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Invest Ophthalmol Vis Sci. 2012 Jun 28;53(7):4152-7. doi: 10.1167/iovs.11-9268.

Variation in the lysyl oxidase (LOX) gene is associated with keratoconus in family-based and case-control studies.

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  • 1Regenerative Medicine Institute, Ophthalmology Research, Department of Surgery, Division of Surgical Research, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.

Abstract

PURPOSE:

Keratoconus is a bilateral noninflammatory progressive corneal disorder with complex genetic inheritance and a common cause for cornea transplantation in young adults. A genomewide linkage scan in keratoconus families identified a locus at 5q23.2, overlapping the gene coding for the lysyl oxidase (LOX). LOX encodes an enzyme responsible for collagen cross-linking in a variety of tissues including the cornea. Corneal collagen cross-linking with long-wave ultraviolet light and riboflavin is a promising new treatment for keratoconus. To determine whether LOX is a genetic determinant of the pathogenesis of keratoconus, we analyzed association results of LOX polymorphisms in two independent case-control samples and in keratoconus families.

METHODS:

Association results were analyzed of single-nucleotide polymorphisms (SNPs) in the LOX gene from a Genome-Wide Association Study (GWAS) investigation in two independent panels of patients with keratoconus and controls and in keratoconus families.

RESULTS:

Evidence of association was found at SNPs rs10519694 and rs2956540 located in intron 4 of LOX in the GWAS discovery case-control panel with P values of 2.3×10(-3) and 7×10(-3), respectively. The same two SNPs were found to be associated with keratoconus by family-based association testing with P values of 2.7×10(-3) and 7.7×10(-4), respectively. Meta P values of 4.0×10(-5) and 4.0×10(-7) were calculated for SNPs rs10519694 and rs2956540 by analyzing case-control and family samples simultaneously. Sequencing of LOX exons in a subset of keratoconus patients identified two polymorphisms, rs1800449 and rs2288393, located in LOX transcripts I and II, associated with keratoconus in case-control and family samples with a meta P value of 0.02.

CONCLUSIONS:

Results provided strong genetic evidence that LOX variants lead to increased susceptibility to developing of keratoconus.

PMID:
22661479
[PubMed - indexed for MEDLINE]
PMCID:
PMC3760233
Free PMC Article
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