Abstract
BackgroundLipoprotein(a) (Lp[a]), which consists of a low-density lipoprotein (LDL) bound to apolipoprotein(a), is one of the strongest genetic risk factors for atherosclerotic cardiovascular diseases. Few studies have performed hypothesis-free direct comparisons of the Lp(a) and the LDL proteomes. Our objectives were to compare the Lp(a) and the LDL proteomic profiles and to evaluate the effect of lifelong exposure to elevated Lp(a) or LDL cholesterol levels on the plasma proteomic profile. MethodsWe performed a label-free analysis of the Lp(a) and LDL proteomic profiles of healthy volunteers in a discovery (n = 6) and a replication (n = 9) phase. We performed inverse variance weighted Mendelian randomization to document the effect of lifelong exposure to elevated Lp(a) or LDL cholesterol levels on the plasma proteomic profile of participants of the INTERVAL study. ResultsWe identified 15 proteins that were more abundant on Lp(a) compared with LDL (serping1, pi16, itih1, itih2, itih3, pon1, podxl, cd44, cp, ptprg, vtn, pcsk9, igfals, vcam1, and ttr). We found no proteins that were more abundant on LDL compared with Lp(a). After correction for multiple testing, lifelong exposure to elevated LDL cholesterol levels was associated with the variation of 18 plasma proteins whereas Lp(a) did not appear to influence the plasma proteome. ConclusionsResults of this study highlight marked differences in the proteome of Lp(a) and LDL as well as in the effect of lifelong exposure to elevated LDL cholesterol or Lp(a) on the plasma proteomic profile.
Highlights
Lipoprotein(a) (Lp[a]), which consists of a low-density lipoprotein (LDL) bound to apolipoprotein(a), is one of the strongest genetic risk factors for atherosclerotic cardiovascular diseases
We reported that Lp(a)-bound autotaxin promotes mineralization and inflammation of the aortic valve[8,9] and this increased plasma atx activity associated with Lp(a) levels is predictive of calcific aortic valve stenosis (CAVS) risk.[10]
In light of the growing body of evidence supporting a causal role for Lp(a) particles in the pathobiology of atherosclerotic cardiovascular diseases (ACVD) and of the development of Lp(a)-lowering therapies to lower the risk of ACVD, we set out to gain more knowledge on the physico-chemical characteristics of Lp(a) such as its proteome using semiquantitative proteomics and the potential effect of Lp(a)-lowering therapy on the plasma proteome using Mendelian randomization (MR)
Summary
Lipoprotein(a) (Lp[a]), which consists of a low-density lipoprotein (LDL) bound to apolipoprotein(a), is one of the strongest genetic risk factors for atherosclerotic cardiovascular diseases. Few studies have performed hypothesis-free direct comparisons of the Lp(a) and the LDL proteomes. Our objectives were to compare the Lp(a) and the LDL proteomic profiles and to evaluate the effect of RESUME Contexte : La lipoproteine(a) (Lp[a]), qui est constituee d’une lipoproteine de basse densite (LDL) liee à une apolipoproteine(a), est l’un des plus importants facteurs de risque genetiques de survenue d’une maladie cardiovasculaire atherosclereuse. Circulating levels of apolipoprotein (apo) B-containing lipoproteins such as low-density lipoprotein (LDL) and lipoprotein(a) (Lp[a]) are causal risk factors for a broad range of atherosclerotic cardiovascular diseases (ACVD).[1] The evidence linking LDL cholesterol levels with ACVD risk emerged from experimental preclinical studies, follow-up of patients with
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