Dataset Information

Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels.

ABSTRACT: BACKGROUND:Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose-response curve of target perturbation. OBJECTIVES:The goal of this study was to establish the full phenotypic impact of LPA gene variation and to estimate a dose-response curve between genetically altered plasma Lp(a) and risk for CHD. METHODS:We leveraged genetic variants at the LPA gene from 3 data sources: individual-level data from 112,338 participants in the U.K. Biobank; summary association results from large-scale genome-wide association studies; and LPA gene sequencing results from case subjects with CHD and control subjects free of CHD. RESULTS:One SD genetically lowered Lp(a) level was associated with a 29% lower risk of CHD (odds ratio [OR]: 0.71; 95% confidence interval [CI]: 0.69 to 0.73), a 31% lower risk of peripheral vascular disease (OR: 0.69; 95% CI: 0.59 to 0.80), a 13% lower risk of stroke (OR: 0.87; 95% CI: 0.79 to 0.96), a 17% lower risk of heart failure (OR: 0.83; 95% CI: 0.73 to 0.94), and a 37% lower risk of aortic stenosis (OR: 0.63; 95% CI: 0.47 to 0.83). We observed no association with 31 other disorders, including type 2 diabetes and cancer. Variants that led to gain of LPA gene function increased the risk for CHD, whereas those that led to loss of gene function reduced the CHD risk. CONCLUSIONS:Beyond CHD, genetically lowered Lp(a) levels are associated with a lower risk of peripheral vascular disease, stroke, heart failure, and aortic stenosis. As such, pharmacological lowering of plasma Lp(a) may influence a range of atherosclerosis-related diseases.

SUBMITTER: Emdin CA

PROVIDER: S-EPMC5328146 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels.

Emdin Connor A CA Khera Amit V AV Natarajan Pradeep P Klarin Derek D Won Hong-Hee HH Peloso Gina M GM Stitziel Nathan O NO Nomura Akihiro A Zekavat Seyedeh M SM Bick Alexander G AG Gupta Namrata N Asselta Rosanna R Duga Stefano S Merlini Piera Angelica PA Correa Adolfo A Kessler Thorsten T Wilson James G JG Bown Matthew J MJ Hall Alistair S AS Braund Peter S PS Samani Nilesh J NJ Schunkert Heribert H Marrugat Jaume J Elosua Roberto R McPherson Ruth R Farrall Martin M Watkins Hugh H Willer Cristen C Abecasis Gonçalo R GR Felix Janine F JF Vasan Ramachandran S RS Lander Eric E Rader Daniel J DJ Danesh John J Ardissino Diego D Gabriel Stacey S Saleheen Danish D Kathiresan Sekar S

Journal of the American College of Cardiology 20161201 25

<h4>Background</h4>Genomic analyses have suggested that the LPA gene and its associated plasma biomarker, lipoprotein(a) (Lp[a]), represent a causal risk factor for coronary heart disease (CHD). As such, lowering Lp(a) levels has emerged as a therapeutic strategy. Beyond target identification, human genetics may contribute to the development of new therapies by defining the full spectrum of beneficial and adverse consequences and by developing a dose-response curve of target perturbation.<h4>Obj ...[more]

PMID: 28007139

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Project description:Stimulating meniscus regeneration using meniscal progenitor cells has been suggested as a promising new strategy. However, there is a lack of studies which decisively identify and characterize progenitor cell populations in human meniscus tissues. In this study, donor-matched progenitor cells were isolated via selective fibronectin adhesion from the avascular and vascular regions of the meniscus and chondroprogenitors from articular cartilage (n = 5). The mixed populations of cells from these regions were obtained by standard isolation techniques for comparison. The colony formation efficacy of avascular progenitors, vascular progenitors and chondroprogenitors was monitored using Cell-IQ® live cell imaging. Proliferation rates of progenitors were compared with their mixed population counterparts. Cell surface markers indicative of mesenchymal stromal cells profile and progenitor markers were characterized by flow cytometry in all populations. The fibrochondrogenic capacity was assessed via fibrochondrogenic differentiation and measuring GAG/DNA content and morphology. All meniscal progenitor and chondroprogenitor populations showed superior colony forming efficacy and faster proliferation rates compare to their mixed populations. Progenitor populations showed significantly higher positivity for CD49b and CD49c compared to their mixed population counterparts and chondroprogenitors had a higher positivity level of CD166 compared to mixed chondrocytes. GAG/DNA analysis demonstrated that progenitor cells generally produced more GAG than mixed populations. Our study demonstrates that the human meniscus contains meniscal progenitor populations in both the avascular and vascular regions. Meniscal progenitors derived from the vascular region exhibit enhanced proliferative and fibrochondrogenic characteristics compared to those from the avascular region; this may associate with the enhanced meniscal healing potential in the vascular region. These findings build on the body of evidence which suggests that meniscal progenitors represent an attractive cell therapy strategy for meniscal regeneration.

Project description:BACKGROUND:Routine apolipoprotein (apo) measurements for cardiovascular disease (CVD) are restricted to apoA-I and apoB. Here, the authors measured an unprecedented range of apolipoproteins in a prospective, population-based study and relate their plasma levels to risk of CVD. OBJECTIVES:This study sought to measure apolipoproteins directly by mass spectrometry and compare their associations with incident CVD and to obtain a system-level understanding of the correlations of apolipoproteins with the plasma lipidome and proteome. METHODS:Associations of 13 apolipoproteins, 135 lipid species, and 211 other plasma proteins with incident CVD (91 events), defined as stroke, myocardial infarction, or sudden cardiac death, were assessed prospectively over a 10-year period in the Bruneck Study (N = 688) using multiple-reaction monitoring mass spectrometry. Changes in apolipoprotein and lipid levels following treatment with volanesorsen, a second-generation antisense drug targeting apoC-III, were determined in 2 human intervention trials, one of which was randomized. RESULTS:The apolipoproteins most significantly associated with incident CVD were apoC-II (hazard ratio per 1 SD [HR/SD]: 1.40; 95% confidence interval [CI]: 1.17 to 1.67), apoC-III (HR/SD: 1.38; 95% CI: 1.17 to 1.63), and apoE (HR/SD: 1.31; 95% CI: 1.13 to 1.52). Associations were independent of high-density lipoprotein (HDL) and non-HDL cholesterol, and extended to stroke and myocardial infarction. Lipidomic and proteomic profiles implicated these 3 very-low-density lipoprotein (VLDL)-associated apolipoproteins in de novo lipogenesis, glucose metabolism, complement activation, blood coagulation, and inflammation. Notably, apoC-II/apoC-III/apoE correlated with a pattern of lipid species previously linked to CVD risk. ApoC-III inhibition by volanesorsen reduced plasma levels of apoC-II, apoC-III, triacylglycerols, and diacylglycerols, and increased apoA-I, apoA-II, and apoM (all p < 0.05 vs. placebo) without affecting apoB-100 (p = 0.73). CONCLUSIONS:The strong associations of VLDL-associated apolipoproteins with incident CVD in the general community support the concept of targeting triacylglycerol-rich lipoproteins to reduce risk of CVD.

Dataset Information

Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels.

Publications

Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels.

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