ApoB Is the Fundamental Driver of Atherogenic Risk: A Multivariable Mendelian Randomization Analysis

This multivariable Mendelian randomization study used genetic instruments from 441,016 participants to estimate the independent causal effects of LDL-C, triglycerides, HDL-C, ApoB, and ApoA-I on coronary heart disease, disentangling their overlapping effects through simultaneous adjustment.

In univariable Mendelian randomization, LDL-C, triglycerides, and ApoB were all associated with increased CHD risk. But when all traits were modeled simultaneously — adjusting each for the others — ApoB was the only robust independent driver of CHD risk (OR 1.92 per SD, p < 0.001). The effect of LDL-C was attenuated to null and numerically reversed after ApoB adjustment. Triglycerides were substantially weakened. The apparent protective associations of HDL-C and ApoA-I in univariable analysis were eliminated after ApoB adjustment.

This is one of the most consequential Mendelian randomization results in lipidology. It establishes that LDL-C and triglycerides do not independently cause CHD — they are associated with CHD because they correlate with ApoB-containing particle number. It is the particles, counted by ApoB, that cause the disease. LDL-C is a proxy for those particles; in patients where the proxy is accurate (LDL-C and ApoB correlate tightly), it works well. In patients where they diverge (metabolic syndrome, insulin resistance, high Lp(a)), ApoB is the clinically correct measurement.

We rate the evidence strong. A landmark multivariable Mendelian randomization establishing ApoB as the causal driver of CHD risk — the most rigorous causal evidence for prioritizing ApoB measurement in clinical practice.