Purpose
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 such as CFH, C2, CFI, C9, and C3 as well as in DNA repair enzymes such as RAD51A, thus implicating these pathways in AMD pathogenesis. Altered mRNA and protein levels of immune molecules have been found in AMD lesions. 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 relevant genes with AMD.
Methods
Three independent sample sets of Caucasian subjects were used: two case-control studies from the National Eye Institute (NEI; 247 cases/162 controls) and a subset of the Age-Related Eye Disease Study (AREDS; 297 cases/193 controls) as well as a nested case-control sample from the Blue Mountains Eye Study (BMES; 54 cases/568 controls). Only late stage AMD cases (geographic atrophy or neovascular AMD) were analyzed. Extracted DNA was genotyped for SNPs in the 3’UTRs of IL17A, RAD51B, CX3CR1, and NLRP3 using Taqman SNP Genotyping Assay. Association analyses were performed using SVS Golden Helix Software version 7.7. Bioinformatic predictions for the effect of the SNP on microRNA binding were determined using miRNASNP_v2.
Results
We found an association between a 3’UTR SNP (rs7747909) in IL17A and AMD in the NEI sample set (OR = 1.73; 95% CI = 1.22 - 2.45; p = 0.002) but not in other tested genes. After correcting for age, smoking status, and gender, the results remained significant (p = 0.031). Bioinformatics predicted that miR-548s, miR-4480, and miR-6513-3p will bind tightly to the major allele at rs7747909 but not the minor allele, leading to decreased IL17A mRNA degradation in subjects with the minor allele. However, although the association direction was consistent in the AREDS and BMES replication groups, neither these samples alone nor combination of all 3 groups reached significance.
Conclusions
Although our data do not provide consistent evidence supporting a link between the IL17A 3’UTR SNP and AMD, possibly from heterogeneity within samples, the potential role for microRNAs in AMD pathogenesis and immune dysregulation warrants further study.
Keywords: 490 cytokines/chemokines •
412 age-related macular degeneration •
539 genetics