Genetic Factors for Glaucoma in the OHTS; Risk, Progression and Mechanism

摘要 青光眼是导致严重视力丧失的常见原因，其特征是视网膜神经节进行性丧失。 细胞。几项针对原发性开角型青光眼(POAG)的大型全基因组关联研究 到目前为止，已经发现了127个以上的危险因素基因。它们通过的机制 导致POAG的基因几乎完全未知。我们的建议旨在1)翻译这些风险因素基因 发现对患者和他们的医生有用的数据，以及2)确定风险的机制 因子基因会带来风险。 这项建议将利用先前GWAS研究的结果以及20年来无与伦比的 来自眼压治疗研究(OHTS)的前瞻性临床数据可发展为POAG风险 包括对患者和医生有用的临床和遗传风险因素的计算器(AIM1A)。 我们还将对OHTS队列进行关联研究，以确定快速反应的遗传风险因素 通过视野参数测量POAG的进展，并在爱荷华州当地队列中进行验证(AIM1B)。 识别与青光眼进展相关的基因具有巨大的个性化和指导性潜力 青光眼管理。 我们还将研究特定的青光眼风险等位基因的功能后果。 互补性技术。AIM2A将测试风险等位基因对基因表达和途径的影响 应用单细胞RNA测序技术(ScRNAseq)对人供眼进行基因分型研究。 基因分型的人供眼的免疫组织化学和ELISA法也将被用来确定效果。 风险等位基因对其编码的蛋白质的丰度和定位的影响。最后，在AIM2B中将使用BIT- STARR-SEQ定位青光眼基因座中与青光眼风险相关的特定变异(SNPs)。这些研究 将开始定义精确的分子步骤，这些步骤将特定遗传风险因素的存在联系在一起 一个人的基因组与青光眼的发展有关。 我们的建议将导致改进的工具，以确定患者的POAG风险或快速风险 POAG的恶化，可以很容易地以更好的诊断和预后的形式转移给临床医生 工具。我们的建议还将定义风险因素等位基因改变基因表达的具体机制 在关键组织(视网膜神经节细胞)，这将确定疾病机制和新的治疗靶点 促进有针对性的治疗的发展。我们的建议具有巨大的潜力来改善青光眼护理和 减少视力损失。

ABSTRACT Glaucoma is a common cause of severe vision loss, characterized by the progressive loss of retinal ganglion cells. Several large genome-wide association studies (GWAS) for primary open angle glaucoma (POAG) have been performed to date and have discovered over 127 risk factor genes. The mechanism by which these genes lead to POAG is almost completely unknown. Our proposal seeks to 1) translate these risk factor gene discoveries into useful data for patients and their doctors and 2) determine the mechanisms by which risk factor genes confer risk. This proposal will leverage the results of prior GWAS studies along with the unmatched, 20-years of prospective clinical data from the Ocular Hypertension Treatment Study (OHTS) to develop a POAG risk calculator that includes both clinical and genetic risk factors that will be useful to patients and doctors (AIM1A). We will also conduct association studies of the OHTS cohort to identify genetic risk factors for rapid progression of POAG as measured by visual field parameters, with validation in a local Iowa cohort (AIM1B). Identifying genes associated with progression of glaucoma has great potential to personalize and guide glaucoma management. We will also investigate the functional consequences of specific glaucoma risk alleles with a range of complementary technologies. AIM2A will test the effects of risk alleles on gene expression and pathways with studies of genotyped human donor eyes using single-cell RNA sequencing (scRNAseq). Immunohistochemistry and ELISA of genotyped human donor eyes will also be used to determine the effects of risk alleles on the abundance and localization of the proteins they encode. Finally, in AIM2B will use BiT- STARR-seq to locate the specific variants (SNPs) in glaucoma loci that confer risk for glaucoma. These studies will begin to define the precise molecular steps that connect the presence of specific genetic risk factors in one’s genome to the development of glaucoma. Our proposal will lead to improved tools for ascertainment of a patient’s risk for POAG or risk for rapid worsening of POAG that can be readily transferred to clinicians in the form of better diagnostic and prognostic tools. Our proposal will also define the specific mechanisms by which risk factor alleles alter gene expression in key tissues (retinal ganglion cells), which will identify disease mechanisms and new therapeutic targets to facilitate development of targeted treatments. Our proposal has great potential to improve glaucoma care and reduce vision loss.