  Citation: Geurts, S.; Mens, M.M.; Bos, M.M.; Ikram, M.A.; Ghanbari, M.; Kavousi, M. Circulatory MicroRNAs in Plasma and Atrial Fibrillation in the General Population: The Rotterdam Study. Genes 2022, 13, 11. https://doi.org/10.3390/ genes13010011 Academic Editor: Mikko P. Turunen Received: 12 November 2021 Accepted: 16 December 2021 Published: 22 December 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). genes G C A T T A C G G C A T Article Circulatory MicroRNAs in Plasma and Atrial Fibrillation in the General Population: The Rotterdam Study Sven Geurts, Michelle M. J. Mens, Maxime M. Bos, M. Arfan Ikram, Mohsen Ghanbari † and Maryam Kavousi * ,† Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; s.geurts@erasmusmc.nl (S.G.); m.mens@erasmusmc.nl (M.M.J.M.); m.m.bos@erasmusmc.nl (M.M.B.); m.a.ikram@erasmusmc.nl (M.A.I.); m.ghanbari@erasmusmc.nl (M.G.) * Correspondence: m.kavousi@erasmusmc.nl † These authors contributed equally to this work and share last authorship. Abstract: Background: MicroRNAs (miRNAs), small non-coding RNAs regulating gene expression, have been shown to play an important role in cardiovascular disease. However, limited population- based data regarding the relationship between circulatory miRNAs in plasma and atrial fibrillation (AF) exist. Moreover, it remains unclear if the relationship differs by sex. We therefore aimed to determine the (sex-specific) association between plasma circulatory miRNAs and AF at the population level. Methods: Plasma levels of miRNAs were measured using a targeted next-generation sequencing method in 1999 participants from the population-based Rotterdam Study. Logistic regression and Cox proportional hazards models were used to assess the associations of 591 well-expressed miRNAs with the prevalence and incidence of AF. Models were adjusted for cardiovascular risk factors. We further examined the link between predicted target genes of the identified miRNAs. Results: The mean age was 71.7 years (57.1% women), 98 participants (58 men and 40 women) had prevalent AF at baseline. Moreover, 196 participants (96 men and 100 women) developed AF during a median follow-up of 9.0 years. After adjusting for multiple testing, miR-4798-3p was significantly associated with the odds of prevalent AF among men (odds ratio, 95% confidence interval, 0.39, 0.24–0.66, p-value = 0.000248). No miRNAs were significantly associated with incident AF. MiR-4798-3p could potentially regulate the expression of a number of AF-related genes, including genes involved in calcium and potassium handling in myocytes, protection of cells against oxidative stress, and cardiac fibrosis. Conclusions: Plasma levels of miR-4798-3p were significantly associated with the odds of prevalent AF among men. Several target genes in relation to AF pathophysiology could potentially be regulated by miR-4798-3p that warrant further investigations in future experimental studies. Keywords: atrial fibrillation; biomarkers; epidemiology; genomics; microRNAs; risk factors; sex-differences 1. Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide [1,2]. The prevalence of AF is expected to increase steeply in the coming decades due to aging of the population [1–3]. Despite the identification of risk factors for AF [4–7] and improvement in its management, AF still confers a high morbidity and mortality risk [1,2,7]. Furthermore, recent evidence suggests that sex-differences in AF pathophysiology and prognosis exist [8]. Women with AF are older at diagnosis, have a higher prevalence of hypertension, valvular heart disease, and have an increased risk of stroke, myocardial infarction, and mortality in comparison to men [8]. MicroRNAs (miRNAs) are a class of small non-coding RNAs that post-transcriptionally regulate gene expression by complementary binding to target transcripts. Dysregulation of miRNA function could affect pathology of diseases [9]. Extensive studies have also shown the potential of miRNAs to be used as disease biomarkers, as their expression remains stable after drawing blood and they are easily accessible in different types of body fluid [10]. Genes 2022, 13, 11. https://doi.org/10.3390/genes13010011 https://www.mdpi.com/journal/genes