Background and aims The causal contribution of apolipoprotein B (apoB) particles to coronary artery disease (CAD) is established. We examined whether this atherogenic contribution is better reflected by non-high-density lipoprotein cholesterol (non-HDL-C) or apoB particle concentration. Method and results We performed Mendelian randomization (MR) analysis using 235 variants as genetic instruments; testing the relationship between their effects on the exposures, non-HDL-C and apoB, and on the outcome CAD using weighted regression. Variant effect estimates on the exposures came from the UK Biobank (N = 376 336) and on the outcome from a meta-analysis of five CAD datasets (187 451 cases and 793 315 controls). Subsequently, we carried out sensitivity and replication analyses. In univariate MR analysis, both exposures associated with CAD (beta(non-HDL-C) = 0.40, P = 2.8 x 10(-48) and beta(apoB) = 0.38, P = 1.3 x 10(-44)). Adding effects on non-HDL-C into a model that already included those on apoB significantly improved the genetically predicted CAD effects (P = 3.9 x 10(-5)), while adding apoB into the model including non-HDL-C did not (P = 0.69). Thirty-five per cent (82/235) of the variants used as genetic instruments had discordant effects on the exposures, associating with non-HDL-C/apoB ratio at P < 2.1 x 10(-4) (0.05/235). Fifty-one variants associated at genome-wide significance. Conclusion Many sequence variants have discordant effects on non-HDL-C and apoB. These variants allowed us to show that the causal mechanism underlying the relationship between apolipoprotein B particles and CAD is more associated with non-HDL-C than apoB particle concentration.Background The causal contribution of apolipoprotein B (apoB) particles to coronary artery disease (CAD) is established. We exam- and aims ined whether this atherogenic contribution is better reflected by non-high-density lipoprotein cholesterol (non-HDL-C) or apoB particle concentration. Method We performed Mendelian randomization (MR) analysis using 235 variants as genetic instruments; testing the relationship be- and results tween their effects on the exposures, non-HDL-C and apoB, and on the outcome CAD using weighted regression. Variant effect estimates on the exposures came from the UK Biobank (N= 376 336) and on the outcome from a meta-analysis of five CAD datasets (187 451 cases and 793 315 controls). Subsequently, we carried out sensitivity and replication analyses. In univariate MR analysis, both exposures associated with CAD (β non-HDL-C = 0.40, P= 2.8 × 10 −48 and β apoB = 0.38, P= 1.3 × 10 −44). Adding effects on non-HDL-C into a model that already included those on apoB significantly improved the genetically predicted CAD effects (P= 3.9 × 10 −5), while adding apoB into the model including non-HDL-C did not (P= 0.69). Thirty-five per cent (82/235) of the variants used as genetic instruments had discordant effects on the exposures, associating with non-HDL-C/apoB ratio at P< 2.1 × 10 −4 (0.05/235). Fifty-one variants associated at genome-wide significance. Conclusion Many sequence variants have discordant effects on non-HDL-C and apoB. These variants allowed us to show that the causal mechanism underlying the relationship between apolipoprotein B particles and CAD is more associated with non-HDL-C than apoB particle concentration.</p
