Genetics of height and risk of atrial fibrillation: A Mendelian randomization study

English version

Autoři: Michael G. Levin ^aff001; Renae Judy ^aff004; Dipender Gill ^aff005; Marijana Vujkovic ^aff002; Shefali S. Verma ^aff010; Yuki Bradford ^aff010; ^aff012; Marylyn D. Ritchie ^aff010; Matthew C. Hyman ^aff001; Saman Nazarian ^aff001; Daniel J. Rader ^aff002; Benjamin F. Voight ^aff010; Scott M. Damrauer ^aff003
Působiště autorů: Division of Cardiovascular Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America ^aff001; Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America ^aff002; Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, United States of America ^aff003; Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America ^aff004; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom ^aff005; Centre for Pharmacology & Therapeutics, Department of Medicine, Imperial College London, London, United Kingdom ^aff006; Novo Nordisk Research Centre Oxford, Oxford, United Kingdom ^aff007; Clinical Pharmacology and Therapeutics Section, Institute of Medical and Biomedical Education and Institute for Infection and Immunity, St George’s, University of London, London, United Kingdom ^aff008; Clinical Pharmacology Group, Pharmacy and Medicines Directorate, St George’s University Hospitals NHS Foundation Trust, London, United Kingdom ^aff009; Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America ^aff010; Institute for Biomedical Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America ^aff011; Tarrytown, New York, United States of America ^aff012; Institute for Translational Medicine and Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America ^aff013; Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America ^aff014
Vyšlo v časopise: Genetics of height and risk of atrial fibrillation: A Mendelian randomization study. PLoS Med 17(10): e32767. doi:10.1371/journal.pmed.1003288
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pmed.1003288

Souhrn

Background

Observational studies have identified height as a strong risk factor for atrial fibrillation, but this finding may be limited by residual confounding. We aimed to examine genetic variation in height within the Mendelian randomization (MR) framework to determine whether height has a causal effect on risk of atrial fibrillation.

Methods and findings

In summary-level analyses, MR was performed using summary statistics from genome-wide association studies of height (GIANT/UK Biobank; 693,529 individuals) and atrial fibrillation (AFGen; 65,446 cases and 522,744 controls), finding that each 1-SD increase in genetically predicted height increased the odds of atrial fibrillation (odds ratio [OR] 1.34; 95% CI 1.29 to 1.40; p = 5 × 10⁻⁴²). This result remained consistent in sensitivity analyses with MR methods that make different assumptions about the presence of pleiotropy, and when accounting for the effects of traditional cardiovascular risk factors on atrial fibrillation. Individual-level phenome-wide association studies of height and a height genetic risk score were performed among 6,567 European-ancestry participants of the Penn Medicine Biobank (median age at enrollment 63 years, interquartile range 55–72; 38% female; recruitment 2008–2015), confirming prior observational associations between height and atrial fibrillation. Individual-level MR confirmed that each 1-SD increase in height increased the odds of atrial fibrillation, including adjustment for clinical and echocardiographic confounders (OR 1.89; 95% CI 1.50 to 2.40; p = 0.007). The main limitations of this study include potential bias from pleiotropic effects of genetic variants, and lack of generalizability of individual-level findings to non-European populations.

Conclusions

In this study, we observed evidence that height is likely a positive causal risk factor for atrial fibrillation. Further study is needed to determine whether risk prediction tools including height or anthropometric risk factors can be used to improve screening and primary prevention of atrial fibrillation, and whether biological pathways involved in height may offer new targets for treatment of atrial fibrillation.

Klíčová slova:

Atrial fibrillation – Cardiovascular disease risk – Coronary heart disease – diabetes mellitus – Genetics – Genetics of disease – Genome-wide association studies – Instrumental variable analysis

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