Variation in the lysyl oxidase (LOX) gene is associated with keratoconus in family-based and case-control studies.
OBJECTIVE
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.
Regenerative Medicine Institute, Ophthalmology Research, Department of Surgery, Division of Surgical Research, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Yelena
Y
Bykhovskaya
Xiaohui
X
Li
Irina
I
Epifantseva
Talin
T
Haritunians
David
D
Siscovick
Anthony
A
Aldave
Loretta
L
Szczotka-Flynn
Sudha K
SK
Iyengar
Kent D
KD
Taylor
Jerome I
JI
Rotter
Yaron S
YS
Rabinowitz
D016022:Case-Control Studies; D003315:Cornea / Q000201:enzymology* / Q000473:pathology; D019781:Corneal Topography; D004247:DNA / Q000032:analysis*; D005190:Family; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007640:Keratoconus / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D011110:Polymorphism, Genetic; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics* / Q000378:metabolism
D004247:DNA; D008249:Protein-Lysine 6-Oxidase