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Yelena Bykhovskaya, Xiaohui Li, Talin Haritunians, David Siscovick, Anthony Aldave, Loretta Szczotka-Flynn, Sudha K. Iyengar, Jerome I. Rotter, Yaron S. Rabinowitz; Variation In The Lysyl Oxidase Gene (LOX) Is Associated With Keratoconus In Family-based And Case-control Studies. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3291.
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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.
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.
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.
Our results provide genetic evidence that common LOX variants lead to increased susceptibility to developing of KC.
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