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Bilirubin and UGT1A1*28, are not associated with lower risk for ischemic stroke in a prospective nested case-referent setting
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.ORCID iD: 0000-0003-2844-1310
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
Medicinkliniken, Skellefteå lasarett.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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(English)Article in journal (Refereed) Submitted
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.

Keyword [en]
acute ischemic stroke, epidemiology, risk factor, bilirubin, UGT1A1*28
National Category
Cardiac and Cardiovascular Systems Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Clinical Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-33753OAI: oai:DiVA.org:umu-33753DiVA: diva2:317821
Available from: 2010-05-05 Created: 2010-05-05 Last updated: 2016-08-22Bibliographically approved
In thesis
1. Oxidants and antioxidants in cardiovascular disease
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. 86 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1339
Keyword
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: 2016-08-19Bibliographically approved

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Ekblom, KimMarklund, Stefan LOsterman, PiaHallmans, GöranWeinehall, LarsWiklund, Per-GunnarHultdin, Johan

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