High-throughput multivariable Mendelian randomization analysis prioritizes apolipoprotein B as key lipid risk factor for coronary artery disease

Abstract

Background: Genetic variants can be used to prioritize risk factors as potential therapeutic targets via Mendelian randomization (MR). An agnostic statistical framework using Bayesian model averaging (MR-BMA) can disentangle the causal role of correlated risk factors with shared genetic predictors. Here, our objective is to identify lipoprotein measures as mediators between lipid-associated genetic variants and coronary artery disease (CAD) for the purpose of detecting therapeutic targets for CAD. Methods: As risk factors we consider 30 lipoprotein measures and metabolites derived from a high-throughput metabolomics study including 24,925 participants. We fit multivariable MR models of genetic associations with CAD estimated in 453,595 participants (including 113,937 cases) regressed on genetic associations with the risk factors. MR-BMA assigns to each combination of risk factors a model score quantifying how well the genetic associations with CAD are explained. Risk factors are ranked by their marginal score and selected using false discovery rate (FDR) criteria. We perform sensitivity and replication analyses varying the dataset for genetic associations with CAD. Results: In the main analysis, the top combination of risk factors ranked by the model score contains apolipoprotein B (ApoB) only. ApoB is also the highest ranked risk factor with respect to the marginal score (FDR< 0.005). Additionally, ApoB is selected in all replication analyses. No other measure of cholesterol or triglyceride is consistently selected otherwise. Conclusions: Our agnostic genetic investigation prioritizes ApoB across all datasets con- sidered, suggesting that ApoB, representing the total number of hepatic-derived lipoprotein particles, is the primary lipid determinant of CAD.

Prioritizing the Role of Major Lipoproteins and Subfractions as Risk Factors for Peripheral Artery Disease

“…Similarly, while the Women’s Health Study (WHS) did not identify an association between baseline ApoB and incident PAD (5), differences in PAD case definitions, ascertainment, and demographics (incident PAD in WHS vs. prevalent in MVP; women in WHS vs. predominately men in MVP and PHS), may account for these differences. Our prioritization of ApoB as the most important lipoprotein-related risk factor for CAD is consistent with recent MR studies establishing ApoB as the primary risk factor for CAD (15,16). In the setting of strong epidemiologic and genetic correlation between CAD and PAD, it is not surprising that these two manifestations of ASCVD share ApoB as a common risk factor.…”

“…There was also nominal evidence for HDL-C (marginal inclusion probability 0.501, p = 0.039), which again no longer persisted after correcting for multiple testing. Similarly, ApoB was identified as the prioritized risk factor for CAD in the primary (marginal inclusion probability 0.92, p = 0.005) ( Table 1B ) and replication (marginal inclusion probability 0.80, p = 0.004) analyses, in keeping with the previously established role of ApoB in CAD ( Supplemental Tables 10-11 ) (15,16). These results provide strong, consistent support for the role of ApoB as the primary lipoprotein risk factor for PAD and CAD.…”

A Comparison of Lipids and apoB in Asian Indians and Americans

“…This is the first analysis to demonstrate that apoB encapsulates the risk from both the apoB and the apoA lipoprotein particles. Finally, the recent Mendelian randomization analysis by Zuber et al [ 35 ], using a different analytic and statistical approach than Richardson, an approach which encompassed more than 30 lipid variables and metabolites, whose individual and collective significance were assessed by Bayesian methods, confirmed that apoB is the key lipid determinant of cardiovascular risk because it incorporates the risk associated with all the atherogenic components within VLDL and LDL particles including triglycerides and cholesterol.…”

A functional variant of the SIDT2 gene involved in cholesterol transport is associated with HDL-C levels and premature coronary artery disease

“…76 A multivariable Mendelian randomization study examining serum lipid and apolipoprotein levels reported that only ApoB retained a robust relationship with the risk of CAD, 77 and recent Mendelian randomization studies suggest that ApoB is the primary lipid determinant of cardiovascular disease risk. 78; 79 Thus, the association of SIDT2 /Val636Ile with decreased cardiovascular risk could be mediated by its effect on ApoB levels.…”