Bilirubin and UGT1A1*28 Are Not Associated with Lower Risk for Ischemic Stroke in a Prospective Nested Case-Referent Setting

Abstract

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.

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”

“…2 However, the main conclusion of both our prospective studies is that bilirubin was not a causative risk factor. This conclusion is based on the concept of mendelian randomization, as UGT-genotypes (resulting in elevated bilirubin levels throughout life) were not associated with risk.…”

Risk of Ischemic Stroke and Decreased Serum Bilirubin Levels

“…21 However, other smaller studies have failed to show the same association. [22][23][24][25] Conversely, it has been shown that patients with Gilbert syndrome have a lower risk of CHD than normobilirubinemic control subjects, thus supporting the concept that mildly elevated (unconjugated) bilirubin levels might help protect against CHD. 26 The underlying mechanisms by which increased TB may exert vasoprotective effects are still incompletely understood, and further research is required to uncover other specific mechanisms by which bilirubin may protect from stroke and CHD events.…”

Evaluating the Beneficial and Detrimental Effects of Bile Pigments in Early and Later Life

“…In a Swedish cohort, plasma bilirubin was lower in 231 cases of ischemic stroke than in 462 matched controls but the difference reached significance only in women (Ekblom et al, 2010). In males with coronary artery disease, there was inverse association between serum total bilirubin and coronary artery calcification score.…”