title: Functional single nucleotide polymorphism in IL-17A 3' untranslated region is targeted by miR-4480 in vitro and may be associated with age-related macular degeneration.
abstract: Age-related macular degeneration (AMD) is a leading cause of irreversible central vision loss in the elderly. Genetic factors contributing to AMD include single nucleotide polymorphisms (SNPs) in immune-related genes including CFH, C2, CFI, C9, and C3, thus implicating these pathways in AMD pathogenesis. MicroRNAs (miRNAs) are powerful regulators of gene expression and execute this function by binding to the 3' untranslated region (3'UTR) of target mRNAs, leading to mRNA degradation. In this study, we searched for the possible association of SNPs in the 3'UTR region of IL-17A, a gene implicated in AMD pathogenesis without any previous SNP association with AMD. Using two independent sample cohorts of Caucasian subjects, six SNPs in the IL-17A 3'-UTR were selected for genotyping based on bioinformatic predictions of the SNP effect on microRNA binding. The SNP rs7747909 was found to be associated with AMD (P < 0.05) in the NEI cohort, using a dominant model logistic regression. Luciferase reporter gene assays and RNA electrophoretic mobility shift assays were performed using ARPE-19 cells to confirm the preferential binding of microRNAs to the major allele of the SNP. Our findings support the hypothesis that microRNA-mediated gene dysregulation may play a role in the pathogenesis of AMD.
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Popp
authors.affiliation: US Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas.
authors.forename: Dianke
authors.initials: D
authors.lastname: Yu
authors.affiliation: US Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas.
authors.forename: Bridgett
authors.initials: B
authors.lastname: Green
authors.affiliation: Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Emily Y
authors.initials: EY
authors.lastname: Chew
authors.affiliation: US Food and Drug Administration, National Center for Toxicological Research, Jefferson, Arkansas.
authors.forename: Baitang
authors.initials: B
authors.lastname: Ning
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jingsheng
authors.initials: J
authors.lastname: Tuo
mesh_terms: D020413:3' Untranslated Regions; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D004843:Epistasis, Genetic; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D020381:Interleukin-17 / Q000737:chemistry / Q000235:genetics*; D015810:Linkage Disequilibrium; D008268:Macular Degeneration / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D034622:RNA Interference; D012306:Risk
chemical_list: D020413:3' Untranslated Regions; C508717:IL17A protein, human; D020381:Interleukin-17; C000607935:MIRN-4480 microRNA, human; D035683:MicroRNAs
keywords: IL-17A; SNPs; age-related macular degeneration; epigenetics; genetics; inflammation; microRNA