Background

: Although Lipoprotein(a) (Lp(a)) is associated with cardiovascular disease, it is unclear whether the associated risk is similar in the presence of other concomitant risk factors. Here, we aimed to investigate the interactions between Lp(a) and common cardiovascular risk factors on coronary artery disease (CAD), calcific aortic valve stenosis (CAVS) and ischemic stroke (IS).

Methods

: We included 127,958 unrelated European-ancestry participants from UK Biobank (54.7 % women) with data available on Lp(a) and without a baseline history of CAD, CAVS and IS. Multivariable-adjusted Cox proportional hazards interaction models were used to study whether the associations of Lp(a) with outcomes varied based on the level of total cholesterol (Total-C), low-density lipoprotein-cholesterol (LDL-C), triglycerides (TG) and other cardiovascular risk factors.

Results

: Higher Lp(a) levels were associated with higher risks of CAD, CAVS and IS. Per 10 mg/dL increase in Lp(a), hazard ratios [95 % confidence interval] were 1.05 [1.04, 1.06], 1.06 [1.04, 1.09], and 1.01 [0.99, 1.03] for CAD, CAVS and IS, respectively. For CAD, interactions were observed between Lp(a) and Total-C (Pinteraction =0.001), LDL-C (Pinteraction =4e-4) and TG (Pinteraction =0.026). In more detail, participants with Lp(a) ≥ 50 mg/dL in the highest quartile of Total-C, LDL-C and TG showed evidence of additive interaction in CAD, with relative excess risk due to interaction (RERI) of 0.42 (0.17, 0.67), 0.44 (0.18, 0.71), and 0.39 (0.12, 0.67), respectively. No such interactions were observed in CAVS and IS.

Conclusions

Lp(a)-associated CAD risk seems to particularly affect those having levels of Total-C, LDL-C and TG above the thresholds from clinical guidelines.

© 2025 The Author(s).