Variation In The Lysyl Oxidase Gene (LOX) Is Associated With Keratoconus In Family-based And Case-control Studies

Abstract

Purpose: : Keratoconus (KC) is a bilateral non-inflammatory progressive corneal disorder with complex genetic inheritance. The Lysyl Oxidase gene (LOX) encodes an enzyme responsible for collagen cross-linking in the cornea. Collagen cross-linking is being utilized as a new treatment for KC. To determine whether LOX is a genetic determinant of the pathogenesis of KC, we performed a comprehensive analysis of the common variants in LOX using case-control samples and compared the results to the linkage scan results of families with KC.

Methods: : Individuals with KC were diagnosed using both clinical signs and videokeratography. Linkage was conducted in sib-pair families, with follow up association by Transmission Disequilibrium Test (TDT). Genotyping of the LOX SNPs was performed as part of a genome-wide association scan using Illumina’s CNV370-Quad beadchip and as a part of confirmation study using custom Illumina’s iSelect beadchip in two independent panels of case-control subjects, consisting of the 222 patients and 3324 controls, and 304 patients and 518 controls, respectively. Allelic testing for association was done under the additive model.

Results: : Our prior genome-wide linkage scan identified a locus at 5q23.2, overlapping the LOX gene. Further TDT analysis of SNPs in LOX identified preferentially untransmitted haplotype of SNPs rs3792803-rs10519694 located in the intron 4 of LOX to the affected family members (p=0.014) (Li, Tang, Rabinowitz ARVO 2008). Allelic testing for association of rs10519694 genotyping data from the first case-control panel replicated results of the family-based analysis (p=0.0001). Analysis of the second case-control panel provided further confirmation of the LOX involvement in the KC phenotype; however a stronger association signal was identified at a different SNP rs2956540 (p=0.002), also located in the intron 4 of LOX.

Conclusions: : Our results provide genetic evidence that common LOX variants lead to increased susceptibility to developing of KC.

Keywords: keratoconus • gene mapping • cornea: basic science