Emdin Connor A. Khera, Amit Natarajan Pradeep Klarin Derek Won Hong-Hee Peloso Gina Stitziel Nathan Nomura Akihiro Zekavat Seyedeh Bick Alexander Gupta Namrata Asselta Rosanna Duga Stefano Merlini Piera Angelica Correa Adolfo Kessler Thorsten Wilson James Bown Matthew Hall Alistair Braund Peter Samani Nilesh Schunkert Heribert Marrugat Jaume Elosua Roberto McPherson Ruth Farrall Martin Watkins Hugh Willer Cristen Abecasis Gonçalo Felix Janine Vasan Ramachandran Lander Eric Rader Daniel Danesh John Ardissino Diego Gabriel Stacey Saleheen Danish Kathiresan Sekar V M O M G G J S S J R F S J Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels Journal Article In: Journal of the American College of Cardiology, 2016. Abstract | Links | BibTeX | Tags: Human lipoprotein(a) @article{EmdinCA2016,
title = {Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels},
author = {Emdin, Connor A.
Khera, Amit V.
Natarajan, Pradeep
Klarin, Derek
Won, Hong-Hee
Peloso, Gina M.
Stitziel, Nathan O.
Nomura, Akihiro
Zekavat, Seyedeh M.
Bick, Alexander G.
Gupta, Namrata
Asselta, Rosanna
Duga, Stefano
Merlini, Piera Angelica
Correa, Adolfo
Kessler, Thorsten
Wilson, James G.
Bown, Matthew J.
Hall, Alistair S.
Braund, Peter S.
Samani, Nilesh J.
Schunkert, Heribert
Marrugat, Jaume
Elosua, Roberto
McPherson, Ruth
Farrall, Martin
Watkins, Hugh
Willer, Cristen
Abecasis, Gonçalo R.
Felix, Janine F.
Vasan, Ramachandran S.
Lander, Eric
Rader, Daniel J.
Danesh, John
Ardissino, Diego
Gabriel, Stacey
Saleheen, Danish
Kathiresan, Sekar},
url = {http://www.onlinejacc.org/content/accj/68/25/2761.full.pdf},
year = {2016},
date = {2016-12-27},
journal = {Journal of the American College of Cardiology},
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.%U },
keywords = {Human lipoprotein(a)},
pubstate = {published},
tppubtype = {article}
}
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.%U |
