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Role of Major Lipoproteins and Subfractions as Risk Factors for PAD
Quick Takes
- Lipoprotein particles (LDL, IDL, VLDL) with surface apoB have varying lipid content (cholesterol and triglycerides) and particle size, which are determinants of atherogenicity and targets for high-dose, high-intensity statins that reduce all cardiovascular events and regression of coronary plaque. In contrast, peripheral artery disease (PAD) is more often associated with elevated triglycerides and low HDL cholesterol, as often found in diabetes.
- That in the future anti-atherosclerotic drug development may target different lipid moieties based on specific genes associated with specific vascular beds makes sense, but a super drug or combination will likely be needed.
- Statins decrease overall death rate and rate of amputations in PAD, and most importantly, PAD is one of the major markers of preventable ischemic events in the heart and brain that is afforded by statins.
Study Questions:
What are the relative contributions of specific lipoproteins to risk of peripheral artery disease (PAD) as compared to coronary artery disease (CAD)?
Methods:
Genome-wide association study (GWAS) summary statistics for circulating lipoprotein-related traits were used to prioritize the most likely causal major lipoprotein and subfraction risk factors for PAD and CAD. Mendelian randomization Bayesian modeling was used to estimate the effect of apolipoprotein B (ApoB) lowering on PAD risk using gene regions proxying lipid-lowering drug targets. Genes relevant to prioritized lipoprotein subfractions were identified using transcriptome-wide association studies.
Results:
ApoB was identified as the most likely causal lipoprotein-related risk factor for both PAD (marginal inclusion probability [MIP], 0.86; p = 0.003) and CAD (MIP, 0.92; p = 0.005). Genetic proxies for ApoB-lowering medications were associated with reduced risk of both PAD (odds ratio [OR], 0.87 per 1 standard deviation decrease in ApoB; 95% confidence interval [CI], 0.84-0.91; p = 9 × 10-10) and CAD (OR, 0.66; 95% CI, 0.63-0.69; p = 4 × 10-73), with a stronger predicted effect of ApoB lowering on CAD (ratio of effects, 3.09; 95% CI, 2.29-4.60; p < 1 × 10-6). Extra-small-VLDL particle concentration (XS.VLDL.P) was identified as the most likely subfraction associated with PAD risk (MIP, 0.91; p = 2.3 × 10-4), while large-LDL particle concentration (L.LDL.P) was the most likely subfraction associated with CAD risk (MIP, 0.95; p = 0.011). Genes associated with XS.VLDL.P and L.LDL.P included canonical ApoB-pathway components, although gene-specific effects were variable. Lipoprotein(a) was associated with increased risk of PAD, independent of ApoB (OR, 1.04; 95% CI, 1.03-1.04; 95% CI, 1.0 × 10-33).
Conclusions:
ApoB was prioritized as the major lipoprotein fraction causally responsible for both PAD and CAD risk. However, ApoB-lowering drug targets and ApoB-containing lipoprotein subfractions had diverse associations with atherosclerotic cardiovascular disease, and distinct subfraction-associated genes suggest possible differences in the role of lipoproteins in the pathogenesis of PAD and CAD.
Perspective:
The remarkable study required the cooperation of faculty from many US and European institutions, the IEU Open GWAS Project, and the very large VA Million Veteran Program. The results are fascinating, but the diagnosis of PAD for inclusion was based simply on VA electronic health records using ICD-9/10 and CPT codes. That includes atherosclerosis of the extremities including claudication, asymptomatic, spasm, testing including angiography and ankle/brachial index, tissue necrosis/gangrene, spasm, large and small vessels, as well as microangiopathy. And one could assume that diabetes would have a major influence on both the lipid parameters, size of vessels, and necrosis and critical limb ischemia in which thrombosis may play a role independent of the lipids.
Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Advanced Lipid Testing, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins
Keywords: Apolipoproteins B, Atherosclerosis, Coronary Artery Disease, Diabetes Mellitus, Cholesterol, Electronic Health Records, Genome-Wide Association Study, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertriglyceridemia, Lipoprotein(a), Lipoproteins, Lipoproteins, VLDL, Myocardial Ischemia, Peripheral Arterial Disease, Pharmaceutical Preparations, Plaque, Atherosclerotic, Primary Prevention, Risk Factors, Transcriptome, Vascular Diseases, Veterans
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