Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility

Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with known sequence variants, we are able to determine that the intraocular pressure-lowering effect of pregabalin is dependent on the Cacna2d1 haplotype. Using human genome-wide association study (GWAS) data, evidence for association of a CACNA2D1 single-nucleotide polymorphism and primary open angle glaucoma is found. Importantly, these results demonstrate that our systems genetics approach represents an efficient method to identify genetic variation that can guide the selection of therapeutic targets

Repeatability of nerve fiber layer thickness measurements in patients with glaucoma and without glaucoma using spectral-domain and time-domain OCT

BACKGROUND: The aim of this work is to assess the repeatability of spectral-domain-OCT (SD-OCT) retinal nerve fiber layer thickness (RNFL) thickness measurements in a non-glaucoma group and patients with glaucoma and to compare these results to conventional time-domain-OCT (TD-OCT). METHODS: In a prospective, comparative, observational case-control study, 50 eyes of 25 non-glaucoma and 22 eyes of 11 patients with primary open angle glaucoma (POAG) were included. SD-OCT and TD-OCT circle scans were centered on the optic disc. In each eye, OCT scans were performed three times by two independent observers. RNFL thickness was measured in four quadrants around the optic disc. In addition, the overall mean RNFL thickness was assessed. Intraclass correlation coefficients (ICC) and coefficients of variation (COV) were calculated. Inter-observer and inter-OCT repeatability was visualized by using Bland-Altman analysis. RESULTS: Intra-observer repeatability for TD- OCT was good with an ICC(mean RNFL thickness) of 0.939 in non-glaucomas and 0.980 in glaucomatous eyes. For SD-OCT, intra-observer repeatability was higher with an ICC of 0.989 for non-glaucomas and 0.997 for glaucomatous eyes. COVs for TD-OCT ranged from 2.9-7.7% in non-glaucomas and from 6.0-13.3% in glaucoma patients. COVs for SD-OCT ranged from 0.3-1% in non-glaucomas and from 0.9-2.3% in glaucomatous eyes. COVs were influenced by various factors. In the glaucoma group, COVs were significantly higher (p < 0.001) compared to the non-glaucoma group. COVs increased by a mean of 5.1% when TD-OCT was used instead of SD-OCT (p < 0.001). CONCLUSIONS: SD-OCT RNFL thickness measurements in healthy volunteers and glaucoma patients showed good intra- and inter-observer repeatability. Especially in glaucomatous eyes, repeatability of SD-OCT was superior to TD-OCT

Rates of retinal nerve fibre layer thickness change in glaucoma patients and control subjects

PURPOSE: To examine the rates of retinal nerve fibre layer thickness (RNFLT) change in glaucoma patients and healthy, age-similar control subjects with three techniques: scanning laser polarimetry with variable corneal compensation (VCC) and enhanced corneal compensation (ECC), and time-domain optical coherence tomography (OCT). METHODS: Sixty-one patients and thirty-three controls were examined with each technique and with standard automated perimetry (SAP) every 6 months. Rates of global RNFLT change and SAP mean deviation (MD) change were estimated with linear mixed-effects models. RESULTS: The median (interquartile range) baseline age was 64.4 (58.2, 71.0) years for patients and 62.4 (56.3, 70.1) years for controls (P=0.56). There was a median of seven examinations over 3.1 years for patients and six examinations in 3.0 years for controls. Baseline visual field MD and RNFLT for all imaging modalities were significantly lower (P<0.01) in patients compared with controls. Rates of RNFLT change were not significantly different between patients and controls (P≥0.19). Mean rates of VCC-measured RNFLT change were −0.18 and −0.37 μm per year in patients and controls, whereas the respective figures for ECC and OCT were −0.13 and −0.31 μm per year, and 0.04 and 0.61 μm per year. Mean rates of MD change were −0.20 and 0.03 dB per year in patients and controls, respectively (P=0.01). CONCLUSION: Rates of RNFLT change in glaucoma patients were not statistically different from control subjects for any modality. A significantly negative rate of MD change in patients suggests a genuine, continued deterioration in these patients not reflected by RNFLT changes