Serum bilirubin and kidney function: a Mendelian randomization study

BACKGROUND: Further investigation is needed to determine the causal effects of serum bilirubin on the risk of chronic kidney disease (CKD). METHODS: This study is a Mendelian randomization (MR) analysis. Among the well-known single-nucleotide polymorphisms (SNPs) related to serum bilirubin levels, rs4149056 in the SLCO1B1 gene was selected as the genetic instrument for single-variant MR analysis, as it was found to be less related to possible confounders than other SNPs. The association between genetic predisposition for bilirubin levels and estimated glomerular filtration rate (eGFR) or CKD was assessed in 337 129 individuals of white British ancestry from the UK Biobank cohort. Two-sample MR based on summary-level data was also performed. SNPs related to total or direct bilirubin levels were collected from a previous genome-wide association study and confounder-associated SNPs were discarded. The independent CKDGen meta-analysis data for CKD were employed as the outcome summary statistics. RESULTS: The alleles of rs4149056 associated with higher bilirubin levels were associated with better kidney function in the UK Biobank data. In the summary-level MR, both of the genetically predicted total bilirubin {per 5 µmol/L increase; odds ratio [OR] 0.931 [95% confidence interval (CI) 0.871–0.995]} and direct bilirubin [per 1 µmol/L increase; OR 0.910 (95% CI 0.834–0.993)] levels were significantly associated with a lower risk of CKD, supported by the causal estimates from various MR sensitivity analyses. CONCLUSION: Genetic predisposition for higher serum bilirubin levels is associated with better kidney function. This result suggests that higher serum bilirubin levels may have causal protective effects against kidney function impairment.