Bilirubin-associated single nucleotide polymorphism (SNP) and respiratory health outcomes: a mendelian randomization study

BACKGROUND: Observational studies have shown an association between higher bilirubin levels and improved respiratory health outcomes. Targeting higher bilirubin levels has been proposed as a novel therapeutic strategy in COPD. However, bilirubin levels are influenced by multiple intrinsic and extrinsic factors, and these observational studies are prone to confounding. Genetic analyses are one approach to overcoming residual confounding in observational studies. OBJECTIVES: To test associations between a genetic determinant of bilirubin levels and respiratory health outcomes. METHODS: COPDGene participants underwent genotyping at the baseline visit. We confirmed established associations between homozygosity for rs6742078 and higher bilirubin, and between higher bilirubin and decreased risk of acute respiratory events within this cohort. For our primary analysis, we used negative binomial regression to test associations between homozygosity for rs6742078 and rate of acute respiratory events. RESULTS: 8,727 participants (n = 6,228 non-Hispanic white and 2,499 African American) were included. Higher bilirubin was associated with decreased rate of acute respiratory events [incidence rate ratio (IRR) 0.85, 95% CI 0.75 to 0.96 per SD increase in bilirubin intensity]. We did not find significant associations between homozygosity for rs6742078 and acute respiratory events (IRR 0.94, 95% CI 0.70 to 1.25 for non-Hispanic white and 1.09, 95% CI 0.91 to 1.31 for African American participants). CONCLUSIONS: A genetic determinant of higher bilirubin levels was not associated with better respiratory health outcomes. These results do not support targeting higher bilirubin levels as a therapeutic strategy in COPD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-023-02471-w.