Identifying Potential Therapeutic Applications and Diagnostic Harms of Increased Bilirubin Concentrations: A Clinical and Genetic Approach

Clin Pharmacol Ther. 2022 Feb;111(2):435-443. doi: 10.1002/cpt.2441. Epub 2021 Oct 24.


Bilirubin has antioxidant and anti-inflammatory properties in vitro and in animal studies and protects against inflammatory, cardiovascular, and other diseases in observational studies; therefore, bilirubin has potential as a therapeutic agent. However, observational studies could be confounded by many factors. We used a genetic (n = 61,281) and clinical (n = 234,670) approach to define the association between bilirubin and 19 conditions with a putative protective signal in observational studies. We also tested if individuals with genetically higher bilirubin levels underwent more diagnostic tests. We used a common variant in UGT1A1 (rs6742078) associated with an 26% increase in bilirubin levels in the genetic studies. Carriers of the variant had higher bilirubin levels (P = 2.2 × 10-16 ) but there was no significant association with any of the 19 conditions. In a phenome-wide association study (pheWAS) to seek undiscovered genetic associations, the only significant finding was increased risk of "jaundice-not of newborn." Carriers of the variant allele were more likely to undergo an abdominal ultrasound (odds ratio = 1.04, [1.00-1.08], P = 0.03). In contrast, clinically measured bilirubin levels were significantly associated with 15 of the 19 conditions (P < 0.003) and with 431 clinical diagnoses in the pheWAS (P < 1 × 10-5 adjusted for sex, age, and follow-up). With additional adjustment for smoking and body mass index, 7 of 19 conditions and 260 pheWAS diagnoses remained significantly associated with bilirubin levels. In conclusion, bilirubin does not protect against inflammatory or other diseases using a genetic approach; the many putative beneficial associations reported clinically are likely due to confounding.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Bilirubin / adverse effects
  • Bilirubin / blood*
  • Biomarkers / blood
  • Confounding Factors, Epidemiologic
  • Databases, Genetic
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Glucuronosyltransferase / genetics*
  • Glucuronosyltransferase / metabolism
  • Heterozygote
  • Humans
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Protective Factors
  • Risk Assessment
  • Risk Factors
  • Up-Regulation


  • Biomarkers
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • Bilirubin