| Title: | Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels |
| Journal: | Journal of the American College of Cardiology |
| Published: | 1 Dec 2016 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/28007139/ |
| DOI: | https://doi.org/10.1016/j.jacc.2016.10.033 |
Publication 8450
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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.</p>
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.</p>
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.</p>
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.</p>
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.</p>
40 Authors
- 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. Braund
- Nilesh J. Samani
- Heribert Schunkert
- Jaume Marrugat
- Roberto Elosua
- Ruth McPherson
- Martin Farrall
- Hugh Watkins
- Cristen 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
- CARDIoGRAM Exome Consortium
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