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Meidtner, K., Podmore, C., Kroger, J., van der Schouw, Y. T., Bendinelli, B., Agnoli, C., . . . Wareham, N. J. (2018). Interaction of Dietary and Genetic Factors Influencing Body Iron Status and Risk of Type 2 Diabetes Within the EPIC-InterAct Study. Diabetes Care, 41(2), 277-285
Open this publication in new window or tab >>Interaction of Dietary and Genetic Factors Influencing Body Iron Status and Risk of Type 2 Diabetes Within the EPIC-InterAct Study
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2018 (English)In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 41, no 2, p. 277-285Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Meat intake has been consistently shown to be positively associated with incident type 2 diabetes. Part of that association may be mediated by body iron status, which is influenced by genetic factors. We aimed to test for interactions of genetic and dietary factors influencing body iron status in relation to the risk of incident type 2 diabetes.

RESEARCH DESIGN AND METHODS: The case-cohort comprised 9,347 case subjects and 12,301 subcohort participants from eight European countries. Single nucleotide polymorphisms (SNPs) were selected from genome-wide association studies on iron status biomarkers and candidate gene studies. A ferritin-related gene score was constructed. Multiplicative and additive interactions of heme iron and SNPs as well as the gene score were evaluated using Cox proportional hazards regression.

RESULTS: Higher heme iron intake (per 1 SD) was associated with higher ferritin levels (β = 0.113 [95% CI 0.082; 0.144]), but not with transferrin (−0.019 [−0.043; 0.006]) or transferrin saturation (0.016 [−0.006; 0.037]). Five SNPs located in four genes (rs1799945 [HFE H63D], rs1800562 [HFE C282Y], rs236918 [PCK7], rs744653 [SLC40A1], and rs855791 [TMPRSS6V736A]) were associated with ferritin. We did not detect an interaction of heme iron and the gene score on the risk of diabetes in the overall study population (Padd = 0.16, Pmult = 0.21) but did detect a trend toward a negative interaction in men (Padd = 0.04, Pmult = 0.03).

CONCLUSIONS: We found no convincing evidence that the interplay of dietary and genetic factors related to body iron status associates with type 2 diabetes risk above the level expected from the sum or product of the two individual exposures.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-147482 (URN)10.2337/dc17-1080 (DOI)000430455100017 ()29167213 (PubMedID)
Available from: 2018-05-07 Created: 2018-05-07 Last updated: 2018-06-09Bibliographically approved
Ekblom, K. & Petersson, A. (2018). Introduction of Cost Display Reduces Laboratory Test Utilization. American Journal of Managed Care, 24(5), E164-E169
Open this publication in new window or tab >>Introduction of Cost Display Reduces Laboratory Test Utilization
2018 (English)In: American Journal of Managed Care, ISSN 1088-0224, E-ISSN 1936-2692, Vol. 24, no 5, p. E164-E169Article in journal (Refereed) Published
Abstract [en]

Objectives: To study the effects on the number of laboratory tests ordered after introduction of cost display (showing the cost in the computerized test ordering system at test ordering and test result delivery) and cost charge (requiring all primary healthcare centers to pay full laboratory costs of the ordered tests).

Study design: The study included cost display for secondary healthcare centers (inpatient hospitals, emergency departments, and outpatient specialist providers) as well as publicly and privately operated primary healthcare centers (sites of nonemergency, nonspecialist healthcare). After 3 months cost charge was introduced by management for all primary healthcare centers.

Methods: Information on laboratory test name in the test ordering system, resulting in cost display both at the moment of test ordering and at the presentation of the test result. Numbers of laboratory tests were obtained from the laboratory information system and calculated as tests per physician visit. Cost charge was managed through the established laboratory invoicing system.

Results: In the publicly operated primary healthcare centers, neither if the interventions had any effect on laboratory test volume, nor did cost display have an effect in the privately operated primary healthcare centers. However, introduction of cost charge significantly decreased laboratory test ordering in the privately operated primary healthcare centers.In contrast, secondary healthcare centers lowered test volumes when cost display was introduced.

Conclusions: The results support cost awareness and cost charge as means of reducing laboratory utilization. However, the outcome varies with the setting.

Place, publisher, year, edition, pages
Managed Care & Healthcare Communications LLC., 2018
National Category
Health Care Service and Management, Health Policy and Services and Health Economy
Identifiers
urn:nbn:se:umu:diva-149027 (URN)000433571600005 ()29851448 (PubMedID)2-s2.0-85047880223 (Scopus ID)
Available from: 2018-06-14 Created: 2018-06-14 Last updated: 2018-06-14Bibliographically approved
Petersson, A. & Ekblom, K. (2017). Methods for counting residual leukocytes in leukocyte-depleted plasma-a comparison between a routine hematology instrument, the Nageotte chamber, flow cytometry, and a fluorescent microscopy analyzer. Transfusion, 57(5), 1192-1198
Open this publication in new window or tab >>Methods for counting residual leukocytes in leukocyte-depleted plasma-a comparison between a routine hematology instrument, the Nageotte chamber, flow cytometry, and a fluorescent microscopy analyzer
2017 (English)In: Transfusion, ISSN 0041-1132, E-ISSN 1537-2995, Vol. 57, no 5, p. 1192-1198Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Counting very low levels of leukocytes is technically challenging but mandatory for quality control of leukocyte-depleted plasma. Established assays, such as flow cytometry and counting in the Nageotte chamber, are laborious and expensive. The aim of this study was to test two alternative assays, the cerebrospinal fluid program in the routine hematology analyzer ADVIA 2120 and a fluorescence microscopy analyzer, the ADAM-rWBC. STUDY DESIGN AND METHODS: Linearity, accuracy, and precision were established for the ADVIA 2120, the ADAM-rWBC analyzer and the Nageotte chamber with flow cytometry as the reference method. Two hundred consecutive leukocyte-depleted donor plasma samples were also tested. RESULTS: The ADAM-rWBC analyzer and the Nageotte chamber fulfilled all quality requirements. Flow cytometry fulfilled the requirements for linearity and precision. The ADVIA 2120 analyzer did not fully reach the quality criteria, and flow cytometry did not reach quality criteria on accuracy. No false-positive results on donor plasma samples were recorded. CONCLUSION: The ADAM-rWBC is suitable for the purpose of quality control of residual leukocytes in leukocyte-depleted plasma. For the ADVIA 2120, further improvements and studies are needed to reach the quality requirements stated in this study.

Place, publisher, year, edition, pages
WILEY, 2017
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-137006 (URN)10.1111/trf.14007 (DOI)000402875300015 ()28130849 (PubMedID)
Available from: 2017-06-29 Created: 2017-06-29 Last updated: 2018-06-09Bibliographically approved
Ekblom, K., Marklund, S. L., Palmqvist, R., Van Guelpen, B., Hallmans, G., Weinehall, L. & Hultdin, J. (2012). Iron Biomarkers in Plasma, HFE Genotypes, and the Risk for Colorectal Cancer in a Prospective Setting. Diseases of the Colon & Rectum, 55(3), 337-344
Open this publication in new window or tab >>Iron Biomarkers in Plasma, HFE Genotypes, and the Risk for Colorectal Cancer in a Prospective Setting
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2012 (English)In: Diseases of the Colon & Rectum, ISSN 0012-3706, E-ISSN 1530-0358, Vol. 55, no 3, p. 337-344Article in journal (Refereed) Published
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.

Identifiers
urn:nbn:se:umu:diva-53248 (URN)10.1097/DCR.0b013e318241199e (DOI)000300636200018 ()
Available from: 2012-03-23 Created: 2012-03-19 Last updated: 2018-06-08Bibliographically approved
Ekblom, K., Marklund, S. L., Jansson, J.-H., Hallmans, G., Weinehall, L. & Hultdin, J. (2011). Iron stores and HFE genotypes are not related to increased risk of first-time myocardial infarction: a prospective nested case-referent study. International Journal of Cardiology, 150(2), 169-172
Open this publication in new window or tab >>Iron stores and HFE genotypes are not related to increased risk of first-time myocardial infarction: a prospective nested case-referent study
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2011 (English)In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 150, no 2, p. 169-172Article in journal (Refereed) Published
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.

Keywords
myocardial infarction, iron, ferritin, HFE, prospective
National Category
Cardiac and Cardiovascular Systems Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Clinical Chemistry
Identifiers
urn:nbn:se:umu:diva-33750 (URN)10.1016/j.ijcard.2010.04.001 (DOI)20447705 (PubMedID)
Available from: 2010-05-05 Created: 2010-05-05 Last updated: 2018-06-08Bibliographically approved
Ekblom, K., Marklund, S. L., Jansson, J.-H., Osterman, P., Hallmans, G., Weinehall, L. & Hultdin, J. (2011). 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". Circulation: Cardiovascular Genetics, 4(1), e2
Open this publication in new window or tab >>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"
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2011 (English)In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 4, no 1, p. e2-Article in journal (Refereed) Published
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-41157 (URN)10.1161/CIRCGENETICS.110.958603 (DOI)21325153 (PubMedID)
Available from: 2011-03-18 Created: 2011-03-18 Last updated: 2018-06-08Bibliographically approved
Ekblom, K., Marklund, S. L., Johansson, L., Osterman, P., Hallmans, G., Weinehall, L., . . . Hultdin, J. (2010). Bilirubin and UGT1A1*28 are not associated with lower risk for ischemic stroke in a prospective nested case-referent setting.. Cerebrovascular Diseases, 30(6), 590-596
Open this publication in new window or tab >>Bilirubin and UGT1A1*28 are not associated with lower risk for ischemic stroke in a prospective nested case-referent setting.
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2010 (English)In: Cerebrovascular Diseases, ISSN 1015-9770, E-ISSN 1421-9786, Vol. 30, no 6, p. 590-596Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Karger, 2010
Keywords
Acute ischemic stroke, epidemiology, Risk factor, Bilirubin, UGT1A1*28 polymorphism
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-39369 (URN)10.1159/000319778 (DOI)000284642400008 ()20948202 (PubMedID)
Available from: 2011-01-25 Created: 2011-01-25 Last updated: 2018-06-08Bibliographically approved
Ekblom, K. (2010). Oxidants and antioxidants in cardiovascular disease. (Doctoral dissertation). Umeå: Umeå University
Open this publication in new window or tab >>Oxidants and antioxidants in cardiovascular disease
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background

Cardiovascular diseases, including myocardial infarction and stroke, are the main reason of death in Sweden and Western Europe. High iron stores are believed to produce oxygen radicals, which is the presumed putative mechanism behind lipid peroxidation, atherosclerosis and subsequent cardiovascular disease. Iron levels are associated with the hemochromatosis associated HFE single nucleotide polymorphisms C282Y and H63D.

Bilirubin is an antioxidant present in relatively high levels in the human body. Several previous studies have found an association between high bilirubin levels and a lower risk for cardiovascular disease. Bilirubin levels are highly influenced by the common promoter polymorphism TA-insertion UGT1A1*28, the main reason for benign hyperbilirubinemia in Caucasians.

There is a lack of prospective studies on both the association of iron and bilirubin levels, and the risk for myocardial infarction and ischemic stroke.

Material and methods

Iron, transferrin iron saturation, TIBC, ferritin and bilirubin were analyzed and HFE C282Y, HFE H63D and UGT1A1*28 were determined in myocardial infarction and stroke cases, and their double matched referents within the Northern Sweden Health and Disease Study Cohort.

Results

There were no associations between iron levels in the upper normal range and risk for myocardial infarction or stroke. No associations were seen for HFE-genotypes, except for a near fivefold increase in risk for myocardial infarction in HFE H63D homozygous women.

Plasma bilirubin was lower in cases vs. referents both in the myocardial infarction and the stroke cohort. Despite a strong gene-dosage effect on bilirubin levels in both cases and referents, the UGT1A1*28 polymorphism did not influence the risk for myocardial infarction or stroke.

Conclusion

High iron stores are not associated with increased risk for neither myocardial infarction, nor stroke. There was no association between UGT1A1*28 and the risk for myocardial infarction or stroke. Consequently data suggests that other factors, which also may lower bilirubin, are responsible for the elevated risk observed in conjunction with lower bilirubin levels.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2010. p. 86
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1339
Keywords
first-ever acute myocardial infarction, first-ever stroke, bilirubin, iron, HFE genotypes, UGT1A1*28, prospective, risk factor
National Category
Cardiac and Cardiovascular Systems Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Clinical Chemistry
Identifiers
urn:nbn:se:umu:diva-33762 (URN)978-91-7264-961-3 (ISBN)
Public defence
2010-05-28, Betula, Byggnad 6M, Norrlands universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2010-05-07 Created: 2010-05-05 Last updated: 2018-06-08Bibliographically approved
Ekblom, K., Marklund, S. L., Jansson, J.-H., Osterman, P., Hallmans, G., Weinehall, L. & Hultdin, J. (2010). Plasma Bilirubin and UGT1A1*28 Are Not Protective Factors Against First-Time Myocardial Infarction in a Prospective, Nested Case–Referent Setting. Circulation: Cardiovascular Genetics (3), 340-347
Open this publication in new window or tab >>Plasma Bilirubin and UGT1A1*28 Are Not Protective Factors Against First-Time Myocardial Infarction in a Prospective, Nested Case–Referent Setting
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2010 (English)In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, no 3, p. 340-347Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Philadelphia, PA: Lippincott Williams & Wilkins, 2010
Keywords
bilirubin, myocardial infarction, risk factors, epidemiology
National Category
Public Health, Global Health, Social Medicine and Epidemiology Cardiac and Cardiovascular Systems
Research subject
Clinical Chemistry
Identifiers
urn:nbn:se:umu:diva-33747 (URN)10.1161/​CIRCGENETICS.109.861773 (DOI)000281006600006 ()20562445 (PubMedID)
Available from: 2010-05-05 Created: 2010-05-05 Last updated: 2018-06-08Bibliographically approved
Ekblom, K., Hultdin, J., Stegmayr, B., Johansson, I., Van Guelpen, B., Hallmans, G., . . . Marklund, S. L. (2007). Iron stores and HFE genotypes are not related to increased risk of ischemic stroke.: a prospective nested case-referent study. Cerebrovascular Diseases, 24(5), 405-411
Open this publication in new window or tab >>Iron stores and HFE genotypes are not related to increased risk of ischemic stroke.: a prospective nested case-referent study
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2007 (English)In: Cerebrovascular Diseases, ISSN 1015-9770, E-ISSN 1421-9786, Vol. 24, no 5, p. 405-411Article in journal (Refereed) Published
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.

Keywords
Adult, Aged, Anthropometry, Cardiovascular Diseases/*etiology/genetics, Europe, Female, Humans, Life Style, Male, Middle Aged, Nutritional Status, Prospective Studies, Questionnaires
National Category
Cardiac and Cardiovascular Systems Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Clinical Chemistry
Identifiers
urn:nbn:se:umu:diva-16977 (URN)10.1159/000108429 (DOI)17878720 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2018-06-09Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-2844-1310

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