LAUSR

BACKGROUND Apolipoprotein A1 (ApoA1) is the principal protein component of high-density lipoprotein (HDL). Although low HDL cholesterol (HDL-C) levels are known to be associated with greater cardiovascular risk, recent studies have also shown heightened mortality risk at very high HDL-C levels. AIM To investigate the sex-specific association between elevated ApoA1 levels and adverse outcomes, and their genetic basis. METHODS A prospective cohort study of United Kingdom Biobank participants without coronary artery disease at enrollment was performed. The primary exposure was serum ApoA1 levels. The primary and secondary outcome measures were cardiovascular and all-cause death, respectively. RESULTS In 402,783 participants followed for a median of 12.1 years, there was a U-shaped relationship between ApoA1 levels and both cardiovascular as well as all-cause mortality, after adjustment for traditional cardiovascular risk factors. Individuals in the highest decile of ApoA1 levels (1.91-2.50 g/L) demonstrated higher cardiovascular (HR 1.21, 95% CI 1.07-1.37, P < 0.0022) and all-cause mortality (HR 1.14, 95% CI 1.07-1.21, P < 0.0001) compared to those within the lowest risk eighth decile (1.67-1.75 g/L). The U-shaped relationship was present in both sexes, though more pronounced in men. Sensitivity analyses showed that cardiovascular mortality rates were higher in those with greater alcohol intake (P < 0.004). Adjustment for polygenic variation associated with higher ApoA1 levels did not attenuate the effect of very high ApoA1 levels on mortality. In the sub-group with very elevated HDL-C levels (>80 mg/dL in men,  > 100 mg/dL in women), there was no association between ApoA1 levels and mortality. CONCLUSION Both very low, as well as very elevated ApoA1 levels are associated with higher cardiovascular and all-cause mortality.