Elucidating novel mechanisms for glucocorticoid-induced ocular hypertension

项目总结/文摘

Project Summary/Abstract Background Information and Relevance: Glucocorticoids (GC) are widely used in ophthalmology and in medicine in general. GC-induced ocular hypertension (OHTN) is a common complication that can be potentially blinding. The rate of this complication for GC injected intravitreally varies between 28-34% depending on the formulation injected. This complication's risk factors are not well understood but there is long-standing evidence that genetic factors play a role. Few genetic studies have been undertaken to identify the implicated variants and no consistent findings have been identified. Hypotheses: Genetic susceptibility to GC-induced OHTN is due to both common and rare variation, and associated variants are more likely to be found in genes with transcripts altered by exposure to GC as well as genes that have glucocorticoid response elements (GREs) or have been associated with primary open angle glaucoma (POAG) or intraocular pressure (IOP). Specific Objectives: 1.To characterize the GC transcriptome in human trabecular meshwork (TM) cells and Schlemm's canal endothelial (SCE) cells. 2. To perform genome-wide genotyping and whole exome sequencing (WES) on 1086 patients with intravitreal GC injection exposure. 3. To identify common and rare genetic variants in both coding and non-coding regions that are associated with GC-induced IOP elevation. Methods: We will expose human TM and SCE cells to dexamethasone as well as media controls and perform RNA sequencing to identify genes that are transcriptionally regulated by GCs. We will perform genome-wide genotyping and WES on 1086 patients who have received an intravitreal GC injection and have serial IOP measurements. Genotyping and WES will be performed as a cost efficient approach for the analyses proposed. We will examine the GC-induced OHTN both as a quantitative trait of change in IOP adjusted for baseline IOP and a dichotomous trait (GC responders vs. non-responders). We will execute genome-wide association and WES analyses as well as targeted analyses. We will target variants in genes that are transcriptionally regulated by GCs as identified in Aim 1, in loci with GREs, and in genes previously associated with IOP or POAG. We will examine rare variants in the same loci for association with disease outcome using aggregate and burden tests. We will enroll a replication cohort of 530 participants and perform targeted sequencing to follow up suggestive or significant findings from the discovery analyses. We will also perform in silico replication of these findings in three external cohorts with existing genomic data. Implications: If genes associated with GC-induced IOP rise are identified, they will not only provide insights into this complication's pathophysiology, but also into POAG mechanisms more broadly. Our findings will have implications for clinical management of patients on GC. If we are able to identify patients at risk of GC-induced OHTN, we may avoid morbidity by using alternative therapies or increasing surveillance while patients receive GC.