Lipoprotein Proteomics and Aortic Valve Transcriptomics Identify Biological Pathways Linking Lipoprotein(a) Levels to Aortic Stenosis.

Lipoprotein(a) (Lp(a)) is one of the most important risk factors for the development of calcific aortic valve stenosis (CAVS). However, the mechanisms through which Lp(a) causes CAVS are currently unknown. Our objectives were to characterize the Lp(a) proteome and to identify proteins that may be differentially associated with Lp(a) in patients with versus without CAVS. Our second objective was to identify genes that may be differentially regulated by exposure to high versus low Lp(a) levels in explanted aortic valves from patients with CAVS. We isolated Lp(a) from the blood of 21 patients with CAVS and 22 volunteers and performed untargeted label-free analysis of the Lp(a) proteome. We also investigated the transcriptomic signature of calcified aortic valves from patients who underwent aortic valve replacement with high versus low Lp(a) levels (n = 118). Proteins involved in the protein activation cascade, platelet degranulation, leukocyte migration, and response to wounding may be associated with Lp(a) depending on CAVS status. The transcriptomic analysis identified genes involved in cardiac aging, chondrocyte development, and inflammation as potentially influenced by Lp(a). Our multi-omic analyses identified biological pathways through which Lp(a) may cause CAVS, as well as key molecular events that could be triggered by Lp(a) in CAVS development.

Sex-Specific Associations of Genetically Predicted Circulating Lp(a) (Lipoprotein(a)) and Hepatic LPA Gene Expression Levels With Cardiovascular Outcomes: Mendelian Randomization and Observational Analyses.

BACKGROUND: Elevated Lp(a) (Lipoprotein(a)) levels are associated with coronary artery disease (CAD), ischemic stroke (IS), and calcific aortic valve stenosis (CAVS). Studies investigating the association between Lp(a) levels and these diseases in women have yielded inconsistent results. METHODS: To investigate the association of Lp(a) with sex-specific cardiovascular outcomes, we determined the association between genetically predicted Lp(a) levels (using 27 single nucleotide polymorphisms at the LPA locus) and hepatic LPA expression (using 80 single nucleotide polymorphisms at the LPA locus associated with LPA mRNA expression in liver samples from the Genotype-Tissue Expression dataset) on CAD, IS, and CAVS using individual participant data from the UK Biobank: 408 403 participants of European ancestry (37 102, 4283, and 2574 with prevalent CAD, IS, and CAVS, respectively). The long-term association between Lp(a) levels and incident CAD, IS, and CAVS was also investigated in European Prospective Investigation into Cancer and Nutrition-Norfolk: 18 721 participants (3964, 846, and 424 with incident CAD, IS, and CAVS, respectively). RESULTS: Genetically predicted plasma Lp(a) levels were positively and similarly associated with prevalent and incident CAD and CAVS in men and women. Genetically predicted plasma Lp(a) levels were associated with prevalent and incident IS when we studied men and women pooled together, and in men only. Genetically predicted LPA expression levels were associated with prevalent CAD and CAVS in men and women but not with IS. CONCLUSIONS: Genetically predicted blood Lp(a) and hepatic LPA gene expression as well as serum Lp(a) levels predict the risk of CAD and CAVS in men and in women. Whether RNA interference therapies aiming at lowering Lp(a) levels could be useful in reducing cardiovascular disease risk in both men and women with high Lp(a) levels needs to be determined in large-scale cardiovascular outcomes trials.

A Comparative Analysis of the Lipoprotein(a) and Low-Density Lipoprotein Proteomic Profiles Combining Mass Spectrometry and Mendelian Randomization.

BACKGROUND: 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 lifelong exposure to elevated Lp(a) or LDL cholesterol levels on the plasma proteomic profile. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: Results 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.

CONTEXTE: La lipoprotéine(a) (Lp[a]), qui est constituée d'une lipoprotéine de basse densité (LDL) liée à une apolipoprotéine(a), est l'un des plus importants facteurs de risque génétiques de survenue d'une maladie cardiovasculaire athéroscléreuse. Peu d'études comparatives directes sans hypothèse ont porté sur le protéome de la Lp(a) et celui des LDL. Nos objectifs étaient de comparer les profils protéomiques de la Lp(a) et des LDL et d'évaluer l'effet d'une exposition à vie à un taux élevé de Lp(a) ou de cholestérol LDL sur le profil protéomique plasmatique. MÉTHODOLOGIE: Nous avons réalisé une analyse sans marquage des profils protéomiques de la Lp(a) et des LDL chez des volontaires en bonne santé dans le cadre d'une phase de découverte (n = 6) et d'une phase de réplication (n = 9). Pour rendre compte de l'effet d'une exposition à vie à un taux élevé de Lp(a) ou de cholestérol des LDL sur le profil protéomique plasmatique des participants de l'étude INTERVAL, nous avons utilisé une analyse de randomisation Mendélienne avec pondération par l'inverse de la variance. RÉSULTATS: Nous avons relevé 15 protéines associées en plus grande abondance à la Lp(a) qu'aux LDL (serping1, pi16, itih1, itih2, itih3, pon1, podxl, cd44, cp, ptprg, vtn, pcsk9, igfals, vcam1 et ttr). Nous n'avons noté aucune protéine associée en plus grande abondance aux LDL qu'à la Lp(a). Après correction pour tenir compte de la multiplicité des tests, l'exposition à vie à un taux élevé de cholestérol LDL a été associée à la variation de 18 protéines plasmatiques, tandis que le taux de Lp(a) ne semblait pas influencer le protéome plasmatique. CONCLUSIONS: Les résultats de notre étude font ressortir les différences marquées entre le protéome de la Lp(a) et celui des LDL, ainsi qu'entre l'effet sur le profil protéomique plasmatique de l'exposition à vie à un taux élevé de cholestérol LDL et celui de l'exposition à vie à un taux élevé de Lp(a).

Interaction of Autotaxin With Lipoprotein(a) in Patients With Calcific Aortic Valve Stenosis.

Our objectives were to determine whether autotaxin (ATX) is transported by lipoprotein(a) [Lp(a)] in human plasma and if could be used as a biomarker of calcific aortic valve stenosis (CAVS). We first found that ATX activity was higher in Lp(a) compared to low-density lipoprotein fractions in isolated fractions of 10 healthy participants. We developed a specific assay to measure ATX-Lp(a) in 88 patients with CAVS and 144 controls without CAVS. In a multivariable model corrected for CAVS risk factors, ATX-Lp(a) was associated with CAVS (p = 0.003). We concluded that ATX is preferentially transported by Lp(a) and might represent a novel biomarker for CAVS.