Genetic Variants Associated With Lp(a) Lipoprotein Level and Coronary Disease

This study is one of the genetic pillars establishing that lipoprotein(a) does not merely associate with heart disease but causes it.

Examining the LPA gene in nearly 16,000 people, the investigators identified two common variants — rs10455872 and rs3798220 — that strongly raised both Lp(a) levels and coronary disease risk, with odds ratios around 1.7 to 1.9, rising further in people carrying two risk variants. The decisive point: when the analysis accounted for Lp(a) levels, the link between these genes and heart disease largely disappeared — meaning the genes act through Lp(a). That is the signature of a causal pathway.

Because genetic variants are randomly assigned at conception and immune to lifestyle confounding, this kind of evidence is far more persuasive than ordinary observation. It helped move Lp(a) from “interesting marker” to “causal target worth a drug.”

We rate the evidence strong. A large, rigorous genetic study, it forms part of the convergent case — alongside the Mendelian randomization and epidemiological literature — that lowering Lp(a) should reduce cardiovascular events.