Bilirubin as a Potential Causal Factor in Type 2 Diabetes Risk: A Mendelian Randomization Study

Abbasi, Ali; Deetman, Petronella E.; Corpeleijn, Eva; Gansevoort, Ron T.; Gans, Rijk O. B.; Hillege, Hans L.; Harst, Pim van der; Stolk, Ronald P.; Navis, Gerjan; Alizadeh, Behrooz Z.; Bakker, Stephan J. L.

doi:10.2337/db14-0228

Cited by 100 publications

(105 citation statements)

References 51 publications

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“…In clinical studies, high serum levels of bilirubin are negatively regulates the prevalence of various disorders including cardiovascular diseases such as 4-10 chronic kidney disease, 26 type 2 diabetes, 27 and its complications such as neuropathy 28 and nephropathy. 29 Low bilirubin is a potent endogenous antioxidant, 11 antioxidant property in various diseases.…”

Section: Discussionmentioning

confidence: 99%

Bilirubin exerts pro-angiogenic property through Akt-eNOS-dependent pathway

et al. 2015

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Low serum bilirubin levels are associated with the risk of cardiovascular diseases including peripheral artery disease. Bilirubin is known to exert its property such as antioxidant effect or the enhancement of flow-mediated vasodilation, however, bilirubin action on angiogenesis remains unclear. To investigate the molecular mechanism of bilirubin on angiogenic effect, we first employed C57BL/6J mice with unilateral hindlimb ischemia surgery and divided the mice into two groups (vehicle-treated group and bilirubin-treated group). The analysis of laser speckle blood flow demonstrated the enhancement of blood flow recovery in response to ischemia of mice with bilirubin treatment. The density of capillaries was significantly higher in ischemic-adductor muscles of bilirubin-treated mice. The phosphorylated levels of endothelial nitric oxide synthase (eNOS) and Akt were increased in ischemic skeletal muscles of mice with bilirubin treatment compared with vehicle treatment. In in vitro experiments by using human aortic endothelial cells, bilirubin augmented eNOS and Akt phosphorylation, cell proliferation, cell migration and tube formation. These bilirubin actions on endothelial cell activation were inhibited by LY294002, a phosphatidylinositol 3-kinase inhibitor. In conclusion, bilirubin promotes angiogenesis through endothelial cells activation via Akt-eNOS-dependent manner.

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Section: Discussionmentioning

confidence: 99%

Bilirubin exerts pro-angiogenic property through Akt-eNOS-dependent pathway

et al. 2015

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“…In order to assess the causal association of eosinophil on complex traits and diseases, we performed MR analyses using eos-GRSs as instrumental variables (Abbasi et al, 2015;Prins et al, 2016) in two approaches. MR approach using individual-level data.…”

Section: Data Analysesmentioning

confidence: 99%

Blood Eosinophil Count and Metabolic, Cardiac and Pulmonary Outcomes: A Mendelian Randomization Study

et al. 2018

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Blood eosinophil count is associated with a variety of common complex outcomes in epidemiological observation. The aim of this study was to explore the causal association between determined blood eosinophil count and 20 common complex outcomes (10 metabolic, 6 cardiac, and 4 pulmonary). Through Mendelian randomization, we investigated genetic evidence for the genetically determined eosinophil in association with each outcomes using individual-level LifeLines cohort data (n = 13,301), where a weighted eosinophil genetic risk score comprising five eosinophil associated variants was created. We further examined the associations of the genetically determined eosinophil with those outcomes using summary statistics obtained from genome-wide association study consortia (6 consortia and 14 outcomes). Blood eosinophil count, by a 1-SD genetically increased, was not statistically associated with common complex outcomes in the LifeLines. Using the summary statistics, we showed that a higher genetically determined eosinophil count had a significant association with lower odds of obesity (odds ratio (OR) 0.81, 95% confidence interval (CI) [0.74, 0.89]) but not with the other traits and diseases. To conclude, an elevated eosinophil count is unlikely to be causally associated to higher risk of metabolic, cardiac, and pulmonary outcomes. Further studies with a stronger genetic risk score for eosinophil count may support these results.

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“…Consistent with this data, higher serum bilirubin levels were reported to protect from diabetes mellitus in the US National Health and Nutrition Examination Survey (NHANES) on almost 16,000 subjects [7]. Importantly, recent report showed that genetically elevated bilirubin levels are causally protective against the development of type 2 diabetes using Mendelian randomization in a cohort study [8].…”

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confidence: 54%