Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels

Connor A. Emdin, Amit V. Khera, Pradeep Natarajan, Derek Klarin, Hong Hee Won, Gina M Peloso, Nathan O. Stitziel, Akihiro Nomura, Seyedeh M Zekavat, Alexander G. Bick, Namrata Gupta, Rosanna Asselta, Stefano Duga, Piera Angelica Merlini, Adolfo Correa, Thorsten Kessler, James G. Wilson, Matthew J. Bown, Alistair S. Hall, Peter S. BraundNilesh J. Samani, Heribert Schunkert, Jaume Marrugat, Roberto Elosua, Ruth McPherson, Martin Farrall, Hugh Watkins, Cristen J. Willer, Gonçalo R. Abecasis, Janine F. Felix, Ramachandran S. Vasan, Eric Lander, Daniel J. Rader, John Danesh, Diego Ardissino, Stacey Gabriel, Danish Saleheen, Sekar Kathiresan, CHARGE–Heart Failure Consortium

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2761-2772
Number of pages12
JournalJournal of the American College of Cardiology
Volume68
Issue number25
DOIs
Publication statusPublished - Dec 27 2016

Fingerprint

Lipoprotein(a)
Coronary Disease
Odds Ratio
Confidence Intervals
Genes
Peripheral Vascular Diseases
Aortic Valve Stenosis
Heart Failure
Stroke
Information Storage and Retrieval
Genome-Wide Association Study
Medical Genetics
Type 2 Diabetes Mellitus
Atherosclerosis
Biomarkers
Pharmacology

Keywords

  • Journal Article

Cite this

Emdin, C. A., Khera, A. V., Natarajan, P., Klarin, D., Won, H. H., Peloso, G. M., ... CHARGE–Heart Failure Consortium (2016). Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels. Journal of the American College of Cardiology, 68(25), 2761-2772. https://doi.org/10.1016/j.jacc.2016.10.033

Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels. / 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 J.; Abecasis, Gonçalo R.; Felix, Janine F.; Vasan, Ramachandran S.; Lander, Eric; Rader, Daniel J.; Danesh, John; Ardissino, Diego; Gabriel, Stacey; Saleheen, Danish; Kathiresan, Sekar; CHARGE–Heart Failure Consortium.

In: Journal of the American College of Cardiology, Vol. 68, No. 25, 27.12.2016, p. 2761-2772.

Research output: Contribution to journalArticle

Emdin, CA, Khera, AV, Natarajan, P, Klarin, D, Won, HH, Peloso, GM, Stitziel, NO, Nomura, A, Zekavat, SM, Bick, AG, Gupta, N, Asselta, R, Duga, S, Merlini, PA, Correa, A, Kessler, T, Wilson, JG, Bown, MJ, Hall, AS, Braund, PS, Samani, NJ, Schunkert, H, Marrugat, J, Elosua, R, McPherson, R, Farrall, M, Watkins, H, Willer, CJ, Abecasis, GR, Felix, JF, Vasan, RS, Lander, E, Rader, DJ, Danesh, J, Ardissino, D, Gabriel, S, Saleheen, D, Kathiresan, S & CHARGE–Heart Failure Consortium 2016, 'Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels', Journal of the American College of Cardiology, vol. 68, no. 25, pp. 2761-2772. https://doi.org/10.1016/j.jacc.2016.10.033
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 J. ; Abecasis, Gonçalo R. ; Felix, Janine F. ; Vasan, Ramachandran S. ; Lander, Eric ; Rader, Daniel J. ; Danesh, John ; Ardissino, Diego ; Gabriel, Stacey ; Saleheen, Danish ; Kathiresan, Sekar ; CHARGE–Heart Failure Consortium. / Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels. In: Journal of the American College of Cardiology. 2016 ; Vol. 68, No. 25. pp. 2761-2772.
@article{82036fabf4154485a0fb37bff5af2314,
title = "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.",
keywords = "Journal Article",
author = "Emdin, {Connor A.} and Khera, {Amit V.} and Pradeep Natarajan and Derek Klarin and Won, {Hong Hee} and Peloso, {Gina M} and Stitziel, {Nathan O.} and Akihiro Nomura and Zekavat, {Seyedeh M} and Bick, {Alexander G.} and Namrata Gupta and Rosanna Asselta and Stefano Duga and Merlini, {Piera Angelica} and Adolfo Correa and Thorsten Kessler and Wilson, {James G.} and Bown, {Matthew J.} and Hall, {Alistair S.} and Braund, {Peter S.} and Samani, {Nilesh J.} and Heribert Schunkert and Jaume Marrugat and Roberto Elosua and Ruth McPherson and Martin Farrall and Hugh Watkins and Willer, {Cristen J.} and Abecasis, {Gon{\cc}alo R.} and Felix, {Janine F.} and Vasan, {Ramachandran S.} and Eric Lander and Rader, {Daniel J.} and John Danesh and Diego Ardissino and Stacey Gabriel and Danish Saleheen and Sekar Kathiresan and {CHARGE–Heart Failure Consortium}",
note = "Copyright {\circledC} 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.",
year = "2016",
month = "12",
day = "27",
doi = "10.1016/j.jacc.2016.10.033",
language = "English",
volume = "68",
pages = "2761--2772",
journal = "Journal of the American College of Cardiology",
issn = "0735-1097",
publisher = "Elsevier USA",
number = "25",

}

TY - JOUR

T1 - Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels

AU - Emdin, Connor A.

AU - Khera, Amit V.

AU - Natarajan, Pradeep

AU - Klarin, Derek

AU - Won, Hong Hee

AU - Peloso, Gina M

AU - Stitziel, Nathan O.

AU - Nomura, Akihiro

AU - Zekavat, Seyedeh M

AU - Bick, Alexander G.

AU - Gupta, Namrata

AU - Asselta, Rosanna

AU - Duga, Stefano

AU - Merlini, Piera Angelica

AU - Correa, Adolfo

AU - Kessler, Thorsten

AU - Wilson, James G.

AU - Bown, Matthew J.

AU - Hall, Alistair S.

AU - Braund, Peter S.

AU - Samani, Nilesh J.

AU - Schunkert, Heribert

AU - Marrugat, Jaume

AU - Elosua, Roberto

AU - McPherson, Ruth

AU - Farrall, Martin

AU - Watkins, Hugh

AU - Willer, Cristen J.

AU - Abecasis, Gonçalo R.

AU - Felix, Janine F.

AU - Vasan, Ramachandran S.

AU - Lander, Eric

AU - Rader, Daniel J.

AU - Danesh, John

AU - Ardissino, Diego

AU - Gabriel, Stacey

AU - Saleheen, Danish

AU - Kathiresan, Sekar

AU - CHARGE–Heart Failure Consortium

N1 - Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

PY - 2016/12/27

Y1 - 2016/12/27

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.jacc.2016.10.033

DO - 10.1016/j.jacc.2016.10.033

M3 - Article

C2 - 28007139

VL - 68

SP - 2761

EP - 2772

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

SN - 0735-1097

IS - 25

ER -