Insight into genetic determinants of resting heart rate Massimo Mezzavilla a , Annamaria Iorio b , Marco Bobbo b , Angela D'Eustacchio c , Marco Merlo b , Paolo Gasparini a , Sheila Ulivi c, ⁎, Gianfranco Sinagra b a Institute for Maternal and Child Health — IRCCS “Burlo Garofolo”— Trieste, University of Trieste, Italy b Cardiovascular Department, Ospedali Riuniti and University of Trieste, Trieste, Italy c Institute for Maternal and Child Health — IRCCS “Burlo Garofolo”— Trieste, Italy abstract article info Article history: Received 6 November 2013 Received in revised form 20 March 2014 Accepted 24 March 2014 Available online 25 March 2014 Keywords: Resting heart rate Genome Wide Association Study Isolate populations Regression tree analysis MAML1 CANX Background: Recent studies suggested that resting heart rate (RHR) might be an independent predictor of cardio- vascular mortality and morbidity. Nonetheless, the interrelation between RHR and cardiovascular diseases is not clear. In order to resolve this puzzle, the importance of genetic determinants of RHR has been recently suggested, but it needs to be further investigated. Objective: The aim of this study was to estimate the contribution of common genetic variations on RHR using Ge- nome Wide Association Study. Methods: We performed a Genome Wide Association Study in an isolated population cohort of 1737 individuals, the Italian Network on Genetic Isolates — Friuli Venezia Giulia (INGI-FVG). Moreover, a haplotype analysis was performed. A regression tree analysis was run to highlight the effect of each haplotype combination on the phe- notype. Results: A significant level of association (p b 5 × 10 -8 ) was detected for Single Nucleotide Polymorphisms (SNPs) in two genes expressed in the heart: MAML1 and CANX. Founding that the three different variants of the haplotype, which encompass both genes, yielded a phenotypic correlation. Indeed, a haplotype in homozy- gosity is significantly associated with the lower quartile of RHR (RHR ≤ 58 bpm). Moreover no significant asso- ciation was found between cardiovascular risk factors and the different haplotype combinations. Conclusion: Mastermind-like 1 and Calnexin were found to be associated with RHR. We demonstrated a relation between a haplotype and the lower quartile of RHR in our populations. Our findings highlight that genetic deter- minants of RHR may be implicated in determining cardiovascular diseases and could allow a better risk stratification. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Several epidemiological studies reported a significant association be- tween resting heart rate (RHR) and cardiovascular mortality (Greenland et al., 1999; Tverdal et al., 2008). Renewed interest in this clinical variable has been elicited by recent observations, suggesting that high RHR is an independent predictor of cardiovascular mortality and morbidity (Diaz et al., 2005; Jouven et al., 2005). Moreover, high RHR has been highlighted as a possible risk factor for cancer and sudden death (Fox et al., 2007; Jouven et al., 2005). Despite this evidence, the complex interrelation be- tween RHR and cardiovascular disease is not completely understood. In particular, it is unclear whether high RHR is a true risk factor or it is merely an epiphenomenon of a common defect underlying a complex clinical condition (Singh et al., 1999). RHR is likely to be a complex trait, depend- ing on hereditary and environmental factors (Martin et al., 2004). The im- portance of the genetic background in RHR has been recently suggested (Eijgelsheim et al., 2010). Several studies based on candidate-gene ap- proach highlighted a significant genetic component for RHR; moreover genome-wide association studies (GWAS) have recently identified com- mon variations associated with RHR (den Hoed et al., 2013; Wilk et al., 2006). The clinical impact of these findings remains unknown; neverthe- less the identification of the genetic background of RHR could allow a bet- ter risk estimation in cardiovascular disease. The use of isolated populations reduces heterogeneity of complex and/or quantitative traits, and proved to be very useful in identifying polymorphisms with relevant clinical impact (Arcos-Burgos and Muenke, 2002). These communities, owing to their origin by few founders, their isolation, a high rate of inbreeding and low immigration, have preserved homogeneous genomes over the centuries (Kristjansson et al., 2002; Thorgeirsson et al., 2003). Therefore, the general reduction of genetic and environmental variation, the availability of well-documented Gene 545 (2014) 170–174 Abbreviations: CANX, Calnexin; MAML1, mastermind like 1; BMI, bone mass index; RHR, resting heart rate; bpm, beats per minute; SNP, single nucleotide polymorphism; ECG, electrocardiogram; maf, minor allele frequency; SERCA, sarco(endo)plasmic reticu- lum Ca 2+ ATPase; FVG, Friuli Venezia Giulia. ⁎ Corresponding author at: via dell'Istria 65/1, Trieste, Italy. E-mail address: sheila.ulivi@burlo.trieste.it (S. Ulivi). http://dx.doi.org/10.1016/j.gene.2014.03.045 0378-1119/© 2014 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Gene journal homepage: www.elsevier.com/locate/gene