Major LOXL1 Risk Allele is Reversed in a South African XFG Population

Abstract

Purpose: : To investigate whether variants in the lysyl oxidase-like 1 (LOXL1) gene are associated with pseudoexfoliation glaucoma (XFG) and primary open-angle glaucoma (POAG) in an African population from South Africa.

Methods: : Individuals with XFG or POAG were identified using standard clinical examination techniques. Fifty individuals were collected for each of the three groups: XFG, POAG, and normal controls. The complete coding region of the LOXL1 gene was sequenced using PCR-based Sanger method with an ABI 3730 capillary sequencer (Applied BioSystems). The allele frequencies of the identified sequence variants were compared between XFG or POAG and controls using Fisher’s exact test or Chi-square test.

Results: : We identified several coding variants in the LOXL1 gene, including rs3825942 and rs1048661. The allele frequencies of both rs3825942 and rs1048661 differed significantly between the XFG and control subjects from South Africa (p= 6.7x10-12 and 1.6x10-4 respectively, two-tailed Fisher’s Exact Probability Test). As in other populations, G is the risk allele for rs1048661 (encoding arginine); however, the A allele of rs3825942 (encoding aspartic acid) is associated with risk in this South African population, in sharp contrast to the G allele (encoding glycine) reported in multiple other populations. There was no significant difference in the allele frequencies of coding variants in the LOXL1 gene between POAG and control subjects.

Conclusions: : This represents the first genetic association study of LOXL1 in an African population with XFG. We have confirmed the association between variants of LOXL1 and XFG. To date, the G allele of the major susceptibility variant rs3825942 has consistently been shown in multiple populations to increase the risk of XFG. Surprisingly, we have found a strong association with the opposite allele in the South African population. This suggests that other as yet unknown variants of LOXL1 contribute to the genetic risk of XFG.

Keywords: candidate gene analysis