Functional Association of Fibulin 5 (FBLN5) Gene in Primary Open Angle Glaucoma

Abstract

Purpose: : The extracellular matrix proteins (ECM) in the trabecular meshwork (TM) have been widely involved in the regulation of intraocular pressure (IOP) in primary open angle glaucoma (POAG) through constant ECM turnover and remodelling. Herein, we provide a functional analysis of an ECM gene, fibulin5 (FBLN5) that exhibited strong association with primary open angle glaucoma (POAG).

Methods: : Two hundred SNPs covering the entire 22 ECM genes were screened by customized genotyping in a large cohort of POAG cases with elevated IOP (n=250) and normal controls with senile cataract (n=250) based on preset inclusion criteria. On confirmation of genetic association, the ECM gene was further assayed in the aqueous humor of a subset of these subjects by ELISA and further validated by western blotting. The localization of this protein in the TM and other ocular tissues of cadaver eyes were undertaken by immunohistochemistry.

Results: : Strong associations were observed in 2 intronic variants, rs2244158 (p=3.01x10^-4) and rs2160079 (p=3.13x10^-4) of FBLN5 that withstood Bonferroni correction (=0.0002) and also generated a risk (G-G) haplotype (p=2.11x10^-4). The genetic data was further validated through resequencing in an additional cohort. There was a significant difference in the expression of FBLN5 in the aqueous of patients compared to controls as seen in ELISA (p<0.05) and also on western blot. Immunohistochemistry revealed that FBLN5 was largely localized largely in the retina followed by cornea and to a relatively lesser extent in the TM.

Conclusions: : This study provides functional genomics data on a novel gene, FBLN5 that may be involved in POAG.

Keywords: genetics • extracellular matrix • aqueous