Abstract
BackgroundGenetic 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.MethodsAs 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 supplementary and sensitivity analyses varying the dataset for genetic associations with CAD.ResultsIn 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 sensitivity analyses. No other measure of cholesterol or triglyceride is consistently selected otherwise.ConclusionsOur agnostic genetic investigation prioritizes ApoB across all datasets considered, suggesting that ApoB, representing the total number of hepatic-derived lipoprotein particles, is the primary lipid determinant of CAD.
Highlights
Genetic variants have the potential to contribute greatly to our understanding of mechanisms underlying disease processes, and to guide target validation for pharmacological and clinical interventions that reduce disease risk.[1]
Whereas it has been shown that genetic variants predisposing individuals to higher levels of lowdensity lipoproteins (LDL)-cholesterol associate with increased coronary artery disease (CAD) risk,[2] genetic variants predisposing individuals to higher levels of high-density lipoproteins (HDL)-cholesterol are not associated with CAD risk[3] after accounting for other lipid traits
Our results add to the growing evidence that apolipoprotein B (ApoB) is the primary causal determinant for CAD risk among lipoprotein measurements.[8,17,18]
Summary
Genetic variants have the potential to contribute greatly to our understanding of mechanisms underlying disease processes, and to guide target validation for pharmacological and clinical interventions that reduce disease risk.[1]. Whereas it has been shown that genetic variants predisposing individuals to higher levels of lowdensity lipoproteins (LDL)-cholesterol associate with increased CAD risk,[2] genetic variants predisposing individuals to higher levels of high-density lipoproteins (HDL)-cholesterol are not associated with CAD risk[3] after accounting for other lipid traits. These genetic analyses may suggest that LDL-cholesterol is a causal risk factor for CAD risk, but HDL-cholesterol is not—as has generally been observed in clinical trials of lipid-altering therapies.[4,5,6] Genetic studies have suggested that triglyceride levels are an independent risk factor for CAD risk.[7] Triglycerides are another component of body fat which are transported by lipoprotein particles, and in particular by very low-density lipoproteins (VLDL).
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