Serum apolipoproteins and mortality risk: evidence from observational and Mendelian randomization analyses.

BACKGROUND: Apolipoproteins (APOs) have emerged as significant players in lipid metabolism that affects the risk of chronic disease. However, the impact of circulating APO concentrations on premature death remains undetermined.

OBJECTIVE: To investigate the associations of serum APOs with all-cause, cardiovascular disease (CVD), and cancer mortality.

METHODS: We included 340,737 participants who had serum APO measurements from the UK Biobank. Restricted cubic splines and multivariable Cox regression models were used to assess the associations between APOs and all-cause and cause-specific mortality by computing hazard ratios (HR) and 95% confidence intervals (CIs). Based on one-sample MR design including 398,457 participants of white ancestry who had genotyping data from the UK Biobank, we performed instrumental variable analysis with two-stage least squares regression to assess the association between genetically predicted APOs and mortality.

RESULTS: After adjusting for potential confounders including high-density and low-density lipoprotein particles, we observed nonlinear inverse relationships of APOA1 with all-cause, CVD, and cancer mortality (P for nonlinear <0.001). In contrast, positive relationships were observed for APOB and all-cause (P for nonlinear <0.001), CVD (P for linear <0.001), and cancer (P for linear =0.03) mortality. MR analysis showed consistent results, except that the association between APOB and cancer mortality was null. Furthermore, observational and MR analyses both found an inverse association between APOA1 and lung cancer mortality (HR comparing extreme deciles =0.46, 95% CI: (0.26, 0.80) and HR=0.78, 95% CI: (0.63, 0.97), respectively).

CONCLUSION: Our findings indicate that circulating APOA1 has potential beneficial effects on all-cause, CVD, and lung cancer death risk, while APOB may confer detrimental effects on all-cause and CVD death risk.