title: A genetic variant in the seed region of miR-4513 shows pleiotropic effects on lipid and glucose homeostasis, blood pressure, and coronary artery disease.
abstract: MicroRNAs (miRNA) play a crucial role in the regulation of diverse biological processes by post-transcriptional modulation of gene expression. Genetic polymorphisms in miRNA-related genes can potentially contribute to a wide range of phenotypes. The effect of such variants on cardiometabolic diseases has not yet been defined. We systematically investigated the association of genetic variants in the seed region of miRNAs with cardiometabolic phenotypes, using the thus far largest genome-wide association studies on 17 cardiometabolic traits/diseases. We found that rs2168518:G>A, a seed region variant of miR-4513, associates with fasting glucose, low-density lipoprotein-cholesterol, total cholesterol, systolic and diastolic blood pressure, and risk of coronary artery disease. We experimentally showed that miR-4513 expression is significantly reduced in the presence of the rs2168518 mutant allele. We sought to identify miR-4513 target genes that may mediate these associations and revealed five genes (PCSK1, BNC2, MTMR3, ANK3, and GOSR2) through which these effects might be taking place. Using luciferase reporter assays, we validated GOSR2 as a target of miR-4513 and further demonstrated that the miRNA-mediated regulation of this gene is changed by rs2168518. Our findings indicate a pleiotropic effect of miR-4513 on cardiometabolic phenotypes and may improve our understanding of the pathophysiology of cardiometabolic diseases.
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Ghanbari
authors.forename: Paul S
authors.initials: PS
authors.lastname: de Vries
authors.forename: Hans
authors.initials: H
authors.lastname: de Looper
authors.forename: Marjolein J
authors.initials: MJ
authors.lastname: Peters
authors.forename: Claudia
authors.initials: C
authors.lastname: Schurmann
authors.forename: Hanieh
authors.initials: H
authors.lastname: Yaghootkar
authors.forename: Marcus
authors.initials: M
authors.lastname: Dörr
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Joyce B J
authors.initials: JB
authors.lastname: van Meurs
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Erkeland
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Franco
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
mesh_terms: D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism*; D001794:Blood Pressure / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics*; D017931:DNA Primers; D055106:Genome-Wide Association Study; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D050356:Lipid Metabolism; D035683:MicroRNAs / Q000235:genetics*; D011110:Polymorphism, Genetic; D040641:Quantitative Trait Loci
chemical_list: D001786:Blood Glucose; D017931:DNA Primers; C000599249:MIRN-4513 microRNA, human; D035683:MicroRNAs
keywords: cardiometabolic phenotypes; miRNA polymorphism; miRNA seed region