Phenotypic Characterization of Genetically Lowered Human Lipoprotein(a) Levels

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• 作者：Connor A. Emdin ; DPhil^a ; ^b ; Amit V. Khera ; MD^a ; ^b ; Pradeep Natarajan ; MD^a ; ^b ; Derek Klarin ; MD^a ; ^b ; Hong-Hee Won ; PhD^c ; Gina M. Peloso ; PhD^b ; ^d ; Nathan O. Stitziel ; MD ; PhD^e ; Akihiro Nomura ; MD^a ; ^b ; Seyedeh M. Zekavat ; BSc^a ; ^b ; Alexander G. Bick ; MD^b ; Namrata Gupta ; PhD^b ; Rosanna Asselta ; PhD^f ; Stefano Duga ; PhD^f ; Piera Angelica Merlini ; MD^g ; Adolfo Correa ; MD^h ; Thorsten Kessler ; MDⁱ ; ^j ; James G. Wilson ; MD^k ; Matthew J. Bown ; MD^l ; Alistair S. Hall ; MD^m ; Peter S. Braund ; PhD^l ; Nilesh J. Samani ; MD^l ; Heribert Schunkert ; MDⁱ ; Jaume Marrugat ; MD ; PhDⁿ ; Roberto Elosua ; MD ; PhDⁿ ; Ruth McPherson ; MD^o ; Martin Farrall ; PhD^p ; Hugh Watkins ; MD ; PhD^p ; Cristen Willer ; PhD^q ; Gonç ; alo R. Abecasis ; PhD^r ; Janine F. Felix ; MD ; PhD^s ; Ramachandran S. Vasan ; MD^t ; ^u ; Eric Lander ; PhD^b ; Daniel J. Rader ; MD^v ; John Danesh ; MSc ; DPhil^w ; ^x ; ^y ; Diego Ardissino ; MD^z ; ^aa ; Stacey Gabriel ; PhD^b ; Danish Saleheen ; MD^bb ; Sekar Kathiresan ; MD^a ; ^b ; ^{skathiresan1@mgh.harvard.edu} ; ; the CHARGE&ndash ; Heart Failure Consortium
• 关键词：coronary heart disease ; genetics ; phenome-wide association study ; single nucleotide polymorphism
• 刊名：Journal of the American College of Cardiology
• 出版年：2016
• 出版时间：27 December 2016
• 年：2016
• 卷：68
• 期：25
• 页码：2761-2772
• 全文大小：1558 K
• 卷排序：68

文摘

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.ObjectivesThe 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.MethodsWe 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.ResultsOne 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.ConclusionsBeyond 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.