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

Mohsen Ghanbari, OH Franco Duran, Hans de Looper, Bert Hofman, Stefan Erkeland, Abbas Dehghan

Research output: Contribution to journalArticleAcademic

59 Citations (Scopus)

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 11067 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.
Original languageUndefined/Unknown
Pages (from-to)473-486
Number of pages14
JournalCirculation-cardiovascular genetics
Volume8
Issue number3
DOIs
Publication statusPublished - 2015

Research programs

  • EMC MM-02-41-03
  • EMC NIHES-01-64-01

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