The Role of Lipoprotein(a) in Cardiovascular Risk Stratification: IntegratingLow-density Lipoprotein Cholesterol and Polygenic Risk Scores.

High-density lipoprotein(a) (Lp(a)) is a well-established independent risk factor for atherosclerotic cardiovascular diseases (ASCVD). However, the interaction between Lp(a), low-density lipoprotein cholesterol (LDL-C), and polygenic risk score (PRS) in cardiovascular diseases has been the subject of relatively limited research. The present study included a total of 346,751 participants from the UK Biobank. According to the guideline of Lp(a), the study subjects were divided into three groups: the first group was < 75 mmol/L (n = 272,643), the second group was 75 - 125 mmol/L (n = 35,792), and the third group was > 125 mmol/L (n = 38,316). Elevated Lp(a) levels were associated with a progressively increased risk of overall cardiovascular events (CVEs), including ischemic stroke (IS), coronary heart disease (CHD), angina pectoris, and myocardial infarction (MI). In contrast, the risks of atrial fibrillation (AF) and heart failure (HF) decreased with higher Lp(a) levels. Additive interaction analyses revealed significant synergistic effects between Lp(a) and LDL-C for CHD [relative excess risk interaction (RERI) = 0.081, attributable proportion of interaction (AP) = 0.046, synergy index (SI) = 1.117], angina pectoris [RERI = 0.112, AP = 0.055, SI = 1.121], and MI [RERI = 0.183, AP = 0.079, SI = 1.161], with MI showing the strongest synergy. Incorporating PRS further amplified these effects, and the RERI [CHD: RERI = 0.721; angina pectoris: RERI = 0.781; MI: RERI = 1.318] and SI [CHD: SI = 2.218; angina pectoris: SI = 1.97; MI: SI = 2.326)] were significantly higher than those of the interaction model containing only Lp(a) and LDL-C. In conclusion, Lp(a) and LDL-C show a significant synergistic effect in ASCVD, and this effect is more prominent in individuals with a higher PRS, suggesting that dual lipid management should be strengthened for such populations. While AF and HF may require alternative risk factor management.