Genetic Variations in MicroRNA-Binding Sites Affect MicroRNA-Mediated Regulation of Several Genes Associated With Cardio-metabolic Phenotypes

Mohsen Ghanbari; Oscar H Franco; Hans W J de Looper; Albert Hofman; Stefan J Erkeland; Abbas Dehghan

doi:10.1161/CIRCGENETICS.114.000968

Genetic Variations in MicroRNA-Binding Sites Affect MicroRNA-Mediated Regulation of Several Genes Associated With Cardio-metabolic Phenotypes

Circ Cardiovasc Genet. 2015 Jun;8(3):473-86. doi: 10.1161/CIRCGENETICS.114.000968. Epub 2015 Mar 26.

Authors

Mohsen Ghanbari¹, Oscar H Franco¹, Hans W J de Looper¹, Albert Hofman¹, Stefan J Erkeland¹, Abbas Dehghan²

Affiliations

¹ From the Department of Epidemiology (M.G., O.H.F., A.H., A.D.) and Department of Hematology, Cancer Institute (H.d.L., S.E.), Erasmus University Medical Center, Rotterdam, The Netherlands; and Department of Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran (M.G.).
² From the Department of Epidemiology (M.G., O.H.F., A.H., A.D.) and Department of Hematology, Cancer Institute (H.d.L., S.E.), Erasmus University Medical Center, Rotterdam, The Netherlands; and Department of Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran (M.G.). a.dehghan@erasmusmc.nl.

PMID: 25814643
DOI: 10.1161/CIRCGENETICS.114.000968

Abstract

Background: Genome-wide association studies enabled us to discover a large number of variants and genomic loci contributing to cardiovascular and metabolic disorders. However, because the vast majority of the identified variants are thought to merely be proxies for other functional variants, the causal mechanisms remain to be elucidated. We hypothesized that the part of the functional variants involved in deregulating cardiometabolic genes is located in microRNA (miRNA)-binding sites.

Methods and results: Using the largest genome-wide association studies available on glycemic indices, lipid traits, anthropometric measures, blood pressure, coronary artery diseases, and type 2 diabetes mellitus, we identified 11,067 variants that are associated with cardiometabolic phenotypes. Of these, 230 variants are located within miRNA-binding sites in the 3'-untranslated region of 155 cardiometabolic genes. Thirty-seven of 230 variants were found to fulfill our predefined criteria for being functional in their genomic loci. Ten variants were subsequently selected for experimental validation based on genome-wide association studies results, expression quantitative trait loci (eQTL) analyses, and coexpression of their host genes and regulatory miRNAs in relevant tissues. Luciferase reporter assays revealed an allele-specific regulation of genes hosting the variants by miRNAs. These cotransfection experiments showed that rs174545 (FADS1:miR-181a-2), rs1059611 (LPL:miR-136), rs13702 (LPL:miR-410), rs1046875 (FN3KRP:miR-34a), rs7956 (MKRN2:miR-154), rs3217992 (CDKN2B:miR-138-2-3p), and rs11735092 (HSD17B13:miR-375) decrease or abrogate miRNA-dependent regulation of the genes. Conversely, 2 variants, rs6857 (PVRL2:miR-320e) and rs907091 (IKZF3:miR-326), were shown to enhance the activity of miRNAs on their host genes.

Conclusions: We provide evidence for a model in which polymorphisms in miRNA-binding sites can both positively and negatively affect miRNA-mediated regulation of cardiometabolic genes.

Keywords: Genome-Wide Association Study; cardiovascular diseases; genetic variation; microRNASNPs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions
Alleles
Binding Sites
Blood Pressure / genetics
Coronary Artery Disease / genetics
Coronary Artery Disease / pathology
Delta-5 Fatty Acid Desaturase
Diabetes Mellitus, Type 2 / genetics
Diabetes Mellitus, Type 2 / pathology
Genetic Variation*
Genome-Wide Association Study*
Humans
MicroRNAs / genetics
MicroRNAs / metabolism*
Myocardium / metabolism
Phenotype
Polymorphism, Single Nucleotide
Quantitative Trait Loci

Substances

3' Untranslated Regions
Delta-5 Fatty Acid Desaturase
MicroRNAs
FADS1 protein, human