Genetics
Lp(a) and LDL-C synergistically raise MI risk, amplified by polygenic risk score, UK Biobank cohort of 346,751 (Am J Cardiol 2026)
Original title: The Role of Lipoprotein(a) in Cardiovascular Risk Stratification: Integrating Low-density Lipoprotein Cholesterol and Polygenic Risk Scores
UK Biobank cohort of 346,751 participants, divided into Lp(a) groups (below 75 nmol/L, n=272,643; 75-125 nmol/L, n=35,792; above 125 nmol/L, n=38,316), testing interaction between Lp(a), LDL-C and a polygenic risk score (PRS) for cardiovascular events. Elevated Lp(a) was associated with progressively higher risk of ischaemic stroke, coronary heart disease, angina and myocardial infarction (MI), but paradoxically lower risk of atrial fibrillation and heart failure. Lp(a) and LDL-C showed significant additive synergy for coronary heart disease (relative excess risk due to interaction, RERI, 0.081), angina (RERI 0.112) and MI (RERI 0.183, strongest synergy, synergy index 1.161). Incorporating PRS markedly amplified these interactions (MI RERI 1.318, synergy index 2.326). The authors conclude Lp(a) and LDL-C act synergistically on ASCVD risk, most strongly in individuals with higher polygenic risk, supporting intensified dual lipid management in this group, while atrial fibrillation and heart failure may need separate risk-factor strategies.
Original abstract
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 3 groups: the first group was <75 mmol/L (n = 272,643), the second group was 75 to 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.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.