Csiszar, Katalin PhD

Research Overview

2010-2011 RMATRIX Collaboration Pilot Projects Program Awards

(Co-funded in Partnership with the RTRN Small Grant Awards Program)

Project Description

Abstract

Genetic Risk for Exfoliation Glaucoma in Pacific Islanders and Puerto Ricans

The overall goal of this multi-disciplinary, collaborative translational pilot project is to determine the prevalence of exfoliation glaucoma (XFG) in Pacific Islander and Puerto Rican XFG patient cohorts and determine linkage to allelic variants of the LOXL1 gene that have been recently recognized as major genetic risk factors for XFG. Glaucoma is a group of diseases that progressively damage the optic nerve and result in vision loss and is one of the leading causes of blindness. XFG, the most common type of secondary glaucoma, occurs in the context of a late onset systemic condition, exfoliation syndrome (XFS) characterized by the progressive deposition of fibrillar extracellular matrix (ECM) that in the eye, obstructs the outflow of aqueous humor. In genome-wide association studies the LOXL1 gene was found strongly associated with XFG, and the G153D allele identified as a major risk-associated allele. Ethnic differences have been also noted in the severity of XFG and frequency of LOXL1 alleles. However, no systematic clinical and genetic studies have been conducted in Pacific Islander or Hispanic XFG patients, even though high incidence and severe manifestation of XFG have been observed in these populations. Our hypothesis for this pilot project is that the varying prevalence and severity of XFG among diverse populations is affected by ethnic group-specific frequencies of high-risk alleles of the LOXL1 gene. Furthermore, that these risk-alleles determine altered LOXL1 functions leading to aberrant ECM and the development of XFG. To test these hypotheses we propose the following specific aims: Aim 1. Establish the prevalence and severity of XFG in Hawaiian Filipino-American and Puerto Rican glaucoma cohorts using concise XFG diagnostic criteria. Aim 2. Determine in these study cohorts the occurrence and frequencies of LOXL1 risk alleles G153D and R141L and establish linkage of these alleles to the XFG phenotype. Aim 3. In order to uncover LOXL1-associated and potentially ethnicity-specific XFG pathomechanism(s), establish a cell model using panels of selected XFG patient-derived cells containing LOXL1 risk-alleles together with cells from appropriate unaffected and genotyped controls. RELEVANCE: Results from this study will determine the involvement of the high-risk alleles of the LOXL1 gene in the development of exfoliative glaucoma (XFG) in understudied Pacific Islander and Puerto Rican cohorts that have a high prevalence and severe clinical manifestation of XFG. New data from this project will serve as the foundation for genetic epidemiological studies aimed at improved ethnic-specific diagnosis and therapy.