Association Between Serum Total Bilirubin and COPD: Results from a Cross-Sectional Study and a Bidirectional Mendelian Randomization Analysis

BACKGROUND: The potential protective role of serum total bilirubin (TB) for chronic obstructive pulmonary disease (COPD) is controversial. We aimed to investigate whether serum TB could prevent airflow limitation (reduce the risk of COPD) and whether these associations were causal or reversely causal. METHODS: We conducted a multi-center and cross-sectional study including 3069 participants. Logistic regression model (LRM) with restricted cubic spline (RCS) and priori defined quintile categories were used to assess the associations of TB with COPD. Besides, ordinary least squares (OLS) regression model with RCS curves were applied to assess the dose-response relationship between serum TB and airflow limitation (FEV(1)/FVC). To verify the causal direction between TB and COPD, a bidirectional Mendelian randomization analysis was carried out with GWAS data from European ancestry. RESULTS: In the cross-sectional study, the relationship between levels of TB and COPD risk was U shaped (P=0.001), and the low and high concentrations of TB apparently increasing the risk of COPD (OR 1.40, 95% CI 1.07 to 1.82 for less than 9 μmol/L; OR 1.36, 95% CI 1.06 to 1.76 for 9.01–1 0.88 μmol/L; OR 1.50, 95% CI 1.16 to 1.95 for more than 13 μmol/L). There was a significant non-linear relationship between TB and FEV(1)/FVC (non-linear p=0.004). Furthermore, results of bidirectional Mendelian randomization analysis (OR 1.000; 95% CI 0.983 to 1.017 for MR and OR 0.998; 95% CI 0.976 to 1.020 for reversal MR) did not support the causal effects between serum TB and FEV(1)/FVC after controlling the effect of potential confounders and revised causality. CONCLUSION: Our study reveals that there was non-linear does-response pattern between serum TB and COPD. However, there was little evidence for the linear causal associations of serum TB with airflow limitation. The relationship of TB with COPD needs further study and careful interpretation.