Age-related macular degeneration (AMD) is a complex neurodegenerative disease and is the leading cause of blindness in the aging community. AMD progresses, has an early and intermediate stages (both dry and two late stages, neovascular and geographic atrophy (GA). It is the late stages that are responsible for the majority of visual impairment and blindness. Available medicines are directed against the less common wet form and do not cure or reverse vision loss. Therefore, it is imperative to identify preventive and therapeutic targets. As the mechanism for AMD is unclear, one, way is to interrogate well characterized disease affected tissue in the appropriate geographic region that is the macular neural retina and macular retina pigment epithelium (RPE)/choroid. We investigated differential gene expression (DEG) across the clinical stages of AMD in the macula of the primary affected tissue compared to well characterized normal using a standardized published protocol (Owen et al., 2019). Donor eyes (n=27) were Caucasian with an age range of 60-94 and 63% were male, and tissue from the macula RPE/choroid and macula neural retina were taken from the same eye. Donor eyes were recovered within 6 hours post mortem interval time and phenotyped by ophthalmic experts using multi modal imaging (fundus photos and SD-OCT) to ensure maximal preservation of RNA quality and accuracy of diagnosis. Utilizing DESeq2, followed PCA, Benjamini Hockberg Analysis to control for the FDR, Bonferonni for the paired comparisons: a total of 26,650 genes were expressed in the macula RPE/choroid and/or macula retina with 1,204 genes found to be statistically different between neovascular AMD and normal eyes, 40 genes found between intermediate AMD (AREDS3) and normal eyes, and 1,194 genes found between intermediate AMD and neovascular AMD. A comparison of the DEGs from intermediate AMD with normal eyes and neovascular AMD with normal eyes showed an overlap of six genes: MTRNR2L1, CLEC2L, CCM2L, CYP4X1, GLDN, and SMAD7. The top pathways of DEGs identified through Ingenuity Pathway Analysis (IPA) for intermediate AMD with normal eyes were the interferon signaling and Th1 and Th2 activation pathways, while for neovascular AMD with normal eyes it was the phototransduction and SNARE signaling pathways. Allele specific expression (ASE) revealed known coding regions in previously reported GWAS loci demonstrated that significant ASE for C3 rs2230199 and CFH rs1061170 occurred in the macula RPE/choroid for normal, and intermediate AMD while ASE for CFH rs1061147 occurred in the macula RPE/choroid for normal, and intermediate and neovascular AMD. An investigation of previously identified GWAS loci (Fritsche et al., 2016) revealed that 76% of the 34 loci previously identified were significantly differentially expressed between normal macular RPE/choroid and macular neural retina, with 77% of these identified loci expressed higher in the RPE. Pathway analysis was conducted on these DEGs to reveal the involvement of pathways previously implicated in AMD as well as being the first study to assess ASE across the clinical spectrum of AMD. By utilizing a systems biology approach that integrates clinical, experimental, genomic, and phenotypic data to aid in the understanding of the pathogenesis of AMD.
Glaucoma is the leading cause of irreversible blindness, affecting 76 million globally. It is characterized by irreversible damage to the optic nerve. Pharmacotherapy manages intraocular pressure (IOP) and slows disease progression. However, non-adherence to glaucoma medications remains problematic, with 41–71% of patients being non-adherent to their prescribed medication. Despite substantial investment in research, clinical effort, and patient education protocols, non-adherence remains high. Therefore, we aimed to determine if there is a substantive genetic component behind patients’ glaucoma medication non-adherence. We assessed glaucoma medication non-adherence with prescription refill data from the Marshfield Clinic Healthcare System’s pharmacy dispensing database. Two standard measures were calculated: the medication possession ratio (MPR) and the proportion of days covered (PDC). Non-adherence on each metric was defined as less than 80% medication coverage over 12 months. Genotyping was done using the Illumina HumanCoreExome BeadChip in addition to exome sequencing on the 230 patients (1) to calculate the heritability of glaucoma medication non-adherence and (2) to identify SNPs and/or coding variants in genes associated with medication non-adherence. Ingenuity pathway analysis (IPA) was utilized to derive biological meaning from any significant genes in aggregate. Over 12 months, 59% of patients were found to be non-adherent as measured by the MPR80, and 67% were non-adherent as measured by the PDC80. Genome-wide complex trait analysis (GCTA) suggested that 57% (MPR80) and 48% (PDC80) of glaucoma medication non-adherence could be attributed to a genetic component. Missense mutations in TTC28, KIAA1731, ADAMTS5, OR2W3, OR10A6, SAXO2, KCTD18, CHCHD6, and UPK1A were all found to be significantly associated with glaucoma medication non-adherence by whole exome sequencing after Bonferroni correction (p < 10−3) (PDC80). While missense mutations in TINAG, CHCHD6, GSTZ1, and SEMA4G were found to be significantly associated with medication non-adherence by whole exome sequencing after Bonferroni correction (p < 10−3) (MPR80). The same coding SNP in CHCHD6 which functions in Alzheimer’s disease pathophysiology was significant by both measures and increased risk for glaucoma medication non-adherence by three-fold (95% CI, 1.62–5.8). Although our study was underpowered for genome-wide significance, SNP rs6474264 within ZMAT4 (p = 5.54 × 10–6) was found to be nominally significant, with a decreased risk for glaucoma medication non-adherence (OR, 0.22; 95% CI, 0.11–0.42)). IPA demonstrated significant overlap, utilizing, both standard measures including opioid signaling, drug metabolism, and synaptogenesis signaling. CREB signaling in neurons (which is associated with enhancing the baseline firing rate for the formation of long-term potentiation in nerve fibers) was shown to have protective associations. Our results suggest a substantial heritable genetic component to glaucoma medication non-adherence (47–58%). This finding is in line with genetic studies of other conditions with a psychiatric component (e.g., post-traumatic stress disorder (PTSD) or alcohol dependence). Our findings suggest both risk and protective statistically significant genes/pathways underlying glaucoma medication non-adherence for the first time. Further studies investigating more diverse populations with larger sample sizes are needed to validate these findings.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.