title: Bilirubin and Stroke Risk Using a Mendelian Randomization Design.
abstract: Circulating bilirubin, a natural antioxidant, is associated with decreased risk of stroke. However, the nature of the relationship between the two remains unknown. We used a Mendelian randomization analysis to assess the causal effect of serum bilirubin on stroke risk in Koreans.
  
  
  
  The 14 single-nucleotide polymorphisms (SNPs) (<10-7) including rs6742078 of uridine diphosphoglucuronyl-transferase were selected from genome-wide association study of bilirubin level in the KCPS-II (Korean Cancer Prevention Study-II) Biobank subcohort consisting of 4793 healthy Korean and 806 stroke cases. Weighted genetic risk score was calculated using 14 SNPs selected from the top SNPs.
  
  
  
  Both rs6742078 (F statistics=138) and weighted genetic risk score with 14 SNPs (F statistics=187) were strongly associated with bilirubin levels. Simultaneously, serum bilirubin level was associated with decreased risk of stroke in an ordinary least-squares analysis. However, in 2-stage least-squares Mendelian randomization analysis, no causal relationship between serum bilirubin and stroke risk was found.
  
  
  
  There is no evidence that bilirubin level is causally associated with risk of stroke in Koreans. Therefore, bilirubin level is not a risk determinant of stroke.
authors.affiliation: From the Department of Public Health, Graduate School (S.J.L.), Institute for Health Promotion (K.J.J., S.H., S.H.J.), and Department of Epidemiology (S.H.J.), Yonsei University, Seoul, Republic of Korea; MRC Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (Y.H.J.); and DNA Link Inc, Seoul, Republic of Korea (E.S.S.). jsunha@yuhs.ac.
authors.forename: Sun Ju
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: From the Department of Public Health, Graduate School (S.J.L.), Institute for Health Promotion (K.J.J., S.H., S.H.J.), and Department of Epidemiology (S.H.J.), Yonsei University, Seoul, Republic of Korea; MRC Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (Y.H.J.); and DNA Link Inc, Seoul, Republic of Korea (E.S.S.).
authors.forename: Yon Ho
authors.initials: YH
authors.lastname: Jee
authors.affiliation: From the Department of Public Health, Graduate School (S.J.L.), Institute for Health Promotion (K.J.J., S.H., S.H.J.), and Department of Epidemiology (S.H.J.), Yonsei University, Seoul, Republic of Korea; MRC Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (Y.H.J.); and DNA Link Inc, Seoul, Republic of Korea (E.S.S.).
authors.forename: Keum Ji
authors.initials: KJ
authors.lastname: Jung
authors.affiliation: From the Department of Public Health, Graduate School (S.J.L.), Institute for Health Promotion (K.J.J., S.H., S.H.J.), and Department of Epidemiology (S.H.J.), Yonsei University, Seoul, Republic of Korea; MRC Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (Y.H.J.); and DNA Link Inc, Seoul, Republic of Korea (E.S.S.).
authors.forename: Seri
authors.initials: S
authors.lastname: Hong
authors.affiliation: From the Department of Public Health, Graduate School (S.J.L.), Institute for Health Promotion (K.J.J., S.H., S.H.J.), and Department of Epidemiology (S.H.J.), Yonsei University, Seoul, Republic of Korea; MRC Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (Y.H.J.); and DNA Link Inc, Seoul, Republic of Korea (E.S.S.).
authors.forename: Eun Soon
authors.initials: ES
authors.lastname: Shin
authors.affiliation: From the Department of Public Health, Graduate School (S.J.L.), Institute for Health Promotion (K.J.J., S.H., S.H.J.), and Department of Epidemiology (S.H.J.), Yonsei University, Seoul, Republic of Korea; MRC Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (Y.H.J.); and DNA Link Inc, Seoul, Republic of Korea (E.S.S.).
authors.forename: Sun Ha
authors.initials: SH
authors.lastname: Jee
mesh_terms: D000328:Adult; D000368:Aged; D001663:Bilirubin / Q000097:blood* / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D056910:Republic of Korea; D012306:Risk; D020521:Stroke / Q000097:blood* / Q000235:genetics; D014015:Tissue Banks; D000099148:UGT1A1 Enzyme
chemical_list: D001663:Bilirubin; D014453:Glucuronosyltransferase; D000099148:UGT1A1 Enzyme
keywords: bilirubin; causality; epidemiology; genes; stroke