Identification of Candidate Regulatory Variants in Exfoliation Glaucoma

Abstract

Purpose: : Exfoliation glaucoma (XFG) is the most common identifiable form of open-angle glaucoma in the world. XFG is defined by the production and extrusion of fibrillar extracellular proteins by multiple tissues within the eye and systemically. It is theorized that abnormal protein aggregates impair function of the trabecular meshwork which causes intraocular pressure elevation and subsequent glaucomatous optic nerve damage. Genetic association studies have implicated the role of LOXL1 in XFG. However, functional variants have not been identified to date. The purpose of this study is to identify potential regulatory variants in the LOXL1 locus and to examine their genetic associations with XFG in multiple populations.

Methods: : This study utilized two case-control XFG datasets, a Caucasian cohort (90 cases and 1030 controls) and a black South African cohort (103 XFG cases and 136 controls). The Sanger method was used to sequence the complete genomic region of LOXL1 including 10kb of the promoter region in 48 cases and 48 controls in the South African dataset. The identified sequence variants were compared between cases and controls in South African samples for genetic association. Candidate variants were genotyped in both populations, using TaqMan-based allelic discrimination assays. Logistic regression was performed to test the genetic association of these variants using additive models.

Results: : Over 100 sequence variants were identified within the genomic region sequenced in the black South African cases and controls. The strongest associations were located in the boundary of exon 1 and intron 1. Nine candidate variants were selected for further analysis in the entire Caucasian and South African datasets. All nine variants were significantly associated with XFG in both Caucasian and black South African populations with p values as small as 2x10^-14. However, except for 2 SNPs, rs1992314 and rs2028387, all XFG risk alleles were reversed between Caucasians and South Africans. These two variants showed the same risk allele in both study populations. Thus, these two variants in intron 1 may play a regulatory role in LOXL1 expression.

Conclusions: : We have performed fine mapping to identify candidate functional variants in the LOXL1 region for XFG. We have identified two potential regulatory variants that are associated with XFG in both Caucasians and black South Africans.

Keywords: candidate gene analysis • genetics • gene mapping