Abstract
Purpose :
African Americans (AA) have higher prevalence, earlier onset and more rapid progression of primary open angle glaucoma (POAG) compared to Caucasian Americans (CC). Genome-wide association studies have found significant associations between a common sequence variant located near Caveolin1/Caveolin2 (CAV1/CAV2) with POAG in CC. This prospective study evaluated expression of a caveolae-related gene, SDPR/Cavin2, in trabecular meshwork (TM) tissue from healthy cadaver donors and POAG surgical patients with a focus on racial background.
Methods :
The study was approved by the Institutional Review Board at Washington University. RNA sequencing (RNAseq) analysis evaluated differential gene expression among AA and CC POAG patients (40-80 years old) using trabeculectomy specimens. Fresh, healthy TM was collected from cadaver donor corneoscleral rims by precise laser microdissection to avoid contamination with adjacent tissues. Additional TM surgical specimens (trabeculectomy and goniotomy) from POAG patients were collected to evaluated SDPR/Cavin2 and other caveolar genes by qPCR. Immunohistochemical staining of healthy donor TM was performed for SDPR (rabbit polyclonal antibody) and CAV1 (mouse monoclonal antibody) expression. Comprehensive patient information was recorded including self-reported race, sex, age, POAG severity stage, medications, and surgical history. Spearman correlation matrix and multi-dimentsional scaling plots were applied for RNAseq analysis. Unpaired t-test was used for qPCR studies.
Results :
RNAseq analysis identified significantly reduced (by 5.6 log-fold) expression of SDPR/Cavin2 in AA (n=3) compared to CC (n=4) POAG TM. qPCR further confirmed significantly decreased SDPR/Cavin2 expression in AA POAG TM compared to CC (AA=11, CC=12, p=0.005). However, there was no significant difference in expression of SDPR/Cavin2 and other caveolar genes (CAV1, CAV2) in healthy TM (AA=8, CC=9). SDPR protein expression was localized in TM, Schlemm's canal (SC) and adjacent blood vessels. Specimens from AA cadaver donors showed markedly lower expression in corneoscleral and uveoscleral TM compared to CC, but preserved in SC and juxtacanalicular TM.
Conclusions :
Differential SDPR expression in a distinct pattern in the TM, particularly in AA with POAG, may indicate an important role of this protein in the pathogenesis of glaucoma by altering caveolar structures/functions leading to IOP elevation.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.