Causal association between serum bilirubin and ischemic stroke: multivariable Mendelian randomization
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OBJECTIVES Previous research has predominantly focused on total bilirubin levels without clearly distinguishing between direct and indirect bilirubin. In this study, the differences between these forms were examined, and their potential causal relationships with ischemic stroke were investigated. METHODS Two-sample multivariable Mendelian randomization (MVMR) analysis was employed, extracting summary data on bilirubin from the Korean Cancer Prevention Study-II (n=159,844) and the Korean Genome and Epidemiology Study (n=72,299). Data on ischemic stroke were obtained from BioBank Japan (n=201,800). Colocalization analysis was performed, focusing on the UGT1A1, SLCO1B1, and SLCO1B3 genes, which are the primary loci associated with serum bilirubin levels. RESULTS Crude 2-sample Mendelian randomization analysis revealed a significant negative association between total bilirubin levels and ischemic stroke. However, in MVMR analyses, only indirect bilirubin demonstrated a significant negative association with ischemic stroke (odds ratio, 0.76; 95% confidence interval, 0.59 to 0.98). Colocalization analysis did not identify a shared causal variant between the 3 genetic loci related to indirect bilirubin and the risk of ischemic stroke. CONCLUSIONS Our study establishes a causal association between higher genetically determined levels of serum indirect bilirubin and reduced risk of ischemic stroke in an Asian population. Future research should include more in-depth analysis of shared genetic variants between indirect bilirubin and ischemic stroke.
Abstract
OBJECTIVES Previous research has predominantly focused on total bilirubin levels without clearly distinguishing between direct and indirect bilirubin. In this study, the differences between these forms were examined, and their potential causal relationships with ischemic stroke were investigated. METHODS Two-sample multivariable Mendelian randomization (MVMR) analysis was employed, extracting summary data on bilirubin from the Korean Cancer Prevention Study-II (n=159,844) and the Korean Genome and Epidemiology Study (n=72,299). Data on ischemic stroke were obtained from BioBank Japan (n=201,800). Colocalization analysis was performed, focusing on the UGT1A1, SLCO1B1, and SLCO1B3 genes, which are the primary loci associated with serum bilirubin levels. RESULTS Crude 2-sample Mendelian randomization analysis revealed a significant negative association between total bilirubin levels and ischemic stroke. However, in MVMR analyses, only indirect bilirubin demonstrated a significant negative association with ischemic stroke (odds ratio, 0.76; 95% confidence interval, 0.59 to 0.98). Colocalization analysis did not identify a shared causal variant between the 3 genetic loci related to indirect bilirubin and the risk of ischemic stroke. CONCLUSIONS Our study establishes a causal association between higher genetically determined levels of serum indirect bilirubin and reduced risk of ischemic stroke in an Asian population. Future research should include more in-depth analysis of shared genetic variants between indirect bilirubin and ischemic stroke.
참고문헌 (31)
- Sierra C, "Vascular mechanisms in the pathogenesis of stroke", Curr Hypertens Rep, 13, pp.200~207 (2011)[DOI]
- Allen CL, "Oxidative stress and its role in the pathogenesis of ischaemic stroke", Int J Stroke, 4, pp.461~470 (2009)[DOI]
- Khoshnam SE, "Pathogenic mechanisms following ischemic stroke", Neurol Sci, 38, pp.1167~1186 (2017)[DOI]
- Kunutsor SK, "Circulating total bilirubin and risk of incident cardiovascular disease in the general population", Arterioscler Thromb Vasc Biol, 35, pp.716~724 (2015)[DOI]
- Djoussé L, "Total serum bilirubin and risk of cardiovascular disease in the Framingham offspring study", Am J Cardiol, 87, pp.1196~1200 (2001)[DOI]
- Kimm H, "Low serum bilirubin level as an independent predictor of stroke incidence : a prospective study in Korean men and women", Stroke, 40, pp.3422~3427 (2009)[DOI]
- Oda E, "A possible cross-sectional association of serum total bilirubin with coronary heart disease and stroke in a Japanese health screening population", Heart Vessels, 27, pp.29~36 (2012)[DOI]
- Sedlak TW, "Bilirubin benefits : cellular protection by a biliverdin reductase antioxidant cycle", Pediatrics, 113, pp.1776~1782 (2004)[DOI]
- Gazzin S, "A novel perspective on the biology of bilirubin in health and disease", Trends Mol Med, 22, pp.758~768 (2016)[DOI]
- Lee SJ, "Bilirubin and stroke risk using a Mendelian randomization design", Stroke, 48, pp.1154~1160 (2017)[DOI]
- Choi Y, "Causal associations between serum bilirubin levels and decreased stroke risk : a two-sample Mendelian randomization study", Arterioscler Thromb Vasc Biol, 40, pp.437~445 (2020)[DOI]
- Kim Y, "Cohort profile : the Korean Genome and Epidemiology Study(KoGES)consortium", Int J Epidemiol, 46, pp.e20~ (2017)[DOI]
- Jee YH, "Cohort profile : the Korean Cancer Prevention Study-II(KCPS-II)biobank", Int J Epidemiol, 47, pp.385~ (2018)[DOI]
- Coolidge TB, "Chemistry of the van den Bergh reaction", J Biol Chem, 32, pp.119~127 (1940)
- Nagai A, "Overview of the BioBank Japan project : study design and profile", J Epidemiol, 27(3S), pp.S2~S8 (2017)[DOI]
- O’Brien L, "Biliverdin reductase isozymes in metabolism", Trends Endocrinol Metab, 26, pp.212~220 (2015)[DOI]
- Tomaro ML, "Bilirubin : its role in cytoprotection against oxidative stress", Int J Biochem Cell Biol, 34, pp.216~220 (2002)[DOI]
- Sundararaghavan VL, "Glucuronidation and UGT isozymes in bladder : new targets for the treatment of uroepithelial carcinomas?", Oncotarget, 8, pp.3640~3648 (2017)[DOI]
- Kwak JY, "Bilirubin inhibits the activation of superoxide-producing NADPH oxidase in a neutrophil cell-free system", Biochim Biophys Acta, 1076, pp.369~373 (1991)[DOI]
- Stocker R, "Bilirubin is an antioxidant of possible physiological importance", Science, 235, pp.1043~1046 (1987)[DOI]
- Li Y, "Decreased serum bilirubin is associated with arterial stiffness in men", Nutr Metab Cardiovasc Dis, 23, pp.375~381 (2013)[DOI]
- Mahabadi AA, "Association of bilirubin with coronary artery calcification and cardiovascular events in the general population without known liver disease : the Heinz Nixdorf Recall study", Clin Res Cardiol, 103, pp.647~653 (2014)[DOI]
- Li RY, "Decreased serum bilirubin is associated with silent cerebral infarction", Arterioscler Thromb Vasc Biol, 34, pp.946~951 (2014)[DOI]
- Perlstein TS, "Serum total bilirubin level, prevalent stroke, and stroke outcomes : NHANES 1999-2004", Am J Med, 121, pp.781~788 (2008)[DOI]
- Baranano DE, "Biliverdin reductase : a major physiologic cytoprotectant", Proc Natl Acad Sci U S A, 99, pp.16093~16098 (2002)[DOI]
- Neuzil J, "Bilirubin attenuates radical-mediated damage to serum albumin", FEBS Lett, 331, pp.281~284 (1993)[DOI]
- Minetti M, "Bilirubin is an effective antioxidant of peroxynitrite-mediated protein oxidation in human blood plasma", Arch Biochem Biophys, 352, pp.165~174 (1998)[DOI]
- Lanone S, "Bilirubin decreases NOS2 expression via inhibition of NAD(P)H oxidase : implications for protection against endotoxic shock in rats", FASEB J, 19, pp.1890~1892 (2005)[DOI]
- Stocker R, "Synergistic interaction between vitamin E and the bile pigments bilirubin and biliverdin", Biochim Biophys Acta, 1002, pp.238~244 (1989)[DOI]
- Neuzil J, "Free and albumin-bound bilirubin are efficient co-antioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation", J Biol Chem, 269, pp.16712~16719 (1994)
- Shin JW, "Serum bilirubin subgroups and cancer risk : insights with a focus on lung cancer", Cancer Epidemiol, 94, pp.102727~ (2024)[DOI]