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  • 1. Andersen, Vibeke
    et al.
    Chan, Simon
    Luben, Robert
    Khaw, Kay-Tee
    Olsen, Anja
    Tjonneland, Anne
    Kaaks, R.
    Grip, Olof
    Bergmann, M. M.
    Boeing, H.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Overvad, Kim
    Oldenburg, Bas
    Opstelten, Jorrit
    Boutron-Ruault, Marie-Christine
    Carbonnel, Franck
    Racine, Antoine
    Key, Timothy
    Masala, Giovanna
    Palli, Domenico
    Tumino, R.
    Trichopoulou, A.
    Riboli, Elio
    Hart, Andrew
    Fibre intake and the development of inflammatory bowel disease: A European prospective multi-centre cohort study (EPIC-IBD)2018In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 12, no 2, p. 129-136Article in journal (Refereed)
    Abstract [en]

    Background and Aims: Population-based prospective cohort studies investigating fibre intake and development of inflammatory bowel disease are lacking. Our aim was to investigate the association between fibre intake and the development of Crohn's disease [CD] and ulcerative colitis [UC] in a large European population.

    Methods: In total, 401 326 participants, aged 20-80 years, were recruited in eight countries in Europe between 1991 and 1998. At baseline, fibre intake [total fibres, fibres from fruit, vegetables and cereals] was recorded using food frequency questionnaires. The cohort was monitored for the development of inflammatory bowel disease. Each case was matched with four controls and odds ratios [ORs] for the exposures were calculated using conditional logistic regression. Sensitivity analyses according to smoking status were computed.

    Results: In total, 104 and 221 participants developed incident CD and UC, respectively. For both CD and UC, there were no statistically significant associations with either quartiles, or trends across quartiles, for total fibre or any of the individual sources. The associations were not affected by adjusting for smoking and energy intake. Stratification according to smoking status showed null findings apart from an inverse association with cereal fibre and CD in non-smokers [Quartile 4 vs 1 OR = 0.12, 95% confidence interval = 0.02-0.75, p = 0.023, OR trend across quartiles = 0.50, 95% confidence interval = 0.29-0.86, p = 0.017].

    Conclusion: The results do not support the hypothesis that dietary fibre is involved in the aetiology of UC, although future work should investigate whether there may be a protective effect of specific types of fibre according to smoking status in CD.

  • 2.
    Arslan, Alan A
    et al.
    Department of Environmental Medicine, New York University School of Medicine.
    Clendenen, Tess V
    Department of Environmental Medicine, New York University School of Medicine.
    Koenig, Karen L
    Department of Environmental Medicine, New York University School of Medicine.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Enquist, Kerstin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Ågren, Åsa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lukanova, Annekatrin
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
    Sjodin, Hubert
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zeleniuch-Jacquotte, Anne
    Department of Environmental Medicine, New York University School of Medicine.
    Shore, Roy E
    Radiation Effects Research Foundation, Hiroshima, Japan.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Toniolo, Paolo
    Department of Environmental Medicine, New York University School of Medicine.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Circulating vitamin d and risk of epithelial ovarian cancer2009In: Journal of oncology, ISSN 1687-8450, Vol. 2009, p. 672492-672500Article in journal (Refereed)
    Abstract [en]

    We conducted a nested case-control study within two prospective cohorts, the New York University Women's Health Study and the Northern Sweden Health and Disease Study, to examine the association between prediagnostic circulating levels of 25-hydroxy vitamin D (25(OH)D) and the risk of subsequent invasive epithelial ovarian cancer (EOC). The 25(OH)D levels were measured in serum or plasma from 170 incident cases of EOC and 373 matched controls. Overall, circulating 25(OH)D levels were not associated with the risk of EOC in combined cohort analysis: adjusted OR for the top tertile versus the reference tertile, 1.09 (95% CI, 0.59-2.01). In addition, there was no evidence of an interaction effect between VDR SNP genotype or haplotype and circulating 25(OH)D levels in relation to ovarian cancer risk, although more complex gene-environment interactions may exist.

  • 3.
    Berggren Söderlund, Maria
    et al.
    Klinisk kemi, labmedicin Skåne.
    Nilsson-Ehle, Herman
    Sahlgrenska universitetssjukhuset Göteborg.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Jonsson, Magnus
    Klinisk kemi, labmedicin Skåne.
    Vitaminer och spårämnen2012In: Laurells klinisk kemi i praktisk medicin / [ed] Nilsson Ehle P, Berggren Söderlund M, Theodorsson E, Lund: Studentlitteratur, 2012, 9, p. 655-673Chapter in book (Refereed)
  • 4.
    Berggren Söderlund, Maria
    et al.
    Klinisk kemi och transfusionsmedicin, Kronoberg.
    Ridefelt, Peter
    Klinisk kemi och farmakologi, Akademiska sjukhuset Uppsala.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Vitaminer och spårämnen2018In: Laurells Klinisk kemi i praktisk medicin / [ed] Elvar Theodorsson & Maria Berggren Söderlund, Lund: Studentlitteratur AB, 2018, 10, p. 681-703Chapter in book (Refereed)
  • 5.
    Biström, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, O.
    Alonso-Magdalena, L.
    Jons, D.
    Gunnarsson, M.
    Vrethem, M.
    Sundström, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Leptin levels are associated with multiple sclerosis risk2019In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 25, p. 904-904Article in journal (Other academic)
  • 6.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Johansson, L.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Nygren, E.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Arlestig, L.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Vitamin D in individuals before onset of rheumatoid arthritis: relation to vitamin D binding protein and its associated genetic variants2018In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 47, p. 23-24Article in journal (Other academic)
  • 7.
    Brink, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Johansson, L.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Nygren, E.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Ärlestig, L.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Rantapää-Dahlqvist, Solbritt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Rheumatology.
    Vitamin d in individuals before onset of rheumatoid arthritis: relation to vitamin d binding protein and its associated genetic variants2018In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 77, p. 282-282Article in journal (Other academic)
  • 8.
    Brännström, Thomas
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Forsberg, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jonsson, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stegmayr, Ch.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Stegmayr, Bernd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Micro embolies of air are deposited in the organs in hemodialysis patients: a case report2011In: International Journal of Artificial Organs, ISSN 0391-3988, E-ISSN 1724-6040, Vol. 34, no 8, p. 636-636Article in journal (Other academic)
  • 9.
    Bölenius, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Nursing.
    Söderberg, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Lindkvist, Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Brulin, Christine
    Umeå University, Faculty of Medicine, Department of Nursing.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Minor improvement of venous blood specimen collection practices in primary health care after a large-scale educational intervention2013In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 51, no 2, p. 303-310Article in journal (Refereed)
    Abstract [en]

    Background: Venous blood specimen collection is a common health care practice that has to follow strict guidelines, non-compliance among sampling staff may compromise patient safety. We evaluated a large-scale 2 h educational intervention that emphasised guideline adherence to assess possible improvements of venous blood specimen collection practices.

    Methods: Blood specimen haemolysis is usually caused by inadequate venous blood specimen collection and handling, reflecting overall pre-analytical handling. We monitored haemolysis of serum samples with haemolysis index corresponding to ≥150 mg/L of free haemoglobin for specimens sent from 11 primary health care centres and analysed on a Vitros 5,1 clinical chemistry analyser before (2008, n=6652 samples) and after (2010, n=6121 samples) the intervention.

    Results: The total percentage of haemolysed specimens was 11.8% compared to 10.5% (p=0.022) before the intervention. As groups, rural primary health care centres demonstrated a significant reduction [Odds ratios (OR)=0.744] of haemolysed specimens after intervention, whereas urban primary health care centres demonstrated a significant increase (OR=1.451) of haemolysis.

    Conclusions: A large-scale 2 h educational intervention to make venous blood specimen collection staff comply with guideline practices had minor effects on collection practices. Educational interventions may be effective in wards/care centres demonstrating venous blood specimen collection practices with larger deviations from guidelines.

  • 10.
    Connolly-Andersen, Anne-Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Sundberg, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Baudin, Maria
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Larsson, Johanna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Dunne, Eimear
    Clinical Research Centre, Royal College of Surgeons in Ireland, Dublin .
    Kenny, Dermot
    Clinical Research Centre, Royal College of Surgeons in Ireland, Dublin .
    Lindahl, Tomas L.
    Department of Clinical and Experimental Medicine, Linköping University, Sweden.
    Ramström, Sofia
    Department of Clinical and Experimental Medicine, Linköping University, Sweden.
    Nilsson, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Increased Thrombopoiesis and Platelet Activation in Hantavirus-Infected Patients2015In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 212, no 7, p. 1061-1069Article in journal (Refereed)
    Abstract [en]

    Background. Thrombocytopenia is a common finding during viral hemorrhagic fever, which includes hemorrhagic fever with renal syndrome (HFRS). The 2 main causes for thrombocytopenia are impaired thrombopoiesis and/or increased peripheral destruction of platelets. In addition, there is an increased intravascular coagulation risk during HFRS, which could be due to platelet activation. Methods. Thrombopoiesis was determined by quantification of platelet counts, thrombopoietin, immature platelet fraction, and mean platelet volume during HFRS. The in vivo platelet activation was determined by quantification of soluble P-selectin (sP-selectin) and glycoprotein VI (sGPVI). The function of circulating platelets was determined by ex vivo stimulation followed by flow cytometry analysis of platelet surface-bound fibrinogen and P-selectin exposure. Intravascular coagulation during disease was determined by scoring for disseminated intravascular coagulation (DIC) and recording thromboembolic complications. Results. The levels of thrombopoietin, immature platelet fraction, and mean platelet volume all indicate increased thrombopoiesis during HFRS. Circulating platelets had reduced ex vivo function during disease compared to follow-up. Most interestingly, we observed significantly increased in vivo platelet activation in HFRS patients with intravascular coagulation (DIC and thromboembolic complications) as shown by sP-selectin and sGPVI levels. Conclusions. HFRS patients have increased thrombopoiesis and platelet activation, which contributes to intravascular coagulation.

  • 11.
    Dahlin, Anna M
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Plasma vitamin B12 concentrations and the risk of colorectal cancer: a nested case-referent study2008In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 32, no 2, p. 304-314Article in journal (Refereed)
    Abstract [en]

    In this nested case-referent study, we related plasma concentrations of vitamin B12 to the risk of colorectal cancer, taking into consideration prediagnostic plasma folate and total homocysteine concentrations. Subjects were 226 cases and double matched referents from the population-based Northern Sweden Health and Disease Study. Follow-up times from recruitment to diagnosis ranged from 0.1 to 12.7 years, with a median of 4.2 years. Plasma vitamin B12 concentrations were inversely associated with the risk of rectal cancer: univariate odds ratio for the highest versus lowest quintile 0.34 (95% confidence interval (95% CI) 0.13-0.83), p(trend) = 0.004. Risk estimates were attenuated slightly but remained statistically significant after adjustment for body mass index, current smoking, recreational and occupational physical activity, alcohol intake and prediagnostic plasma folate and total homocysteine concentrations: OR 0.30 (95% CI 0.08-0.99), p(trend) = 0.025. The corresponding univariate and fully adjusted odds ratios for colon cancer were 1.25 (CI 0.66-2.36), p(trend) = 0.185 and 1.42 (CI 0.67-3.05), p(trend) = 0.113, respectively. The observed over-risk was attributable to left-sided colon cancer. Interaction analyses including vitamin B12, folate and homocysteine were in line with the results for vitamin B12 alone. In conclusion, these results suggest that increasing levels of plasma vitamin B12, alone or together with other factors involved in one-carbon metabolism, may reduce the risk of rectal cancer, whereas for colon cancer, the association appears to be less clear.

  • 12.
    Ekblom, Kim
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Stegmayr, Birgitta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    Johansson, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Wiklund, Per-Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Iron stores and HFE genotypes are not related to increased risk of ischemic stroke.: a prospective nested case-referent study2007In: Cerebrovascular Diseases, ISSN 1015-9770, E-ISSN 1421-9786, Vol. 24, no 5, p. 405-411Article in journal (Refereed)
    Abstract [en]

    Background: High iron levels can increase the formation of noxious oxygen radicals, which are thought to contribute to cerebrovascular disease. The aim of this prospective study was to determine if iron status and HFE genotypes constitute risk factors for stroke.

    Methods: First-ever stroke cases (231 ischemic and 42 hemorrhagic) and matched double referents from the population-based Northern Sweden cohorts were studied in a nested case-referent setting.

    Results: For total iron binding capacity, an increased risk of ischemic stroke was seen in the highest quartile (OR 1.80; 95% CI 1.14-2.83; p for trend 0.012). The highest quartile of transferrin iron saturation showed a decreased risk of ischemic stroke in men (OR 0.44; 95% CI 0.22-0.87; p for trend 0.028), but not in women. There was an increased risk of hemorrhagic stroke in the second (OR 4.07; 95% CI 1.09-15.20) and third quartile (OR 4.22; 95% CI 1.08-16.42) of ferritin. Neither quartiles of plasma iron concentrations nor the HFE C282Y and H63D genotypes were associated with ischemic or hemorrhagic stroke.

    Conclusions: Iron stores were not positively related to increased risk of ischemic stroke. Furthermore, HFE genotypes did not influence the risk of ischemic or hemorrhagic stroke. Copyright (c) 2007 S. Karger AG, Basel.

  • 13.
    Ekblom, Kim
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Iron stores and HFE genotypes are not related to increased risk of first-time myocardial infarction: a prospective nested case-referent study2011In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 150, no 2, p. 169-172Article in journal (Refereed)
    Abstract [en]

    Objectives: Our objectives were to study the relationship between iron stores, HFE genotypes and the risk for first-ever myocardial infarction.

    Methods: First-ever myocardial infarction cases (n=618) and double matched referents from the Northern Sweden Health and Disease Cohort Study were studied in a prospective nested case-referent setting. Plasma iron, total iron binding capacity, transferrin iron saturation and ferritin were analyzed, as well as several confounders. HFE C282Y and H63D genotypes were determined.

    Results: There was an inverse risk association for myocardial infarction in the highest quartiles of iron (OR 0.68; 95% CI 0.48-0.96) and transferrin iron saturation (OR 0.62; 95% CI 0.42-0.89) in men. This association, however, was lost after adjusting for C-reactive protein. Women homozygous for H63D had a higher risk for myocardial infarction.

    Conclusions: No risk association between high iron stores and first-ever myocardial infarction was found. The higher risk in female H63D homozygotes is probably not related to iron metabolism.

  • 14.
    Ekblom, Kim
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Jansson, Jan-Håkan
    Medicinkliniken, Skellefteå lasarett.
    Osterman, Pia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Plasma Bilirubin and UGT1A1*28 Are Not Protective Factors Against First-Time Myocardial Infarction in a Prospective, Nested Case–Referent Setting2010In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, no 3, p. 340-347Article in journal (Refereed)
    Abstract [en]

    Background: Bilirubin, an effective antioxidant, shows a large variation in levels between individuals and has been positively associated with reduced cardiovascular disease risk. A major reason for the variability is a common promoter polymorphism, UGT1A1*28, which reduces the transcription of the enzyme that conjugates bilirubin, UDP-glucuronosyltransferase 1A1. The aim of the study was to evaluate a possible protective effect of plasma bilirubin and the UGT1A1*28 polymorphism against myocardial infarction in a prospective case-referent setting.

    Methods and Results: 618 subjects with a first-ever myocardial infarction (median event age 60.5 years, median lag time 3.5 years) and 1184 matched referents were studied. Plasma bilirubin was lower in cases vs. referents. Despite a strong gene-dosage effect on bilirubin levels in both cases and referents, the UGT1A1*28 polymorphism did not influence the risk of myocardial infarction. Among multiple other variables, serum iron showed one of the strongest associations with bilirubin levels.

    Conclusion: We found no evidence for a protective effect of the UGT1A1*28 polymorphism against myocardial infarction and consequently neither for bilirubin. The lower bilirubin levels in cases might be caused by decreased production, increased degradation or increased elimination.

  • 15.
    Ekblom, Kim
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Jansson, Jan-Håkan
    Osterman, Pia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Response to letter regarding article "Plasma bilirubin and UGT1A1*28 are not protective factors against first-time myocardial infarction in a prospective nested case-referent setting"2011In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 4, no 1, p. e2-Article in journal (Refereed)
  • 16.
    Ekblom, Kim
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Lars
    Osterman, Pia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wiklund, Per-Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Bilirubin and UGT1A1*28 are not associated with lower risk for ischemic stroke in a prospective nested case-referent setting.2010In: Cerebrovascular Diseases, ISSN 1015-9770, E-ISSN 1421-9786, Vol. 30, no 6, p. 590-596Article in journal (Refereed)
    Abstract [en]

    Background: Bilirubin, an antioxidant, has been associated with reduced cardiovascular disease risk. A major cause of elevated plasma bilirubin is the common UGT1A1*28 promoter polymorphism in the gene of the bilirubin-conjugating enzyme UDP-glucuronosyltransferase 1A1, which reduces transcription by 70%. Earlier studies reporting a protective effect of bilirubin on stroke have not included analysis of UGT1A1*28. The purpose of this study is to investigate if bilirubin and UGT1A1*28 are protective against ischemic stroke in a prospective case-referent setting. Methods: Cases with first-ever ischemic stroke (n = 231; median lag time 4.9 years) and 462 matched referents from the Northern Sweden Health and Disease Study Cohort were included. Plasma bilirubin was measured and UGT1A1*28 was analyzed by fragment analysis. Results: Plasma bilirubin was lower in cases than in referents, but the difference reached significance only for women. The UGT1A1*28 polymorphism (allele frequency 30%) showed a strong gene-dose relationship with bilirubin levels both among cases and referents, but was not associated with risk for stroke. Among multiple other variables analyzed, the strongest correlation with bilirubin was found for plasma iron. Conclusions: There was no evidence for a protective effect of the UGT1A1*28 polymorphism against stroke and consequently neither for bilirubin. The findings suggest that other factors influencing the risk for stroke might also affect bilirubin levels.

  • 17.
    Ekblom, Kim
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Lars
    Medicinkliniken, Skellefteå lasarett.
    Osterman, Pia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Wiklund, Per-Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Bilirubin and UGT1A1*28, are not associated with lower risk for ischemic stroke in a prospective nested case-referent settingArticle in journal (Refereed)
    Abstract [en]

    Background: Bilirubin, an antioxidant, has been associated with reduced cardiovascular disease risk. A major cause of elevated plasma bilirubin is the common UGT1A1*28 promoter polymorphism in the gene of the bilirubin-conjugating enzyme UDP-glucuronosyltransferase-1A1, which reduces transcription by 70%. Earlier studies reporting a protective effect of bilirubin on stroke, have not included analysis of UGT1A1*28. The purpose of this study is to investigate if bilirubin and UGT1A1*28 are protective against ischemic stroke in a prospective case-referent setting.

    Methods: Cases with first-ever ischemic stroke (n=231; median lag time 4.9 years), and 462 matched referents from the The Northern Sweden Health and Disease Study Cohort were included. Plasma bilirubin was measured and UGT1A1*28 was analyzed by fragment analysis.

    Results: Plasma bilirubin was lower in cases than in referents, but the difference reached significance only for women. The UGT1A1*28 polymorphism (allele frequency 30%), showed a strong gene-dose relationship with bilirubin levels both among cases and referents, but was not associated with risk for stroke. Among multiple other variables analysed the strongest correlation with bilirubin was found for plasma iron.

    Conclusions: There was no evidence for a protective effect of the UGT1A1*28 polymorphism against stroke and consequently neither for bilirubin. The findings suggest that other factors influencing the risk for stroke also might affect bilirubin levels.

  • 18.
    Ekblom, Kim
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Iron Biomarkers in Plasma, HFE Genotypes, and the Risk for Colorectal Cancer in a Prospective Setting2012In: Diseases of the Colon & Rectum, ISSN 0012-3706, E-ISSN 1530-0358, Vol. 55, no 3, p. 337-344Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: High iron levels can increase the formation of noxious oxygen radicals, which are thought to promote carcinogenesis. OBJECTIVE: The aim of this prospective study was to determine whether iron biomarkers and HFE genotypes, which influence iron regulation, constitute risk factors for colorectal cancer. DESIGN: This is a prospective nested case-referent study. SETTINGS: The study was performed within the population-based Northern Sweden Health and Disease Study. PATIENTS: The study included 226 cases of colorectal cancer and 437 matched referents. MAIN OUTCOME MEASURES: Conditional regression analysis was performed. Adjustments for smoking, smoking and BMI, and HFE C282Y and H63D were performed. RESULTS: The highest quintile of total iron-binding capacity showed significantly higher risk for colorectal cancer, unadjusted OR 2.35 (95% CI 1.38-4.02). When stratified by sex, the findings were only present in women (OR 3.34 (95% CI 1.59-7.02)). Ferritin was associated with reduced risk throughout quintiles 2 to 5 both in univariate and multivariate models. LIMITATIONS: Colorectal cancer may influence iron markers because of occult bleeding. Homozygotes for HFE C282Y were too few to make conclusions for this group. The relatively short follow-up time might be insufficient to detect risk of iron biomarkers. CONCLUSIONS: High iron levels do not increase the risk of colorectal cancer. HFE genotypes influencing iron uptake had no effect on colorectal cancer risk.

  • 19.
    Eklöf, Vincy
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The reduced folate carrier (RFC1) 80G>A and folate hydrolase 1 (FOLH1) 1561C>T polymorphisms and the risk of colorectal cancer: a nested case-referent study2008In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 68, no 5, p. 393-401Article in journal (Refereed)
    Abstract [en]

    Objective. Polymorphisms in genes involved in folate uptake and metabolism may affect folate status and, thereby, the risk of cancer. In this nested case‐referent study, we related two such polymorphisms, reduced folate carrier (RFC1) 80G>A and folate hydrolase 1 (FOLH1) 1561C>T, to the risk of colorectal cancer, taking into account pre‐diagnostic plasma folate and total homocysteine concentrations and the MTHFR 677C>T polymorphism, which were analysed in a previous study.

    Material and methods. Subjects were 220 cases and 414 matched referents from the population‐based Northern Sweden Health and Disease Study.

    Results. The RFC1 80A‐allele was associated with reduced plasma folate and elevated plasma total homocysteine concentrations, but the result was statistically significant only for folate. In contrast, the FOLH1 1561T‐allele was associated with higher plasma folate and reduced plasma total homocysteine concentrations, and the result was statistically significant only for homocysteine. Neither polymorphism was related to the risk of colorectal cancer, either in univariate analysis or after adjusting for body mass index, current smoking, recreational and occupational physical activity and alcohol intake. Further adjustment for folate or homocysteine status or the MTHFR 677C>T polymorphism did not affect risk estimates. Subjects with the RFC1 80AA genotype in combination with low plasma folate concentrations or the MTHFR 677TT genotype had a reduced risk of colorectal cancer of borderline statistical significance.

    Conclusions. These findings suggest that although the RFC1 80G>A and FOLH1 1561C>T polymorphisms may influence folate status, they are not likely to have a major independent role in the development of colorectal cancer.

    Read More: http://informahealthcare.com/doi/abs/10.1080/00365510701805431

  • 20.
    Gylling, Björn
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Ueland, Per Magne
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Low folate levels are associated with reduced risk of colorectal cancer in a population with low folate status2014In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 23, no 10, p. 2136-2144Article in journal (Refereed)
    Abstract [en]

    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 <10.8 years, a statistically significant doubled risk was observed for the middle and highest versus lowest tertile, whereas findings for longer follow-up times were null. A positive risk relationship was also observed for tumor stage III-IV but not I-II. Plasma vitamin B12 concentrations were inversely associated with rectal cancer risk. Homocysteine was not significantly related to colorectal cancer risk.

    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.

  • 21.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Homocysteine in cardiovascular disease with special reference to longitudinal changes2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Abnormalities in homocysteine metabolism have been suggested as risk factors for stroke and myocardial infarction. In retrospective studies, elevated levels of total plasma homocysteine (tHcy) and/or methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism have indicated an increase in risk. However, the fewer prospective studies have not been as conclusive. To further explore this, tHcy was studied in four prospective settings.

    The first was a prospective nested case-referent cohort within the Västerbotten Intervention Program (VIP) and WHO MONICA project on 312 ischemic and 60 haemorrhagic first-ever strokes. The aim was to study tHcy and its main genetic determinant MTHFR. Risk for haemorrhagic stroke increased exponentially through tHcy quartiles, independent of hypertension and BMI, and increased for MTHFR 677 CT and TT. MTHFR 1298A>C appeared to be protective. In multivariate models, after adjustment for tHcy, BMI and hypertension, both tHcy and MTHFR remained as independent predictors for hemorrhagic stroke. Neither tHcy, nor the two MTHFR polymorphisms were significant predictors for ischemic strokes.

    The second was a prospective long-term follow-up study within the VIP and MONICA cohorts to determine whether a first-ever myocardial infarction (AMI) causes increased levels of tHcy. Fifty cases developing AMI after the first screening participated in a second screening (mean follow-up 8.5 years) with 56 matched referents. Increase in tHcy did not differ between cases and referents. tHcy was related to AMI at follow-up, but not at baseline and no longer significant after adjusting for creatinine and albumin.

    The third was a method study to determine if cystatin C, creatinine, albumin and other lipoprotein risk markers of cardiovascular disease could be analysed in Stabilyte™ plasma stored at -80°C. It was found to be suitable for all analyses tested and using this tube would simplify sampling for epidemiological studies.

    The fourth study was a prospective longitudinal long-term study of 735 subjects (340 men and 395 women, age 25-64 at first screening), participating in two MONICA screenings nine years apart, who donated blood in Stabilyte™ tubes to study change over time in tHcy and its determinants. We confirmed the age dependency in a cross sectional setting. In contrast, if followed longitudinally over time, no change in tHcy or in the prevalence of hyperhomocysteinemia was found. Cystatin C and creatinine increased, and albumin decreased. In multivariate models baseline levels of albumin, creatinine, cystatin C, and to some extent hs-CRP, were predictors of tHcy at follow-up but gender differences were seen. Age was not a major determinant of change in tHcy over nine years.

    In conclusion, tHcy and MTHFR are risk factors for first-ever haemorrhagic, but not ischemic stroke in a prospective setting. A first myocardial infarction does not cause an increase in tHcy. No long-term changes were seen in tHcy over a nine-year period in neither men, nor in women.

  • 22.
    Hultdin, Johan
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Nilsson, Torbjörn K
    Analysis of cystatin C, creatinine, albumin, lipids and lipoprotein concentrations in serum and acidified citrate plasma (Stabilyte) tubes compared.2004In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 42, no 8, p. 978-981Article in journal (Other academic)
  • 23.
    Hultdin, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Thøgersen, Ann Margreth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nilsson, T K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Elevated plasma homocysteine: cause or consequence of myocardial infarction?2004In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 256, no 6, p. 491-498Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To determine whether a first myocardial infarction leads to increased plasma homocysteine concentrations and whether the association between homocysteine and myocardial infarction was greater at follow-up compared with baseline. DESIGN: A population-based, prospective, nested case-referent study. SETTING: Screening took place at the nearest health survey centre in northern Sweden. SUBJECTS: Of more than 36,000 persons screened, 78 developed a first myocardial infarction (average 18 months after sampling). Fifty of these had participated in a follow-up health survey (average 8(1/2) years between surveys) and were sex- and age-matched with 56 referents. MAIN OUTCOME MEASURES: Comparison of plasma homocysteine levels in case and referent subjects before and after development of a first myocardial infarction. RESULTS: No statistically significant difference was found between cases and referents regarding homocysteine at baseline or follow-up. Plasma homocysteine and plasma creatinine increased significantly, and plasma albumin decreased significantly over time. Conditional univariate logistic regression indicated that high homocysteine at follow-up but not baseline was associated with first myocardial infarction (OR 2.49; 95% CI: 1.03-6.02), but the relation disappeared in multivariate analyses including plasma creatinine and plasma albumin. High plasma creatinine remained associated with first myocardial infarction at both baseline (OR 2.94; 95% CI: 1.05-8.21) and follow-up (OR 3.38; 95% CI: 1.21-9.48). CONCLUSION: In this study, first myocardial infarction did not cause increased plasma homocysteine concentration.

  • 24.
    Hultdin, Johan
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Nutritional Research.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Plasma folate, vitamin B12, and homocysteine and prostate cancer risk: a prospective study.2005In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 113, no 5, p. 819-824Article in journal (Refereed)
    Abstract [en]

    The role of folate metabolism in cancer development is a topic of much current interest, with maintenance of adequate folate status tending to show a protective effect. Aberrant methylation, primarily hypermethylation of certain genes including tumor suppressors, has been implicated in prostate cancer development. Folate, vitamin B12 and homocysteine are essential for methyl group metabolism and thus also for DNA methylation. We related plasma levels of these factors to prostate cancer risk in a prospective study of 254 case subjects and 514 matched control subjects. Increasing plasma levels of folate and vitamin B12 were statistically significantly associated with increased prostate cancer risk, with an odds ratio of 1.60 (95% CI = 1.03-2.49; p(trend) = 0.02) for folate and 2.63 (95% CI = 1.61-4.29; p(trend) < 0.001) for vitamin B12 for highest vs. lowest quartile. Increasing plasma homocysteine levels were associated with a reduced risk of borderline significance (OR = 0.67; 95% CI = 0.43-1.04; p(trend) = 0.08). After adjustment for the other 2 plasma variables, body mass index and smoking, a statistically significant increased risk remained only for vitamin B12 (OR = 2.96; 95% CI = 1.58-5.55; p(trend) = 0.001). Adjusted OR for folate and homocysteine were 1.30 (95% CI = 0.74-2.24; p(trend) = 0.17) and 0.91 (95% CI = 0.51-1.58; p(trend) = 0.60), respectively. Our results suggest that factors contributing to folate status are not protective against prostate cancer. On the contrary, vitamin B12, associated with an up to 3-fold increase in risk, and possibly also folate, may even stimulate prostate cancer development. These findings are novel and should be explored further in future studies. (c) 2004 Wiley-Liss, Inc.

  • 25.
    Hultdin, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Winkvist, Anna
    Department of Clinical Nutrition, Göteborg University, Gothenburg, Sweden.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Stegmayr, Birgitta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nilsson, Torbjörn K.
    Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Prospective study of first stroke in relation to plasma homocysteine and MTHFR 677C > T and 1298A > C genotypes and haplotypes: evidence for an association with hemorrhagic stroke2011In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 49, no 9, p. 1555-1562Article in journal (Refereed)
    Abstract [en]

    Background: Abnormalities in homocysteine metabolism have been suggested as risk factors for stroke. The aim of this prospective study was to examine whether total plasma homocysteine concentration (tHcy) and its main genetic determinant, methylene tetrahydrofolate reductase (MTHFR) polymorphisms, were associated with first ischemic or hemorrhagic stroke.

    Methods: This was a nested case-referent study of 321 ischemic and 60 hemorrhagic stroke cases, defined by WHO MONICA criteria and each matched with two event-free referents for sex, age, cohort, recruitment date and geographical area. All subjects were from the population-based Northern Sweden Health and Disease Study cohorts. Odds ratios were determined by conditional logistic regression.

    Results: The mean follow-up time was 4.2 years. Both tHcy and MTHFR were independent predictors of hemorrhagic stroke in multivariate models including body mass index, hypertension and, for MTHFR, tHcy [OR for the highest vs. lowest tHcy quartile 8.13 (95% CI 1.83-36.1), p(trend)=0.002; OR for MTHFR 677TT vs. 677CC genotype 3.62 (95% CI 0.77-17.0), p(trend)=0.040]. Haplotype analyses confirmed that the MTHFR 677T-1298A haplotype was positively associated with hemorrhagic stroke [OR 1.81 (95% CI 1.09-3.00), p=0.022], whereas the MTHFR 677C-1298C haplotype was not significantly related to either hemorrhagic or ischemic stroke. Neither tHcy nor the MTHFR polymorphisms were significant predictors of ischemic stroke.

    Conclusion: Both elevated plasma homocysteine levels and the MTHFR 677T allele are indicators of increased risk of hemorrhagic stroke in the northern Swedish population.

  • 26.
    Johansson, Ingegerd
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, M
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Validity of food frequency questionnaire estimated intakes of folate and other B vitamins in a region without folic acid fortification.2010In: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 64, no 8, p. 905-913Article in journal (Refereed)
    Abstract [en]

    Background/Objectives: 

    B vitamins have been implicated in major chronic diseases but results have been inconsistent. This study evaluated the accuracy of dietary intakes of folate, vitamin B12, riboflavin and vitamin B6 as measured by the Northern Sweden Food Frequency Questionnaire (FFQ) against repeated 24-h recalls (24HR) and plasma levels, taking into consideration the MTHFR 677C>T polymorphism.

    Subjects/Methods: 

    B vitamin intakes assessed by a semi-quantitative FFQ designed to measure the intake over the previous year were compared with those from 10 24HR, as well as to plasma levels of folate and vitamin B12, in randomly selected men (n=96) and women (n=99) aged 30–60 years. FFQ-based B-vitamin intakes were also compared with plasma levels of B-vitamins and with MTHFR 677C4T genotype in 878 men, aged 40–61 years.

    Results: 

    Intakes of vitamins B12 and riboflavin were similar, whereas folate and B6 intakes were 16–27% higher, as estimated by FFQ versus 24HR. Spearman correlation coefficients between the two methods ranged from 0.31 to 0.63 (all P0.002), and were lowest for vitamin B12. Intakes estimated by FFQ were correlated with plasma levels, but coefficients were lower (range: 0.13–0.33), particularly for vitamin B12 in men (0.15–0.18). Folate intake was not correlated with plasma levels in subjects with the MTHFR 677 T/T genotype.

    Conclusions: 

    The validity of the Northern Sweden FFQ for assessing B vitamin intake is similar to that of many other FFQs used in large-scale studies. The FFQ is suitable for ranking individuals by intake of folate, riboflavin, vitamin B6 and to a lesser extent vitamin B12.

  • 27.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Wiklund, Fredrik
    Adami, Hans-Olov
    Bälter, Katarina
    Grönberg, Henrik
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    The MTHFR 677C --> T polymorphism and risk of prostate cancer: results from the CAPS study2007In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 18, no 10, p. 1169-1174Article in journal (Refereed)
    Abstract [en]

    The methylenetetrahydrafolate reductase (MTHFR) enzyme may influence cancer development by affecting DNA methylation, synthesis and repair. The MTHFR 677C→T single nucleotide polymorphism (SNP) has been associated with decreased enzyme activity and has therefore been implicated in cancer development. We analyzed the MTHFR 677C→T SNP in 2,777 incident prostate cancer cases and 1,639 population controls from the CAncer Prostate in Sweden study (CAPS). No significant association was found overall between prostate cancer risk and the 677C→T SNP (p = 0.27) with heterozygote (CT) and homozygote (TT) allele carriers showing ORs of 1.12 (95% CI: 0.98–1.27) and 1.02 (95% CI: 0.80–1.30), respectively. In the subgroup of low risk prostate cancer, heterozygote—but not homozygote—allele carriers displayed a slight over-risk with an OR of 1.21 (95% CI: 1.03–1.41). Among men under 65 years of age, the 677C→T SNP was associated with prostate cancer risk (p = 0.007), with odds ratios of 1.33 (95% CI: 1.09–1.63) for heterozygote allele carriers and 0.86 (95% CI: 0.6–1.24) for homozygote allele carriers. However, this association was attributed to a shift in the genotype distribution in the young controls. In conclusion, our results do not provide strong support for the hypothesis that the MTHFR 677C→T polymorphism is related to prostate cancer risk.

  • 28.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Vollset, Stein Emil
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Key, Tim
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Ueland, Per M
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Prospective investigation of one-carbon metabolism in relation to prostate cancer risk: results from the NSHDC studyManuscript (Other academic)
  • 29.
    Johansson, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. International Agency for Research on Cancer (IARC-WHO), Lyon, France.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Vollset, Stein Emil
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Key, Tim
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Midttun, Øivind
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Ueland, Per M
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    One-carbon metabolism and prostate cancer risk: prospective investigation of seven circulating B vitamins and metabolites2009In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 18, no 5, p. 1538-1543Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Components of one-carbon metabolism are believed to influence cancer development with suggested mechanisms, including DNA methylation and DNA repair mechanisms. However, few prospective studies have investigated one-carbon metabolism in relation to prostate cancer risk, and the results have been conflicting. The aim of this study was to do a comprehensive investigation of the components of one-carbon metabolism in relation to prostate cancer risk. A panel of seven circulating B vitamins and related metabolites was selected, most of which have not been studied before. MATERIALS AND METHODS: We analyzed plasma concentrations of betaine, choline, cysteine, methionine, methylmalonic acid (MMA), vitamin B2, and vitamin B6 in 561 cases and 1,034 controls matched for age and recruitment date, nested within the population-based Northern Sweden Health and Disease Cohort. Relative risks of prostate cancer were estimated by conditional logistic regression. RESULTS: Positive associations with prostate cancer risk were observed for choline and vitamin B2, and an inverse association was observed for MMA. The relative risks for a doubling in concentrations were 1.46 [95% confidence interval (95% CI), 1.04-2.05; P(trend) = 0.03] for choline, 1.11 (95% CI, 1.00-1.23; P(trend) = 0.04) for vitamin B2, and 0.78 (95% CI, 0.63-0.97; P(trend) = 0.03) for MMA. Concentrations of betaine, cysteine, methionine, and vitamin B6 were not associated with prostate cancer risk. CONCLUSION: The results of this large prospective study suggest that elevated plasma concentrations of choline and vitamin B2 may be associated with an increased risk of prostate cancer. These novel findings support a role of one-carbon metabolism in prostate cancer etiology and warrant further investigation. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1538-43).

  • 30.
    Karling, Pontus
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lundgren, David
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Eklöf, Vincy
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Improved monitoring of inflammatory activity in patients with ulcerative colitis by combination of faecal tests for haemoglobin and calprotectin2019In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686Article in journal (Refereed)
    Abstract [en]

    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.

  • 31. Kivipelto, M
    et al.
    Annerbo, S
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Bäckman, L
    Viitanen, M
    Fratiglioni, L
    Lökk, J
    Homocysteine and holo-transcobalamin and the risk of dementia and Alzheimers disease: a prospective study.2009In: European journal of neurology : the official journal of the European Federation of Neurological Societies, ISSN 1468-1331, Vol. 16, no 7, p. 808-813Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Elevated total homocysteine (tHcy) levels may be caused by vitamin B12 deficiency and are linked to Alzheimers disease (AD) in some studies, although the evidence is mixed. Another marker of vitamin B12 deficiency, holo-transcobalamin (holo-TC), has not been studied in a prospective setting. OBJECTIVE: To investigate the association between tHcy and holo-TC and the subsequent development of dementia and AD in a prospective study. METHODS: A sub-sample of 228 non-demented subjects was taken from the Kungsholmen Project, a population-based longitudinal study amongst persons 75+ years. tHcy and holo-TC were analysed at baseline. RESULTS: Increasing tHcy levels were related to an increased risk of dementia (n = 83) and AD (n = 61) after a mean follow-up time of 6.7 years. Persons with high tHcy (the fourth quartile) had more than twice as high a risk of developing AD than persons with low tHcy, even after adjusting for confounding or mediating factors. The third quartile of holo-TC was associated with a reduced risk of AD, after adjusting for Hcy and other confounders. CONCLUSIONS: These results suggest that Hcy is involved in the development of dementia and AD. The role of holo-TC was less clear and this marker needs to be studied further.

  • 32.
    Ljungberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Holmgren, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Norberg, Margareta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lipoprotein(a) and the Apolipoprotein B/A1 Ratio Independently Associate With Surgery for Aortic Stenosis Only in Patients With Concomitant Coronary Artery Disease2017In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 6, no 12, article id e007160Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Aortic stenosis (AS) has different clinical phenotypes, including AS with or without concomitant coronary artery disease (CAD). It is unknown whether these phenotypes share the same risk factors. In particular, lipoprotein(a) [Lp(a)] and apolipoproteins (Apo) are associated with AS, but it is unknown whether these associations differ among phenotypes. In this prospective analysis we examined the impact of Lp(a) and Apo in subgroups of patients with AS.

    METHODS AND RESULTS: We identified 336 patients (mean age at survey 56.7 years, 48% female) who underwent surgery for AS after a median 10.9 years (interquartile range 9.3 years), participants in 1 of 3 large population surveys. For each patient, 2 matched referents were allocated. Lp(a) and Apo were analyzed in the baseline samples. Uni- and multivariable logistic regression analyses were used to estimate risks related to a 1 (ln) standard deviation increase in Lp(a) and the ratio of Apo B to Apo A1 (Apo B/A1 ratio). High levels of Lp(a) predicted surgery for AS in 203 patients with concomitant CAD (odds ratio [95% confidence intervals]) (1.29 [1.07-1.55]), but not in 132 patients without CAD (1.04 [0.83-1.29]) in the fully adjusted model. Similarly, a high Apo B/A1 ratio predicted surgery in patients with concomitant CAD (1.43 [1.16-1.76]) but not in those without CAD (0.87 [0.69-1.10]).

    CONCLUSIONS: High levels of Lp(a) and a high Apo B/A1 ratio were associated with surgery for AS in patients with concomitant CAD but not in those with isolated AS. This finding may lead to a new avenue of research for targeted risk factor interventions in this population.

  • 33.
    Ljungberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Janiec, Mikael
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Holmgren, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Siegbahn, Agneta
    Fall, Tove
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Proteomic Biomarkers for Incident Aortic Stenosis Requiring Valvular Replacement2018In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 138, no 6Article in journal (Refereed)
    Abstract [en]

    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.

  • 34.
    Ljungberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Holmgren, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Mild impairment of renal function (shrunken pore syndrome) is associated with increased risk for future surgery for aortic stenosis2019In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 79, no 7, p. 524-530Article in journal (Refereed)
    Abstract [en]

    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.

  • 35.
    Ljungberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Holmgren, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Näslund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Early impairment of renal function (shrunken pore syndrome) is associated with increased risk for future surgery for aortic stenosisManuscript (preprint) (Other academic)
    Abstract [en]

    Introduction 

    Renal insufficiency is a known risk factor for cardiovascular disease. However, it is unknown if early impairment in renal function is associated with increased risk for aortic stenosis (AS). Recently a new approach was proposed to detect early impairment in renal function by using the ratio between glomerular filtration rate (GFR) calculated by cystatin C and GFR calculated by creatinine. 

    Purpose 

    To evaluate if the ratio between GFR cystatin C and GFR creatinine is associated with increased risk for AS requiring surgery and further, to evaluate if the ratio associates with survival. 

    Methods 

    We identified 334 patients that underwent surgery for AS after participation in population surveys (median age (interquartile range) 59.4 (10.3) years at survey and 68.3 (12.7) at surgery, 48% females). For each patient, two matched referents were allocated. Circulating levels of cystatin C and creatinine were determined at baseline (survey). Estimated glomerular filtration rates (eGFR) were calculated using the CAPA and Lund-Malmö-Revised formulas. Uni- and multivariable conditional logistic regression analyses were used to estimate the risk (odds ratio (OR) with [95% confidence interval]) related to one (ln) standard deviation increase in cystatin C, creatinine, eGFR cystatin C, eGFR creatinine, and in the ratio between eGFR cystatin C and eGFR creatinine, respectively. 

    Results 

    A high ratio was associated with lower risk for AS requiring surgery (OR 0.84 [0.73–0.97]). After stratification for sex, this effect was seen in women but not in men (0.74 [0.60–0.92] and 0.93 [0.76 [0.76–1.13], respectively). After further stratification for CAD, the association remained in women with CAD, but the effect was not seen in men with CAD (0.60 [0.44–0.83] and 0.96 [0.76 [0.75–1.23]). A high ratio was associated with longer survival in the entire cohort (HR 0.84 [0.75–0.95]). 

    Conclusion 

    A high ratio between eGFR based on cystatin C and eGFR based on creatinine was associated with lower risk for surgery for AS in those with CAD with a clear sex-difference. Early renal impairment is thus associated with future risk for AS requiring surgery. Further, a high ratio relates to longer survival. 

  • 36.
    Lundgren, David
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Eklöf, Vincy
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Proton pump inhibitor use is associated with elevated faecal calprotectin levels. A cross-sectional study on subjects referred for colonoscopy2019In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 54, no 2, p. 152-157Article in journal (Refereed)
    Abstract [en]

    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 mu g/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 mu g/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.

  • 37.
    Lundqvist, Anette
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Wennberg, Anna-Lena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Högberg, Ulf
    Uppsala, Sweden.
    Hamberg, Katarina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Sandström, Herbert
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Reported dietary intake in early pregnant compared to non-pregnant women: a cross-sectional study2014In: BMC Pregnancy and Childbirth, ISSN 1471-2393, E-ISSN 1471-2393, Vol. 14, no 373Article in journal (Refereed)
    Abstract [en]

    Background: A woman's nutritional status before conception and during pregnancy is important for maternal health and the health of the foetus. The aim of the study was to compare diet intake in early pregnant women with non-pregnant women. Methods: Between September 2006 and March 2009, 226 women in early pregnancy were consecutively recruited at five antenatal clinics in Northern Sweden. Referent women (n = 211) were randomly selected from a current health screening project running in the same region (the Vasterbotten Intervention Program; VIP). We collected diet data with a self-reported validated food frequency questionnaire with 66 food items/food aggregates, and information on portion size, alcohol consumption, and supplement intake. Data were analysed using descriptive, comparative statistics and multivariate partial least square modelling. Results: Intake of folate and vitamin D from foods was generally low for both groups. Intake of folate and vitamin D supplements was generally high in the pregnant group and led to significantly higher total estimated intake of vitamin D and folate in the pregnant group. Iron intake from foods tended to be lower in pregnant women although iron supplement intake evened out the difference with respect to iron intake from foods only. Energy intake was slightly lower in pregnant women but not significant, a reflection of that they reported consuming significantly less of potatoes/rice/pasta, meat/fish, and vegetables (grams/day) than the women in the referent group. Conclusions: In the present study, women in early pregnancy reported less intake of vegetables, potatoes, meat, and alcohol than non-pregnant women. As they also had a low intake (below the Nordic Nutritional Recommendations) of folate, vitamin D, and iron from foods, some of these women and their unborn children are possibly at risk for adverse effects on the pregnancy and birth outcome.

  • 38.
    Lundqvist, Anette
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Sandström, Herbert
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Vitamin D Status during Pregnancy: a Longitudinal Study in Swedish Women from Early Pregnancy to Seven Months Postpartum2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0150385Article in journal (Refereed)
    Abstract [en]

    Low vitamin D levels during pregnancy may have negative consequences for the health of both the mother and child. Cross-sectional studies in childbearing women suggest that vitamin D levels are low during pregnancy, but few studies have followed the same women during pregnancy and postpartum. The aims of this study were to longitudinally assess vitamin D status during pregnancy and postpartum and identify the factors associated with vitamin D status in pregnant women in northern Sweden. Between September 2006 and March 2009, 184 women were consecutively recruited at five antenatal primary care clinics. Blood was sampled, and dietary intake was estimated using a food frequency questionnaire with 66 food items/food aggregates and questions on the intake of vitamin supplements at gestational weeks 12, 21, and 35, as well as at 12 and 29 weeks after birth. Plasma 25(OH) vitamin D levels were analyzed using liquid chromatography tandem-mass spectrometry. At least one-third of the women had 25(OH) vitamin D levels <50 nmol/L on at least one sampling occasion. Plasma levels increased slightly over the gestation period and peaked in late pregnancy. The levels reverted to the baseline levels after birth. Multivariate analysis showed that gestational and postpartum week, season, dietary intake of vitamin D, and vitamin supplementation were significantly related to plasma levels. There was also an influence of season on the longitudinal concentration patterns. In conclusion, more than one-third of the women studied had low 25(OH) vitamin D levels, and gestational and postpartum week was related to 25(OH) vitamin D levels after adjustment for season and vitamin D intake.

  • 39. Midttun, Oivind
    et al.
    Theofylaktopoulou, Despoina
    McCann, Adrian
    Fanidi, Anouar
    Muller, David C.
    Meyer, Klaus
    Ulvik, Arve
    Zheng, Wei
    Shu, Xiao-Ou
    Xiang, Yong-Bing
    Prentice, Ross
    Thomson, Cynthia A.
    Pettinger, Mary
    Giles, Graham G.
    Hodge, Allison
    Cai, Qiuyin
    Blot, William J.
    Wu, Jie
    Johansson, Mikael
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Stevens, Victoria L.
    McCullough, Marjorie L.
    Weinstein, Stephanie J.
    Albanes, Demetrius
    Langhammer, Arnulf
    Hveem, Kristian
    Naess, Marit
    Sesso, Howard D.
    Gaziano, J. Michael
    Buring, Julie E.
    Lee, I-Min
    Severi, Gianluca
    Zhang, Xuehong
    Han, Jiali
    Stampfer, Meir J.
    Smith-Warner, Stephanie A.
    Zeleniuch-Jacquotte, Anne
    le Marchand, Loic
    Yuan, Jian-Min
    Butler, Lesley M.
    Koh, Woon-Puay
    Wang, Renwei
    Gao, Yu-Tang
    Ericson, Ulrika
    Sonestedt, Emily
    Ziegler, Regina G.
    Freedman, Neal D.
    Visvanathan, Kala
    Jones, Miranda R.
    Relton, Caroline
    Brennan, Paul
    Johansson, Mattias
    Ueland, Per M.
    Circulating concentrations of biomarkers and metabolites related to vitamin status, one-carbon and the kynurenine pathways in US, Nordic, Asian, and Australian populations2017In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 105, no 6, p. 1314-1326Article in journal (Refereed)
    Abstract [en]

    Background: Circulating concentrations of biomarkers that are related to vitamin status vary by factors such as diet, fortification, and supplement use. Published biomarker concentrations have also been influenced by the variation across laboratories, which complicates a comparison of results from different studies. Objective: We robustly and comprehensively assessed differences in biomarkers that are related to vitamin status across geographic regions. Design: The trial was a cross-sectional study in which we investigated 38 biomarkers that are related to vitamin status and one-carbon and tryptophan metabolism in serum and plasma from 5314 healthy control subjects representing 20 cohorts recruited from the United States, Nordic countries, Asia, and Australia, participating in the Lung Cancer Cohort Consortium. All samples were analyzed in a centralized laboratory. Results: Circulating concentrations of riboflavin, pyridoxal 5'-phosphate, folate, vitamin B-12, all-trans retinol, 25-hydroxyvitamin D, and a-tocopherol as well as combined vitamin scores that were based on these nutrients showed that the general B-vitamin concentration was highest in the United States and that the B vitamins and lipid soluble vitamins were low in Asians. Conversely, circulating concentrations of metabolites that are inversely related to B vitamins involved in the one-carbon and kynurenine pathways were high in Asians. The high B-vitamin concentration in the United States appears to be driven mainly by multivitamin-supplement users. Conclusions: The observed differences likely reflect the variation in intake of vitamins and, in particular, the widespread multivitamin-supplement use in the United States. The results provide valuable information about the differences in biomarker concentrations in populations across continents.

  • 40. Muller, D. C.
    et al.
    Hodge, A. M.
    Fanidi, A.
    Albanes, D.
    Mai, X. M.
    Shu, X. O.
    Weinstein, S. J.
    Larose, T. L.
    Zhang, X.
    Han, J.
    Stampfer, M. J.
    Smith-Warner, S. A.
    Ma, J.
    Gaziano, J. M.
    Sesso, H. D.
    Stevens, V. L.
    McCullough, M. L.
    Layne, T. M.
    Prentice, R.
    Pettinger, M.
    Thomson, C. A.
    Zheng, W.
    Gao, Y. T.
    Rothman, N.
    Xiang, Y. B.
    Cai, H.
    Wang, R.
    Yuan, J. M.
    Koh, W. P.
    Butler, L. M.
    Cai, Q.
    Blot, W. J.
    Wu, J.
    Ueland, P. M.
    Midttun, O.
    Langhammer, A.
    Hveem, K.
    Johansson, M.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Arslan, A. A.
    Le Marchand, L.
    Severi, G.
    Brennan, P.
    No association between circulating concentrations of vitamin D and risk of lung cancer: an analysis in 20 prospective studies in the Lung Cancer Cohort Consortium (LC3)2018In: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 29, no 6, p. 1468-1475Article in journal (Refereed)
    Abstract [en]

    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.

  • 41.
    Myte, Robin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Gylling, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Ueland, Per Magne
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Components of One-carbon Metabolism Other than Folate and Colorectal Cancer Risk2016In: Epidemiology, ISSN 1044-3983, E-ISSN 1531-5487, Vol. 27, no 6, p. 787-796Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite extensive study, the role of folate in colorectal cancer remains unclear. Research has therefore begun to address the role of other elements of the folate-methionine metabolic cycles. This study investigated factors other than folate involved in one-carbon metabolism, i.e., choline, betaine, dimethylglycine, sarcosine, and methionine and relevant polymorphisms, in relation to the risk of colorectal cancer in a population with low intakes and circulating levels of folate.

    METHODS: This was a prospective case-control study of 613 case subjects and 1,190 matched control subjects nested within the population-based Northern Sweden Health and Disease Study. We estimated odds ratios (OR) by conditional logistic regression, and marginal risk differences with weighted maximum likelihood estimation using incidence data from the study cohort.

    RESULTS: Higher plasma concentrations of methionine and betaine were associated with modest colorectal cancer risk reductions (OR [95% confidence interval {CI}] for highest versus lowest tertile: 0.76 [0.57, 0.99] and 0.72 [0.55, 0.94], respectively). Estimated marginal risk differences corresponded to approximately 200 fewer colorectal cancer cases per 100,000 individuals on average. We observed no clear associations between choline, dimethylglycine, or sarcosine and colorectal cancer risk. The inverse association of methionine was modified by plasma folate concentrations (OR [95% CI] for highest/lowest versus lowest/lowest tertile of plasma methionine/folate concentrations 0.39 [0.24, 0.64], Pinteraction = 0.06).

    CONCLUSIONS: In this population-based, nested case-control study with a long follow-up time from baseline to diagnosis (median: 8.2 years), higher plasma concentrations of methionine and betaine were associated with lower colorectal cancer risk. See Video Abstract at http://links.lww.com/EDE/B83.

  • 42.
    Nilsson, Mats
    et al.
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Family Medicine.
    Norberg, Bo
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Sandström, Herbert
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Family Medicine.
    Westman, Göran
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Family Medicine.
    Lökk, Johan
    Medical intelligence in Sweden. Vitamin B12: oral compared with parenteral?2005In: Postgraduate medical journal, ISSN 0032-5473, E-ISSN 1469-0756, Vol. 81, no 953, p. 191-193Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Sweden is the only country in which oral high dose vitamin B12 has gained widespread use in the treatment of deficiency states. OBJECTIVE: The aim of the study was to describe prescribing patterns and sales statistics of vitamin B12 tablets and injections in Sweden 1990-2000.Design, setting, and sources: Official statistics of cobalamin prescriptions and sales were used. RESULTS: The use of vitamin B12 increased in Sweden 1990-2000, mainly because of an increase in the use of oral high dose vitamin B12 therapy. The experience, in statistical terms a "total investigation", comprised 1,000,000 patient years for tablets and 750,000 patient years for injections. During 2000, 13% of residents aged 70 and over were treated with vitamin B12, two of three with the tablet preparation. Most patients in Sweden requiring vitamin B12 therapy have transferred from parenteral to oral high dose vitamin B12 since 1964, when the oral preparation was introduced. CONCLUSION: The findings suggest that many patients in other post-industrial societies may also be suitable for oral vitamin B12 treatment.

  • 43. Polaschegg, H. D.
    et al.
    Stegmayr, B.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forsberg, U.
    Jonsson, P.
    Stegmayr, C.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Microbubbles of air during hemodialysis: negligible for the patient?2011In: International Journal of Artificial Organs, ISSN 0391-3988, E-ISSN 1724-6040, Vol. 34, no 8, p. 654-654Article in journal (Refereed)
    Abstract [en]

    The symposium covers information about the presence of microbubbles in hemodialysis. Physical basis, technical considerations and regulations will be presented by Hans-Dietrich Polaschegg (Koestenberg, Austria). Per Jonsson (Umeå, Sweden) will cover experimental projects that were focused to evaluate the presence of microbubble air as contamination in the

    in vitro setting and some experiences. Those data and techniques were further used in in vitro testing of prevailing materials and basis for initial clinical studies on chronic hemodialysis sessions (Bernd Stegmayr, Umeå, Sweden). The symposium will thereafter focus on more clinical studies to investigate various clinical settings in relation to micro bubble exposure. This will be presented by Ulf Forsberg (Skellefteå, Sweden). The importance of microbubbles of air may be questioned. Therefore post mortem investigations were performed on hemodialysis patients. These data will be presented by Thomas Brännström (Umeå, Sweden). The symposium will end with time for discussion.

  • 44.
    Salih, Abdulkadir
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Widbom, Lovisa
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Smoking is associated with risk for developing inflammatory bowel disease including late onset ulcerative colitis: a prospective study2018In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 53, no 2, p. 173-178Article in journal (Refereed)
    Abstract [en]

    Objectives: Life style factors have been associated with inflammatory bowel disease (IBD) but there is a lack of data on the exposure of life styles factors before the onset of IBD. Our aim was to study the association between lifestyle factors and the development of IBD in a prospective setting.

    Materials and methods: We performed a case control study of 72 patients who later developed ulcerative colitis (UC), 26 patients who developed Crohn's disease (CD) and 427 healthy controls from the Vasterbotten intervention project matched for gender, age, year of health survey and area of residence. At recruitment, participants completed validated lifestyle questionnaires including data on alcohol intake. Information from this was used to assess the connection between lifestyle factors and later developing IBD.

    Results: For CD and UC, the median age at diagnosis was 53 and 52 years and median time of survey was 4 and 6 years before diagnosis, respectively. Multivariate odds ratio (OR) showed an association between never smoking and not developing IBD, including both UC and CD, OR (95% CI) 0.341 (0.136-0.853) and 0.473 (0.259-0.864), respectively. Marital status, educational level, alcohol consumption, reported physical activity and use of moist smokeless tobacco (snus) did not differ between patients and controls.

    Conclusions: Smoking proves to be a risk factor for both CD and UC in this prospective case-control study. No association was seen for snus users, implying a non-nicotine pathogenic mechanism from combusted tobacco.

  • 45.
    Samuelsson, Eva
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Groth, Katarina
    medicinkliniken och Brunflo Hälsocentral, Jämtlands läns landsting.
    Hedenmalm, Karin
    Läkemedelsverket, Uppsala.
    Ung kvinna med p-ring drabbad av armtrombos: möjligt samband med mutation i protrombingenen2007In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 104, no 1-2, p. 32-34Article in journal (Other academic)
    Abstract [en]

    We report a case of axillary vein thrombosis in a young woman. The only identified risk factors included heterozygosity for the prothrombin 20210A variant, heavy lifting, and use of NuvaRing, a novel form of combined hormonal contraception. Thrombosis of the upper extremity veins is a rare condition that is often associated with specific local risk factors such as the presence of a central venous catheter, strenuous muscular effort or upper limb trauma. Recent research has also shown an association to traditional risk factors for venous thromboembolism (VTE) including coagulation abnormalities, surgery, immobilization, use of hormonal contraception and a family history of VTE. It is important to be aware of the rare occurrence of VTE associated with combined hormonal contraception. There is no evidence that vaginal administration is associated with a lower risk of VTE. Four cases of VTE with NuvaRing have hitherto been reported to the Swedish Medical Products Agency accounting for a reported incidence of 5,3 (95% CI 1,4-13,5) cases per 10 000 women years of use.

  • 46.
    Späth, Florentin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Krop, Esmeralda
    Utrecht University.
    Izarra, Antonio
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Ann Sofie
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Vermeulen, Roel
    Utrecht University.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Immune marker changes and risk of multiple myeloma: a nested case-control study using repeated prediagnostic blood samplesManuscript (preprint) (Other academic)
    Abstract [en]

    Biomarkers reliably predicting progression to multiple myeloma (MM) are lacking. Myeloma risk has been associated with low blood levels of monocyte chemotactic protein-3 (MCP-3), macrophage inflammatory protein-1 alpha (MIP-1α), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), fractalkine, and transforming growth factor alpha (TGF-α). In this study, we aimed to replicate these findings and also study the individual dynamics of each marker in a prospective longitudinal cohort, thereby examining their potential as markers of myeloma progression. For this purpose, we identified 65 myeloma cases within the Northern Sweden Health and Disease Study as well as 65 individually matched controls, each with two donated blood samples. Samples from myeloma cases were donated in median 13 and 4 years prior to myeloma diagnosis. Known risk factors of progression were determined by protein-, and immunofixation electrophoresis, and free light chain assays. We observed lower levels of MCP-3, VEGF, FGF-2, fractalkine, and TGF-α in myeloma patients than in controls, consistent with previous data. We also observed that these markers decreased among future myeloma patients while remaining stable in controls. Decreasing trajectories were marked for TGF-α (P = 2.5 x 10-4) indicating progression to MM. Investigating this, we found that low levels of TGF-α assessed at time of the repeated sample were independently associated with risk of progression in a multivariable model (hazard ratio = 3.5; P = 0.003). TGF-α can potentially improve early detection of MM.

  • 47.
    Späth, Florentin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wibom, Carl
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Krop, Esmeralda J M
    Izarra Santamaria, Antonio
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Ann Sofie
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergdahl, Ingvar
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Vermeulen, Roel
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Immune marker changes and risk of multiple myeloma: a nested case-control study using repeated prediagnostic blood samples.2019In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, article id haematol.2019.216895Article in journal (Refereed)
    Abstract [en]

    Biomarkers reliably predicting progression to multiple myeloma are lacking. Myeloma risk has been associated with low blood levels of monocyte chemotactic protein 3, macrophage inflammatory protein 1 alpha, vascular endothelial growth factor, fibroblast growth factor 2, fractalkine, and transforming growth factor alpha. In this study, we aimed to replicate these findings and study the individual dynamics of each marker in a prospective longitudinal cohort, thereby examining their potential as markers of myeloma progression. For this purpose, we identified 65 myeloma cases and 65 matched cancer-free controls each with two donated blood samples within the Northern Sweden Health and Disease Study. Samples from myeloma cases were donated in median 13 and 4 years before myeloma diagnosis. Known risk factors of progression were determined by protein-, and immunofixation electrophoresis, and free light chain assays. We observed lower levels of monocyte chemotactic protein 3, vascular endothelial growth factor, fibroblast growth factor 2, fractalkine, and transforming growth factor alpha in myeloma patients than controls, consistent with previous data. We also observed that these markers decreased among future myeloma patients while remaining stable in controls. Decreasing trajectories were marked for transforming growth factor alpha (P = 2.5 x 10-4) indicating progression to multiple myeloma. Investigating this, we found that low levels of transforming growth factor alpha assessed at time of the repeated sample were independently associated with risk of progression in a multivariable model (hazard ratio = 3.5; P = 0.003). Transforming growth factor alpha can potentially improve early detection of multiple myeloma. .

  • 48.
    Stegmayr, Bernd
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forsberg, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jonson, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stegmayr, Christofer
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Microbubbles of air may occur in the organs of hemodialysis patients2012In: ASAIO journal (1992), ISSN 1058-2916, E-ISSN 1538-943X, Vol. 58, no 2, p. 177-179Article in journal (Refereed)
    Abstract [en]

    During hemodialysis (HD), blood that passes the dialysis device gets loaded with microbubbles (MB) of air that are returned to the patient without inducing an alarm. The aim with this study was to clarify if these signals are due to microembolies of air, clots, or artifacts, by histopathology of autopsy material of HD patients. These first results are from a patient on chronic HD. Due to pulmonary edema he was ultrafiltered. Within 30 minutes after the start, he suffered from a cardiac arrest and died. Autopsy verified the clinical findings. Microscopic investigation verified microembolies of air that were surrounded by fibrin in the lungs, brain, and heart. The study verified that MBs can enter the blood during HD and are trapped in the lungs. In addition, MBs pass the pulmonary capillaries and enter the arterial part of the body and are dispersed throughout the body. This can contribute to organ damage and be part of the poor prognoses seen in HD patients. Data support the importance to reduce MBs in the dialysis circuit.

  • 49.
    Sundberg, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Nilsson, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Evidence of disseminated intravascular coagulation in a hemorrhagic fever with renal syndrome-scoring models and severe illness2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 6, p. e21134-Article in journal (Refereed)
    Abstract [en]

    Background: Viral hemorrhagic fevers (VHF) are considered to be a serious threat to public health worldwide with up to 100 million cases annually. The general hypothesis is that disseminated intravascular coagulation (DIC) is an important part of the pathogenesis. The study objectives were to study the variability of DIC in consecutive patients with acute hemorrhagic fever with renal syndrome (HFRS), and to evaluate if different established DIC-scores can be used as a prognostic marker for a more severe illness.

    Method and Findings: In a prospective study 2006–2008, data from 106 patients with confirmed HFRS were analyzed and scored for the presence of DIC according to six different templates based on criteria from the International Society on Thrombosis and Haemostasis (ISTH). The DIC-scoring templates with a fibrinogen/CRP-ratio were most predictive, with predictions for moderate/severe illness (p<0.01) and bleeding of moderate/major importance (p<0.05). With these templates, 18.9–28.3% of the patients were diagnosed with DIC.

    Conclusions: DIC was found in about one fourth of the patients and correlated with a more severe disease. This supports that DIC is an important part of the pathogenesis in HFRS.

    ISTH-scores including fibrinogen/CRP-ratio outperform models without. The high negative predictive value could be a valuable tool for the clinician. We also believe that our findings could be relevant for other VHFs.

  • 50.
    Söderberg, Johan
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Jonsson, PA
    Wallin, Olof
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Haemolysis index: an estimate of preanalytical quality in primary health care!2009In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 47, no 8, p. 940-944Article in journal (Refereed)
    Abstract [en]

    Background: Haemolysis is usually caused by inadequate specimen collection or preanalytical handling, and is suggested to be a suitable indicator of preanalytical quality. We investigated the prevalence of detectable haemolysis in all routine venous blood samples to identify differences in preanalytical quality. Methods: Haemolysis index (HI) values were obtained from a Vitros 5,1 in the routine clinical chemistry laboratory for samples collected in primary health care centres (PHCs), nursing homes, and a hospital emergency department (ED). Haemolysis was defined as a HI ≥ 15 (detection limit). Results: Samples from the PHC with the highest prevalence of haemolysis were 6.1 times (95% confidence interval (CI) 4.0-9.2) more often haemolysed compared to the centre with the lowest prevalence. Of the samples collected in primary health care, 10.4% were haemolysed compared to 31.1% in the ED (p< 0.001). A notable difference in haemolysed samples was found between the ED section staffed by emergency medicine physicians and the section staffed by primary health care physicians (34.8% vs. 11.3%, p<0.001). Conclusions: The significant variation in haemolysis indices among the investigated units is likely to reflect varying preanalytical conditions. The HI is a valuable tool for estimation and follow-up of preanalytical quality in primary health care.

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