Triglyceride-Lowering LPL Variants and LDL-Lowering LDLR Variants With Risk of Coronary Heart Disease

This elegant genetic study may be the clearest single demonstration of a unifying principle: what matters for heart disease is the number of apoB particles you lower, not which lipid you happen to measure.

Across more than 650,000 people, Ference and colleagues compared genetic variants that lower triglycerides (via LPL) against variants that lower LDL cholesterol (via LDLR). Per unit of apoB reduction, the two produced nearly identical reductions in coronary disease — odds ratios of 0.771 versus 0.773. And in the decisive step, when the analysis adjusted for apoB, the apparent effects of triglycerides and LDL cholesterol both vanished, while apoB’s effect remained. The benefit was proportional to apoB lowering, full stop.

This is the genetic proof that apoB is the true causal currency of lipid-related risk — and that lowering triglycerides or LDL helps only insofar as it removes apoB particles from the circulation.

We rate the evidence strong, with very high clinical significance. A massive, rigorous Mendelian randomization study, it is a cornerstone of the modern, apoB-centric understanding of atherogenic lipoproteins.