title: Genetic variants in microRNAs and their binding sites within gene 3'UTRs associate with susceptibility to age-related macular degeneration.
abstract: Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, is a complex disease that results from multiple genetic and environmental factors. MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally regulate target mRNAs and are frequently implicated in human diseases. Here, we investigated the association of genetic variants in miRNAs and miRNA-binding sites within gene 3'-untranslated regions (3'UTRs) with AMD using data from the largest AMD genome-wide association study. First, we identified three variants in miRNAs significantly associated with AMD. These include rs2168518:G>A in the miR-4513 seed sequence, rs41292412:C>T in pre-miR-122/miR-3591, and rs4351242:C>T in the terminal-loop of pre-miR-3135b. We demonstrated that these variants reduce expression levels of the mature miRNAs in vitro and pointed the target genes that may mediate downstream effects of these miRNAs in AMD. Second, we identified 54 variants (in 31 genes) in miRNA-binding sites associated with AMD. Based on stringent prioritization criteria, we highlighted the variants that are more likely to have an impact on the miRNA-target interactions. Further, we selected rs4151672:C>T within the CFB 3'UTR and experimentally showed that while miR-210-5p downregulates expression of CFB, the variant decreases miR-210-5p-mediated repression of CFB. Together, our findings support the notion that miRNAs may play a role in AMD.
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.identifier: 0000-0002-9476-7143
authors.initials: M
authors.lastname: Ghanbari
authors.affiliation: Department of Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Erkeland
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.|Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Colijn
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Franco
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.|Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.|Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, The Netherlands.|Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Caroline C W
authors.initials: CCW
authors.lastname: Klaver
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.|Department of Ophthalmology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Magda A
authors.initials: MA
authors.lastname: Meester-Smoor
mesh_terms: D020413:3' Untranslated Regions; D000072283:A549 Cells; D000465:Algorithms; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D003176:Complement C3 / Q000235:genetics; D011415:Complement Factor B / Q000235:genetics; D019295:Computational Biology; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006239:Haplotypes; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D020413:3' Untranslated Regions; D003176:Complement C3; C543800:MIRN210 microRNA, human; D035683:MicroRNAs; D011415:Complement Factor B
keywords: AMD; Age-related macular degeneration; GWAS; miRNA genetic variants; miRNA-binding site; microRNA