Observational Study

. 2022 Apr 26;79(16):1579-1590.

doi: 10.1016/j.jacc.2022.02.018.

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

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.

PMID: 35450575
PMCID: PMC9584800
DOI: 10.1016/j.jacc.2022.02.018

Observational Study

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

Pedrum Mohammadi-Shemirani et al. J Am Coll Cardiol. 2022.

. 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.

PMID: 35450575
PMCID: PMC9584800
DOI: 10.1016/j.jacc.2022.02.018

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.

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Conflict of interest statement

Funding Support and Author Disclosures Mr Mohammadi-Shemirani and Mr Chong are supported by the Frederick Banting and Charles Best Canada Graduate Scholarship from the Canadian Institute of Health Research. Dr Conen holds a McMaster University Department of Medicine Mid-Career Research Award; and has received consulting fees from Roche Diagnostics, outside of the current work. Dr Thériault holds a junior scholar award from the FRQS (Fonds de recherche du Québec–Santé). Dr Bossé holds a Canada Research Chair in Genomics of Heart and Lung Diseases. Dr Lanktree is a new investigator in the KRESCENT (Kidney Research Scientist Core Education and National Training) program; is supported by the Canadian Institutes of Health Research, Kidney Foundation of Canada, and the Canadian Society of Nephrology; and has received compensation for participation as a speaker and an advisory board member for Otsuka, Reata, Sanofi Genzyme, and Bayer. Dr Pigeyre is supported by the E.J. Moran Campbell Internal Career Research Award from McMaster University. Dr Paré holds the Canada Research Chair in Genetic and Molecular Epidemiology and Cisco Systems Professorship in Integrated Health Biosystems. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Comment in

Lipoprotein(a) and Atrial Fibrillation.
Hegele RA. Hegele RA. J Am Coll Cardiol. 2022 Aug 16;80(7):e49-e50. doi: 10.1016/j.jacc.2022.05.040. J Am Coll Cardiol. 2022. PMID: 35953141 No abstract available.
Reply: Lipoprotein(a) and Atrial Fibrillation.
Mohammadi-Shemirani P, Chong M, Paré G. Mohammadi-Shemirani P, et al. J Am Coll Cardiol. 2022 Aug 16;80(7):e51. doi: 10.1016/j.jacc.2022.06.006. J Am Coll Cardiol. 2022. PMID: 35953142 No abstract available.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

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Grants and funding

LinkOut - more resources

Full Text Sources

Medical

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