acids, and fatty acids in plasma phospholipid fraction and amino acids in blood were assessed. Results: Age, sex and fasting status were associated with the largest proportion of AC variability (partial-r up to 0.19, 0.18 and 0.16, respectively). Some AC species of medium or long-chain fatty acid moiety were associated with the corresponding fatty acids in plasma (partial-r ¼ 0.24) or with intake of specific foods such as dairy foods containing the same fatty acid. ACs of short-chain fatty acid moiety (propionylcarnitine and valerylcarnitine) were moderately associated with concentrations of branched-chain amino acids (partial-r ¼ 0.5). Intake of most other foods and of carnitine showed little association with AC levels. Conclusions: Our results show that determinants of ACs in blood vary according to their fatty acid moiety, and that their concentrations are related to age, sex, diet, and fasting status. Knowledge on their potential determinants may help interpret associations of ACs with disease risk and inform on potential dietary and lifestyle factors that might be modified for disease prevention.

Background Our objective was to determine if patients who later develop inflammatory bowel disease (IBD) show signs of increased inflammatory activity in plasma measured with high sensitivity C-reactive protein (CRP), calprotectin, and albumin before the clinical onset of IBD. Methods We identified 96 subjects who later developed IBD (70 ulcerative colitis [UC] and 26 Crohn’s disease [CD]). High sensitivity CRP, calprotectin, and albumin were analyzed in frozen plasma, donated from cases and sex–age matched controls 1–15 years before diagnosis. Results We found that subjects who later developed UC had lower albumin levels, and subjects who later developed CD had higher CRP levels than controls. Multivariable conditional logistic regression with albumin, calprotectin, and CRP showed a lower risk for developing IBD and UC with higher albumin levels (odds ratio [OR] 0.79, confidence interval [CI] 0.69–0.90; respective OR 0.77, CI 0.66–0.91). Higher CRP levels were associated with an increased risk of developing CD (OR 1.314, CI 1.060–1.630). When adjusting for body mass index or smoking in the logistic regression model, similar results were found. Plasma calprotectin levels in the preclinical period among patients with IBD did not differ from controls. Conclusions In this nested case–control study, subjects who later developed IBD had signs of low-grade systemic inflammation, indicated by significantly higher CRP plasma levels in CD and lower albumin plasma levels in UC, before the onset of clinical disease.

Background Chronic kidney disease (CKD) has a complicated relationship with the heart, leading to many adverse outcomes. Purpose The aim of the study was to evaluate the relationship between CKD and the incidence of atrial fibrillation (AF) and heart failure (HF) along with mortality as a competing risk in general population cohorts. Methods This study was conducted as part of the BiomarCaRE project using harmonised data from 12 population-based cohorts (n=40,212) from Europe. Cox proportional hazards models were used to determine hazard ratios (HRs) for the incidence of AF and HF in CKD and with competing mortality risk after adjusting for covariates. Results Mean age at baseline was 51.1 (standard deviation 11.9) years, and 49.3% were men. Overall, 3.5% had CKD at baseline. The rate for incident AF was 3.9 per 1000 person-years during follow-up. The HR for AF for those with CKD compared with those without was 1.23 (95% CI 1.00–1.52, p=0.0465) after adjustment for covariates. The rate for incident HF was 3.9 per 1000 person-years and the associated risk in the presence of CKD was HR 1.67 (95% CI 1.39–2.01). In subjects with CKD, N-terminal pro-B-type natriuretic peptide (NT-proBNP) showed an association with AF, while NT-proBNP and C-reactive protein (CRP) showed an association with HF. Conclusion CKD is an independent risk factor for subsequent AF and even more so for HF. In patients with CKD, NT-proBNP was clearly associated with subsequent risk of AF. In addition to this marker, hs-CRP was also associated with risk of subsequent HF. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): 7th framework programme collaborative project, grant agreement no. HEALTH-F2-2011_278913. Atrial Fibrillation and HF in CKD

Aims Chronic kidney disease (CKD) has a complicated relationship with the heart, leading to many adverse outcomes. The aim of this study was to evaluate the relationship between CKD and the incidence of atrial fibrillation (AF) and heart failure (HF) along with mortality as a competing risk in general population cohorts. We also included an assessment of baseline biomarkers of inflammation, myocardial injury, and left ventricular dysfunction with risk of AF and HF, respectively, to shed light on the potential underlying pathophysiology. Methods and results This study was conducted within the BiomarCaRE project using harmonized data from 12 European population‐based cohorts (n = 48 518 participants). Renal function was assessed by glomerular filtration rate estimated using the combined Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equation with standardized serum creatinine (Cr) and non‐standardized serum cystatin C (CysC). Incidence of AF and HF respectively, during a median follow‐up of 8 years was recorded. Cox proportional hazards models were used to determine hazard ratios (HRs) for the incidence of AF and HF in CKD and the competing risk of mortality after adjustment for covariates. The mean age at baseline was 51.4 (standard deviation 12.1) years, 49% were men. Overall, 4.3% of subjects had CKD at baseline. The rate for AF was 3.8 per 1000 person‐years during follow‐up. The HR for AF in patients with CKD compared with patients without CKD was 1.28 (95% confidence interval 1.07–1.54) after adjustment for covariates. The rate for incident HF was 4.1 per 1000 person‐years and the HR of CKD for HF was 1.71 (95% confidence interval 1.45–2.01. In subjects with CKD, N‐terminal‐pro‐brain natriuretic peptide (NT‐proBNP) showed an association with AF, whereas NT‐proBNP and C‐reactive protein were associated with HF. Conclusions Chronic kidney disease is an independent risk factor for subsequent AF and is even more closely associated with HF. In these relatively young participants with CKD, NT‐proBNP was strongly associated with subsequent risk of AF. For HF, in addition, elevated levels of hs‐C‐reactive protein at baseline were related to incident events.

Introduction: Many factors influence the clinical course of patients with renal cell carcinoma (RCC). The most commonly used prognostic indicators are TNM stage, tumor size and RCC type. In this study we evaluated the prognostic relevance of albumin and C-reactive protein (CRP), and Glasgow Prognostic scores (GPS), in patients with primary RCC. Methods: We retrospectively reviewed all patients surgically treated for primary RCC between 1982 and 2018 at Umeå University Hospital. There were 872 patients, 527 males and 345 females. Data on albumin, CRP and GPS points before surgery were extracted, as well as TNM stage, RCC type, tumor grade, tumor size, and primary treatment. The patients were followed for recurrence and death for up to 37.2 years. We used Kaplan-Meier estimators, Cox-proportional hazards models, to assess the relation between potentially prognostic indicators and RCC-specific death, and all-cause mortality. Results: Of 872 patients, 708 had clear-cell RCC, 114 papillary RCC, 36 chromophobe RCC and 9 undefined RCC type while 5 patients had missing RCC type data. Except that, women had a significantly (p = 0.002) lower proportion of pRCC, no difference in RCC types and levels of albumin and CRP was observed between genders. Albumin, CRP, and GPSs were all univariately associated to RCC survival (p < 0.001). CRP demonstrated the strongest prognostic association (HR 1.67 95% Ci (1.53–1.83, overriding both albumin and GPS in multivariable models. The AUC for CRP was 0.77 (95% CI: 0.74-0.80). Conclusion: Elevated CRP, low albumin levels, and elevated GPSs were all associated to poor survival in patients with RCC, Only CRP remained independent in multivariate analysis.

Plasma total homocysteine (tHcy) is a risk marker, and smoking is an established risk factor for cardiovascular disease. It is unclear if the effect of smoked tobacco on homocysteine is mediated by nicotine or other combustion products in smoked tobacco. Snus (moist smokeless tobacco) is high nicotine-containing tobacco, and little is known about the effect of snus on plasma homocysteine. Therefore, we studied, in a cross-section of subjects (n = 1375) from the Northern Sweden Health and Disease Study, with strictly defined current smokers (n = 194) and snus users (n = 47), the impact of tobacco exposure on tHcy, assessed by self-reported tobacco habits and plasma cotinine concentrations. The snus users had higher cotinine concentrations than the smokers. Cotinine, creatinine, methylmalonic acid, and the methylenetetrahydrofolate reductase genotype (MTHFR) T allele were positively associated with tHcy among the smokers, but not among the snus users. No association was observed between tHcy and the number of cigarettes/day. There was a positive association between cotinine and tHcy in the smokers, but not among the snus users. This indicates that substances other than nicotine in tobacco smoke could be responsible for the differential effects on homocysteine status. Self-reported smoking should be complemented by a cotinine assay whenever possible. publishedVersion

Background: Obesity early in life has been linked to increased risk of developing multiple sclerosis (MS). Leptin and insulin are both associated with obesity, making them suitable candidates for investigating this connection. Objective: To determine if leptin and insulin are risk factors for relapsing–remitting multiple sclerosis (RRMS). Methods: In this nested case–control study using blood samples from Swedish biobanks, we compared concentrations of leptin and insulin in 649 individuals who later developed RRMS with 649 controls matched for biobank, sex, age and date of sampling. Only pre-symptomatically drawn samples from individuals below the age of 40 years were included. Conditional logistic regression was performed on z-scored values to calculate odds ratios (ORs) with 95% confidence intervals (CIs). Results: A 1-unit leptin z-score increase was associated with increased risk of MS in individuals younger than 20 years (OR = 1.4, 95% CI = 1.1–1.9) and in all men (OR = 1.4, 95% CI = 1.0–2.0). In contrast, for women aged 30–39 years, there was a lower risk of MS with increased leptin levels (OR = 0.74, 95% CI = 0.54–1.0) when adjusting for insulin levels. Conclusion: We show that the pro-inflammatory adipokine leptin is a risk factor for MS among young individuals.

Impaired renal function is associated both with the development of cardiovascular disease and its prognosis. A new syndrome called ′Shrunken Pore Syndrome′ has been suggested, as the estimated glomerular filtration rate for cystatin C (eGFRcystatin C) is affected earlier due to differences in molecular size compared to eGFRcreatinine. The aim was to investigate if a lower eGFRcystatin C/eGFRcreatinine ratio in a prospective setting increases the risk of later developing a first-ever myocardial infarction (MI) independently of other cardiovascular risk factors. We used a nested case-referent study design within the Northern Sweden Health and Disease Study, and 545 subjects (29.0% women) were identified who prospectively developed a first-ever MI, and their 1054 matched referents. For women, but not for men, one standard deviation (SD) increase of ln z-scores of eGFRcystatin C/eGFRcreatinine ratio was associated with a lower risk of a future MI: odds ratio [95% confidence interval] 0.58 [0.34–0.99], adjusted for apolipoprotein B/A1 ratio, CRP, homocysteine, systolic blood pressure, body mass index, and diabetes. Furthermore, a high eGFRcreatinine associated independently with an increased risk of future MI in men only: OR 1.25 [1.05–1.48]. Thus, for women, a lower eGFRcystatin C/eGFRcreatinine ratio is associated with a higher risk of having a future first-ever MI, and it may be a valuable, easily implemented biomarker for risk of cardiovascular disease.

Objective High-sensitivity troponin T (hs-TnT) and high-sensitivity C-reactive protein (hs-CRP) may convey prognostic information in patients with aortic stenosis (AS). However, many association studies were cross-sectional, and the presence of myocardial hypertrophy and concomitant coronary artery disease (CAD) were usually not described. This study evaluated if hs-TnT and hs-CRP relate to myocardial mass, and associate with risk of and time to future surgery for AS in patients with and without concomitant CAD. Design In total, 336 patients who underwent surgery due to AS after participation in large population surveys were identified. Median age [interquartile range] was 59.8 [10.3] years at survey and 68.3 [12.7] years at surgery, and 48% were women. The median time between survey and surgery was 10.9 [9.3] years. Preoperatively, myocardial mass and the presence of CAD were assessed. Two matched referents were allocated for each case, and hs-TnT and hs-CRP were determined in stored plasma samples from the baseline survey. Uni- and multivariable conditional logistic regression analyses were used to estimate the risk (odds ratio [95% confidence interval]) related to one (ln) standard deviation increase in hs-TnT and hs-CRP. Time to surgery was evaluated by Kaplan-Mayer analysis and Cox regression. Results Hs-TnT was independently associated with surgery for AS in patients with concomitant CAD (odds ratio [95% confidence interval]) (1.22 [1.02–1.46]) and without concomitant CAD (1.39 [1.05–1.84]). Hs-CRP was not associated with surgery for AS after adjustment for traditional cardiovascular risk factors (1.06 [0.92–1.23]). Patients with high hs-TnT levels had shorter time to surgery compared those with low levels (Figure, p Conclusions Hs-TnT – but not hs-CRP – was associated with increased risk for, and shorter time to future surgery for AS. Hs-TnT associated with myocardial mass at surgery which indicates that Hs-TnT may be used as a clinical tool and allow for identification of patients with AS who could benefit from earlier intervention. Time to surgery; tertiles of hs-TnT Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): The Swedish Heart–Lung Foundation

Objective: Smoking has previously been associated with inflammatory bowel disease (IBD), but no study has reported on cotinine, an objective, biochemical measure of tobacco use. We aimed at testing the hypothesis that cotinine levels among healthy subjects are associated with an increased risk of developing IBD in later life. Design: We analysed plasma cotinine and evaluated corresponding lifestyle questionnaires that included tobacco habits in subjects (n = 96) who later developed late-onset IBD (70 ulcerative colitis (UC) and 26 Crohn’s disease (CD)) and in sex and age-matched controls (n = 191). Results: Patients who later developed IBD had significantly higher plasma cotinine levels compared to controls. In multivariable analysis, higher log-cotinine was associated with a higher risk of developing IBD (OR 1.34 (95% CI 1.01–1.63)). After stratifying for time to diagnosis, the association was only significant in subjects with shorter time (< 5.1 years) to diagnosis (OR 1.45 (1.09–1.92)). The findings were similar for UC- and CD-cases, but did not reach statistical significance in CD-cases. Although plasma cotinine concentrations were higher in snuff users compared to combusted tobacco users, no increase in the risk of IBD and lower risk of developing IBD among subjects with shorter time (< 5.1 years) to diagnosis was seen among snuff users. Conclusions: Cotinine, a biomarker of tobacco use, is associated with increased risk of developing late-onset IBD in general, and UC in particular. No increased risk among snuff users indicates that other components in combusted tobacco than nicotine may be involved in the pathogenesis of IBD among smokers.

Background: Aortic valve stenosis (AS) is the most common indication for cardiac valve surgery; untreated AS is linked to high mortality. The etiological background of AS is unknown. Previous human studies were typically based on case-control studies. Biomarkers identified in prospective studies could lead to novel mechanistic insights. Methods: Within a large population survey with blood samples obtained at baseline, 334 patients were identified who later underwent surgery for AS (median age [interquartile range], 59.9 [10.4] years at survey and 68.3 [12.7] at surgery; 48% female). For each case, 2 matched referents were allocated. Plasma was analyzed with the multiplex proximity extension assay for screening of 92 cardiovascular candidate proteins. Conditional logistic regression models were used to assess associations between each protein and AS, with correction for multiple testing. A separate set of 106 additional cases with 212 matched referents was used in a validation study. Results: Six proteins (growth differentiation factor 15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and proprotein convertase subtilisin/kexin type 9) were associated with case status in the discovery cohort; odds ratios ranged from 1.25 to 1.37 per SD increase in the protein signal. Adjusting the multivariable models for classical cardiovascular risk factors at baseline yielded similar results. Subanalyses of case-referent triplets (n=133) who showed no visible coronary artery disease at the time of surgery in the index person supported associations between AS and growth differentiation factor 15 (odds ratio, 1.40; 95% confidence interval, 1.10-1.78) and galectin-4 (odds ratio, 1.27; 95% confidence interval, 1.02-1.59), but these associations were attenuated after excluding individuals who donated blood samples within 5 years before surgery. In triplets (n=201), which included index individuals with concurrent coronary artery disease at the time of surgery, all 6 proteins were robustly associated with case status in all sensitivity analyses. In the validation study, the association of all but 1 (interleukin 17 receptor A) of these proteins were replicated in patients with AS with concurrent coronary artery disease but not in patients with AS without coronary artery disease. Conclusions: We provide evidence that 5 proteins were altered years before AS surgery and that the associations seem to be driven by concurrent atherosclerotic disease.

Introduction: Guidelines suggest following monoclonal gammopathy of undetermined significance (MGUS) according to risk of multiple myeloma progression. Follow-up of low-risk MGUS is debated as progression risk is low. Worse myeloma-related outcome was observed in patients followed for low-risk MGUS, potentially due to less optimal follow-up (Bianchi et al. Blood 2010, Sigurdardottir et al. Jama Oncology 2015). However, it is not clear if progressing low-risk MGUS by its nature displays more aggressive biological behavior. To gain better understanding of progression patterns in MGUS, we investigated, independent of follow-up, whether progression from low-risk MGUS is associated with worse outcome in multiple myeloma. The main outcome was overall survival from the time of myeloma diagnosis. Methods: The Northern Sweden Health and Disease Study (NSHDS) is a longitudinal prospective cohort with more than 100,000 participants. Typically, NSHDS participants donate repeated blood samples at intervals of several years. Samples are frozen within one hour and stored at -80° C at Umea University Hospital. Linkage to the Swedish Cancer Registry facilitated identification of myeloma patients with two pre-diagnostic samples in NSHDS (N = 61). Of these, we screened repeated pre-diagnostic samples using protein- and immunofixation electrophoresis and free light chain assays. We identified 42 individuals who had detectable monoclonal gammopathy in both pre-diagnostic samples without MGUS follow-up before myeloma diagnosis, allowing to investigate natural progression patterns in relation to outcome. Overall survival was determined using Kaplan-Meier plots. Hazard ratios and 95% confidence intervals were calculated using multivariable Cox regression including known prognostic factors. Fisher's exact test was used to compare categorical variables. Results: The first pre-diagnostic sample was collected in November 1986 and the last follow-up since myeloma diagnosis was in February 2021, resulting in a 35-year study duration. Median age at myeloma diagnosis was 62 (range 48-84) with a median follow-up of 7 years (range 0.2-18). At first pre-diagnostic blood draw, 12 had low-risk and 30 had MGUS of other risk (Mayo Clinic criteria). Characteristics at myeloma diagnosis except sex were similarly distributed between the two groups. Comorbidities, myeloma treatment and access to novel drugs were balanced between groups. Bone disease (osteolytic lesions and/or vertebral compression fractures attributable to myeloma) at myeloma diagnosis was more common in patients who had low-risk MGUS at first pre-diagnostic blood draw (P = 0.04). This association was pronounced excluding light chain myeloma (P = 0.01). Access to other radiographic imaging than conventional skeletal survey such as CT or MRI was similar for both groups. In low-risk vs. other MGUS, median overall survival since myeloma diagnosis was 2.3 (95% CI, 1.8-2.9) years and 7.5 (95% CI, 4.8-10.2) years (Figure A). Results were similar investigating overall survival since frontline therapy start (excluding 5 patients not requiring therapy) (Figure B). Sex and bone disease were not associated with survival. At repeated pre-diagnostic blood draw (in median 3.7 years prior myeloma diagnosis), 67% vs. 19% had low- or low-intermediate risk MGUS in patients with low-risk vs. other MGUS at first pre-diagnostic blood draw (P = 0.01), suggesting more rapid progression close to myeloma diagnosis in patients with low-risk MGUS at first blood draw. Investigating this further, we plotted M spikes in low-risk vs. other MGUS of IgG isotype (Figures C-D). M spike trajectories were largely similar between groups, although the annual median M spike increase from repeated pre-diagnostic blood draw to myeloma diagnosis was 6.0 g/L in low-risk vs. 2.3 g/L in other MGUS (P = 0.14). Conclusions: Progression from low-risk MGUS is, independent of MGUS follow-up, associated with a higher proportion of bone disease and worse survival. Based on the known phenotypic heterogeneity in multiple myeloma, we speculate that low-risk MGUS in case of malignant progression belongs to a group of more aggressive tumors. Our results need to be interpreted carefully because of the small sample size. Replication and further investigation are needed. If replicated, these findings could help to improve current MGUS follow-up strategies, which are solely based on progression risk. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background Coffee is known to impact on colon motility, alter gut-related immune response, and to affect symptoms among inflammatory bowel disease (IBD) patients. In spite of this, the role of coffee as a determinant of IBD is unclear. The aim of this study was to investigate how coffee correlates to the risk of developing late-onset IBD in general, and subdivided into Crohn’s disease and ulcerative colitis. Methods This nested case-control study within the large, population-based Northern Sweden Health and Disease Study (NSHDS), included data from 78 patients with IBD and 311 controls matched for age, sex, time and area of sample collection. Cases were included in NSHDS at least one year prior to IBD diagnosis. Coffee consumption was assessed by questionnaire-data, differing between drip-filtered and boiled unfiltered coffee. Risk associations were estimated through conditional logistic regressions. Results Results differed between different subgroups of IBD and coffee. Our main finding was a decreased risk of Crohn’s disease in subjects with a daily intake of drip-filtered coffee in comparison with subjects with a less frequent intake (Table). After adjustments for smoking, body-mass-index, educational level and marital status the results remained. Adjusted OR for Crohn’s disease was 0.22; 95% CI 0.07–0.76 Conclusion Our results indicate potential biochemical differences depending on coffee preparation technique on IBD risk, with possible implications for prevention or treatment. Further studies are warranted.

Background Higher circulating 25-hydroxyvitamin-D [25(OH)D] concentrations are consistently inversely associated with colorectal cancer (CRC) risk in observational studies. However, it is unknown whether this association depends on the functional GC-rs4588*A (Thr436Lys) variant encoding the vitamin D–binding protein-2 (DBP2) isoform, which may affect vitamin D status and bioavailability. Methods We analyzed data from 1710 incident CRC cases and 1649 incidence-density–matched controls nested within three prospective cohorts of mostly Caucasians. Study-specific incidence rate ratios (RRs) for associations of prediagnostic, season-standardized 25(OH)D concentrations according to DBP2 isoform with CRC were estimated using multivariable unconditional logistic regression and were pooled using fixed-effects models. All statistical significance tests were two-sided. Results The odds of having 25(OH)D concentrations less than 50 nmol/L (considered insufficient by the Institute of Medicine) were 43% higher for each DBP2-encoding variant (rs4588*A) inherited (per DBP2 odds ratio [OR] = 1.43, 95% confidence interval [CI] = 1.27 to 1.62, Ptrend = 1.2 × 10−8). The association of 25(OH)D concentrations with CRC risk differed by DBP2: 25(OH)D concentrations considered sufficient (≥ 50 nmol/L), relative to deficient ( Conclusions Our results suggest that the 25(OH)D-CRC association may differ by DBP isoform, and those with a DBP2-encoding genotype linked to vitamin D insufficiency may particularly benefit from adequate 25(OH)D for CRC prevention.

Faecal calprotectin (FC) tests and faecal immunological tests (FIT) for haemoglobin have been used to monitor disease activity in patients with ulcerative colitis (UC) but used alone they have some limitation concerning the predictive ability. We aimed to test if an FC test used in combination with FIT could improve the predictive ability. Consecutive out-patients with UC (n = 93) who were admitted for colonoscopy completed a single faecal sample before the start of bowel preparation. A quantitative CALPRO (R) calprotectin ELISA test and a qualitative FIT (cut-off < 40 ng/mL) were analyzed. An estimated Mayo score and a score of histological inflammation was performed blinded to the result of the faecal tests. The sensitivity, specificity, negative predictive value and positive predictive value for endoscopic inflammation (Mayo score > 1) was for FIT 85%, 83%, 96%, 57% and for FC > 186 mu g/g 73%, 87%, 87%, 54%. Corresponding results for FIT*FC > 186 mu g/g (at least one test positive) were 92%, 69%, 97%, 43%. For detecting moderate/severe histological inflammation the results were for FIT 69%, 79%, 92%, 43%, for FC > 75 mu g/g 95%, 62%, 98%, 41%, and for FIT*FC > 75 mu g/g 100%, 60%, 100%, 36%. None of the markers alone or in combination were useful to predict deep remission (Mayo score = 0 and no histological inflammation). We conclude that using the combination of an FC test and FIT shows minor improvement in predictive ability for inflammatory activity and remission in patients with UC.

Background: High 25-hydroxyvitamin D concentrations have been associated with a reduced risk of multiple sclerosis, with indications of a stronger effect among young individuals. Objective: Investigate the 25-hydroxyvitamin D association with multiple sclerosis and test if this association is age dependent. Methods: Prospectively drawn blood samples from individuals later developing relapsing-remitting multiple sclerosis and controls matched for biobank, sex, age and date of sampling, were analysed with liquid chromatography tandem mass spectrometry. Results: High levels of 25-hydroxyvitamin D (top quintile) were associated with a reduced multiple sclerosis risk (odds ratio 0.68, 95% confidence interval 0.50-0.93). Conclusion: These findings further support a role for vitamin D in MS aetiology.

Objectives: Faecal Calprotectin (FC) is a sensitive marker for gut inflammation. However, slightly elevated FC levels are also common in subjects without inflammation. We investigated the association between FC and clinical factors including concomitant use of medical therapy in patients with a normal colonoscopy. Material and methods: Out-patients (n = 1263) referred for colonoscopy, performed FC test (CALPRO) the day before the start of bowel preparation. All subjects answered questionnaires that included questions on the present and past health history, concomitant medical treatment and gastrointestinal symptoms (GSRS). A medical record chart review was performed to check for concomitant disease, cause of referral and the result of the colonoscopy including biopsies. Inclusion criteria were a normal colonoscopy. Exclusion criteria were inflammatory bowel disease, colon cancer and high-grade dysplasia. Results: Five hundred ninety subjects fulfilled the inclusion criteria and completed the study. Thirty-six per cent of the subjects had a FC >50 µg/g. In a logistic regression analysis, age (adjusted OR: 1.051; CI: 1.032–1.071), and the use of proton pump inhibitors (adjusted OR: 3.843; CI: 2.338–6.316), non-steroid anti-inflammatory drugs (adjusted OR: 2.411; CI: 1.162–5.002) and acetylsalicylic acid (adjusted OR: 2.934; CI: 1.085–3.448) were significantly associated with an elevated FC (>50 µg/g). Conclusions: More than one-third of the patients with a normal colonoscopy performed in clinical routine had a slightly elevated FC level. Our results emphasise the need for attention to age, the use of proton pump inhibitors, non-steroid anti-inflammatory drugs and acetylsalicylic acid in the interpretation of FC tests in clinical practice.

Recently, a new approach was proposed to detect mild impairment in renal function: a reduced ratio between estimated glomerular filtration rate (eGFR) calculated by cystatin C and eGFR calculated by creatinine. We aimed to evaluate if this ratio is associated with aortic stenosis (AS) requiring surgery. We identified 336 patients that first participated in population surveys and later underwent surgery for AS (median age [interquartile range] 59.8 [10.3] years at survey and 68.3 [12.7] at surgery, 48% females). For each patient, two matched referents were allocated. Cystatin C and creatinine were determined in stored plasma. eGFR(cystatin C) and eGFR(creatinine) and their ratio were estimated. Conditional logistic regression analyses were used to estimate the risk (odds ratio (OR) with [95% confidence interval (CI)]) related to one (ln) standard deviation increase in the ratio between eGFR(cystatin C) and eGFR(creatinine). A high ratio was associated with lower risk for AS requiring surgery (OR [95% CI]) (OR 0.84 [0.73-0.97]), especially in women (0.74 [0.60-0.92] vs. 0.93 [0.76-1.13] in men). After further stratification for coronary artery disease (CAD), the association remained in women with CAD but not in women without CAD (0.60 [0.44-0.83] and 0.89 [0.65-1.23], respectively). In conclusion, a high ratio between eGFR(cystatin C) and eGFR(creatinine) was associated with lower risk for surgery for AS, especially in women. Mild impairment of renal function is thus associated with future risk for AS requiring surgery.

Background Increased vitamin B6 catabolism related to inflammation, as measured by the PAr index (the ratio of 4-pyridoxic acid over the sum of pyridoxal and pyridoxal-5'-phosphate), has been positively associated with lung cancer risk in two prospective European studies. However, the extent to which this association translates to more diverse populations is not known. Materials and methods For this study, we included 5323 incident lung cancer cases and 5323 controls individually matched by age, sex, and smoking status within each of 20 prospective cohorts from the Lung Cancer Cohort Consortium. Cohort-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between PAr and lung cancer risk were calculated using conditional logistic regression and pooled using random-effects models. Results PAr was positively associated with lung cancer risk in a dose-response fashion. Comparing the fourth versus first quartiles of PAr resulted in an OR of 1.38 (95% CI: 1.19–1.59) for overall lung cancer risk. The association between PAr and lung cancer risk was most prominent in former smokers (OR: 1.69, 95% CI: 1.36–2.10), men (OR: 1.60, 95% CI: 1.28–2.00), and for cancers diagnosed within 3 years of blood draw (OR: 1.73, 95% CI: 1.34–2.23). Conclusion Based on pre-diagnostic data from 20 cohorts across 4 continents, this study confirms that increased vitamin B6 catabolism related to inflammation and immune activation is associated with a higher risk of developing lung cancer. Moreover, PAr may be a pre-diagnostic marker of lung cancer rather than a causal factor. (c) The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. Annals of Oncology 30: 478–485, 2019 doi:10.1093/annonc/mdz002 Published online 30 January 2019 This is an Open Access article under the CC-BY-NC-ND license.

AimsHigh-sensitivity troponin T (hs-TnT) and high-sensitivity C reactive protein (hs-CRP) may convey prognostic information in patients with aortic stenosis (AS). This study evaluated if hs-TnT and hs-CRP associate with myocardial mass, and risk of future surgery for AS.MethodsIn total, 336 patients (48% women) with surgery for AS with previous participation in large population surveys were identified. Preoperatively, myocardial mass and the presence of coronary artery disease (CAD) were assessed. Two matched referents were allocated for each case, and hs-TnT and hs-CRP were determined in stored plasma from the baseline survey. Conditional logistic regression analysis was used to estimate the risk (OR (95% CI)) related to one (natural logarithm) SD increase in hs-TnT and hs-CRP. Kaplan-Mayer and Cox regression analyses were used to evaluate time to surgery.ResultsMedian age (IQR) was 59.8 (10.3) years at survey, and median time between survey and surgery was 10.9 (9.3) years. Hs-TnT was independently associated with surgery for AS (1.24 (1.06–1.44)) irrespective of CAD, whereas Hs-CRP was not (1.05 (0.90–1.22)). Elevated hs-TnT levels at survey associated with shorter time to surgery (pConclusionsHs-TnT—but not hs-CRP—was associated with increased risk of—and shorter time to—future surgery for AS. Hs-TnT associated with myocardial mass at surgery which indicates that hs-TnT could be a potential biomarker for determining intervention.

Background There is observational evidence suggesting that high vitamin D concentrations may protect against lung cancer. To investigate this hypothesis in detail, we measured circulating vitamin D concentrations in prediagnostic blood from 20 cohorts participating in the Lung Cancer Cohort Consortium (LC3). Patients and methods The study included 5313 lung cancer cases and 5313 controls. Blood samples for the cases were collected, on average, 5 years before lung cancer diagnosis. Controls were individually matched to the cases by cohort, sex, age, race/ethnicity, date of blood collection, and smoking status in five categories. Liquid chromatography coupled with tandem mass spectrometry was used to separately analyze 25-hydroxyvitamin D2 [25(OH)D2] and 25-hydroxyvitamin D3 [25(OH)D3] and their concentrations were combined to give an overall measure of 25(OH)D. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for 25(OH)D as both continuous and categorical variables. Results Overall, no apparent association between 25(OH)D and risk of lung cancer was observed (multivariable adjusted OR for a doubling in concentration: 0.98, 95% CI: 0.91, 1.06). Similarly, we found no clear evidence of interaction by cohort, sex, age, smoking status, or histology. Conclusion This study did not support an association between vitamin D concentrations and lung cancer risk. VC The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Background Vitamin D has been implicated as being involved in the aetio-pathogenesis of several autoimmune diseases including rheumatoid arthritis (RA). Previous studies present contradictory results. Vitamin D binding protein (DBP), the major transport protein, is also involved in various inflammatory processes. The aim of this study was to investigate the relationship between circulating levels of 25-hydroxyvitamin D [25(OH) D], DBP and polymorphisms in group-specific component (GC) in pre-symptomatic individuals and matched controls within prospective cohorts of the Northern Sweden. Methods Blood samples donated to the Medical Biobank prior to the onset of symptoms of RA (n = 515, mean [SD] time before the onset of symptoms 6.2 [9.3] years) and from matched (2:1) population-based controls (n = 267) were used. Plasma 25(OH) vitamin D levels were analyzed using liquid chromatography tandem-mass spectrometry and DBP levels were analyzed using enzyme-linked immunosorbent assay. GC polymorphisms (rs4588 and rs7041) were analyzed with TaqMan assays (Applied Biosystems). Results Levels of 25(OH) D or DBP were not statistically different between pre-symptomatic individuals and controls in a crude, or a multiple-adjusted logistic regression model. However, an increased risk for future RA was found in females of DBP (OR 1.014 [95%CI 1.001–1.028]) per 10 mg/L adjusted for carriage of the minor allele of rs4588, in a multiple-adjusted model (p