Elevated Lipoprotein(a) and Risk of Atrial Fibrillation: An Observational and Mendelian Randomization Study

Pedrum Mohammadi-Shemirani; Michael Chong; Sukrit Narula; Nicolas Perrot; David Conen; Jason D Roberts; Sébastien Thériault; Yohan Bossé; Matthew B Lanktree; Marie Pigeyre; Guillaume Paré

doi:10.1016/j.jacc.2022.02.018

Elevated Lipoprotein(a) and Risk of Atrial Fibrillation: An Observational and Mendelian Randomization Study

J Am Coll Cardiol. 2022 Apr 26;79(16):1579-1590. doi: 10.1016/j.jacc.2022.02.018.

Authors

Affiliations

¹ Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; Department of Medical Sciences, McMaster University, Hamilton, Ontario, Canada.
² Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
³ Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.
⁴ Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada; Department of Medicine, Faculty of Medicine, Université Laval, Québec, Québec, Canada.
⁵ Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada.
⁶ Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada.
⁷ Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada; Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Université Laval, Québec, Québec, Canada.
⁸ Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, Québec, Canada.
⁹ Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
¹⁰ Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada.
¹¹ Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada; Department of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Ontario, Canada. Electronic address: pareg@mcmaster.ca.

Abstract

Background: Atrial fibrillation (AF) is a cardiac arrhythmia associated with an elevated risk of stroke, heart failure, and mortality. However, preventative therapies are needed with ancillary benefits on its cardiovascular comorbidities. Lipoprotein(a) (Lp[a]) is a recognized risk factor for atherosclerotic cardiovascular disease (ASCVD), which itself increases AF risk, but it remains unknown whether Lp(a) is a causal mediator of AF independent of ASCVD.

Objectives: This study investigated the role of Lp(a) in AF and whether it is independent of ASCVD.

Methods: Measured and genetically predicted Lp(a) levels were tested for association with 20,432 cases of incident AF in the UK Biobank (N = 435,579). Mendelian randomization analyses were performed by using summary-level data for AF from publicly available genome-wide association studies (N = 1,145,375).

Results: In the UK Biobank, each 50 nmol/L (23 mg/dL) increase in Lp(a) was associated with an increased risk of incident AF using measured Lp(a) (HR: 1.03; 95% CI: 1.02-1.04 ; P = 1.65 × 10^-8) and genetically predicted Lp(a) (OR: 1.03; 95% CI: 1.02-1.05; P = 1.33 × 10^-5). Mendelian randomization analyses using independent data replicated the effect (OR: 1.04 per 50 nmol/L Lp[a] increase; 95% CI: 1.03-1.05 per 50 nmol/L Lp[a] increase; P = 9.23 × 10^-10). There was no evidence of risk-conferring effect from low-density lipoprotein cholesterol or triglycerides, and only 39% (95% CI: 27%-73%) of Lp(a) risk was mediated through ASCVD, suggesting that Lp(a) partly influences AF independent of its known effects on ASCVD.

Conclusions: Our findings implicate Lp(a) as a potential causal mediator in the development of AF which show that the effects of Lp(a) extend across myocardial tissues. Ongoing clinical trials for Lp(a)-lowering therapies should evaluate effects on AF prevention.

Keywords: Mendelian randomization; UK Biobank; atrial fibrillation; genetic risk score; lipoprotein(a); survival analysis.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Atrial Fibrillation* / epidemiology
Atrial Fibrillation* / genetics
Genome-Wide Association Study
Humans
Lipoprotein(a) / genetics
Mendelian Randomization Analysis*
Polymorphism, Single Nucleotide
Risk Factors

Substances

Lipoprotein(a)

Grants and funding

Canadian Institute of Health Research