Combined genetic targeting of lipoprotein(a) and low-density lipoprotein cholesterol reduces coronary artery disease risk additively (Nat Cardiovasc Res 2026)

Original title: Genetic evidence supports the combined targeting of lipoprotein(a) and LDL cholesterol to reduce coronary artery disease risk

Nat Cardiovasc Res · 3 September 2026 · 7

Wang S, Tang Y, Sui Y, Zhao H, Khan A, Yin W, Chen Q, Xu T, Liu Z, Zhang Z, Wang F, Mi S et al.

This Mendelian randomisation study using UK Biobank and Mass General Brigham Biobank data evaluates whether combined genetic lowering of lipoprotein(a) and low-density lipoprotein cholesterol yields additive coronary artery disease risk reduction. Among 408,039 individuals, carriers of LPA or PCSK9 loss-of-function variants had lower risk (odds ratio 0.91 and 0.81), while dual carriers had an odds ratio of 0.73. Two-factor genetic scoring confirmed a stronger risk reduction (odds ratio 0.70) compared to single-trait scores (odds ratio 0.85 and 0.81). Phenome-wide analysis showed cardiometabolic benefits without adverse effects, replicated in 65,171 individuals. The findings reinforce additive risk reduction from dual pathway inhibition but rely on genetic proxies rather than direct pharmacological intervention.

Original abstract

Distinct genetic mechanisms govern how lipoprotein(a) (Lp(a)) and low-density lipoprotein cholesterol (LDL-C) promote atherosclerosis. It remains unclear whether targeting both provides additive cardiovascular benefits. Here we use coding loss-of-function variants in LPA and PCSK9 and genetic scores associated with Lp(a) and LDL-C levels to evaluate the effects of lowering Lp(a) and LDL-C on coronary artery disease (CAD) risk. Among 408,039 individuals from the UK Biobank, LPA or PCSK9 loss-of-function carriers have lower CAD risk than noncarriers (odds ratio (OR) 0.91 and 0.81). Carriers of both variants have even lower CAD risk (OR 0.73). Genetic lowering of Lp(a) and LDL-C showed a stronger reduction of CAD risk (OR 0.70) than either trait individually (OR 0.85 and 0.81) in the two-factor genetic score analysis. Among statin users, Lp(a) reduction was linearly associated with CAD risk. A phenome-wide association study revealed that combined therapy was associated with cardiometabolic benefits without adverse effects. The additive benefits were replicated in 65,171 individuals from the Mass General Brigham Biobank.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 6 September 2026. Methods.