Variation in the Lysyl Oxidase (LOX) Gene Is Associated with Keratoconus in Family-Based and Case-Control Studies

Regenerative Medicine Institute, Ophthalmology Research, Department of Surgery, Division of Surgical Research, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Investigative ophthalmology & visual science (Impact Factor: 3.4). 06/2012; 53(7):4152-7. DOI: 10.1167/iovs.11-9268
Source: PubMed


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

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Available from: Jerome I Rotter, Oct 13, 2015
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    • "Artificial collagen fibre cross-linking following riboflavin and UV light exposure is a procedure currently being tested for the treatment of keratoconus and therefore this gene may have therapeutic implications [106]. Two SNPs (rs10519694 and rs2956540) in LOX showing nominal genome-wide significance were associated with keratoconus by family-based association testing that were also found to be significantly associated with keratoconus in case-control cohorts [107]. Other studies so far have provided conflicting evidence for the role of LOX in keratoconus [51, 108]. "
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    ABSTRACT: Keratoconus is a progressive thinning and anterior protrusion of the cornea that results in steepening and distortion of the cornea, altered refractive powers, and reduced vision. Keratoconus has a complex multifactorial etiology, with environmental, behavioral, and multiple genetic components contributing to the disease pathophysiology. Using genome-wide and candidate gene approaches several genomic loci and genes have been identified that highlight the complex molecular etiology of this disease. The review focuses on current knowledge of these genetic risk factors associated with keratoconus.
    Journal of Ophthalmology 08/2014; 2014:641708. DOI:10.1155/2014/641708 · 1.43 Impact Factor
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    • "However, a similar number of studies did not find VSX1 mutations to be specific to the disease [18-26]; therefore, VSX1 mutations may be responsible for a small fraction of keratoconus cases, suggesting that other genetic factors have more powerful effects on the development of keratoconus. In addition to VSX1, several other candidate genes have been reported, including superoxide dismutase 1 [16,27,28], lipoxygenase [29], transforming growth factor, beta 1 [30], secreted protein acidic and rich in cysteine [16], human leukocyte antigen [31-33], mitochondrial complex I genes [34], and collagen type IV, alpha 3 and collagen type IV, alpha four [35]. In recent genome-wide association studies, hepatocyte growth factor [36] and 2q21.3 including RAB3 GTPase activating protein subunit 1 (catalytic) [37] were reported to be associated with keratoconus. "
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    ABSTRACT: Polymorphisms in the interleukin 1 alpha (IL1A) and IL1B gene regions were previously associated with keratoconus in a Korean population. In the present study, we investigated whether the IL1A and IL1B polymorphisms are associated with keratoconus in a Japanese population. A total of 169 Japanese patients with keratoconus and 390 Japanese healthy controls were recruited. We genotyped one IL1A single nucleotide polymorphism (SNP; rs2071376) and two IL1B SNPs (rs1143627 and rs16944) to compare the frequencies of alleles, genotypes, and haplotypes between cases and controls. Statistically significant association was observed for rs1143627 (-31 T>C) in the IL1B promoter region; the T allele of rs1143627 was associated with an increased risk of keratoconus (p=0.014, corrected p value [pc]=0.043, odds ratio=1.38). The C allele of rs16944 (-511 C>T) in the IL1B promoter region had a 1.33-fold increased risk of keratoconus, although this increase did not reach statistical significance (p=0.033, pc=0.098). The TT genotype of rs1143627 was weakly associated with an increased risk of keratoconus (p=0.033, pc=0.099, odds ratio=1.52). However, no significant differences were found in the allele and genotype frequencies between the cases and controls for rs2071376 in IL1A. Regarding haplotypic diversity, the haplotype created by the T allele of rs1143627 and C allele of rs16944 was associated with a 1.72-fold increased risk of keratoconus (p=4.0×10(-5), pc=1.6×10(-4)). Our results replicate associations reported recently in a Korean population. Thus, IL1B may play an important role in the development of keratoconus through genetic polymorphisms.
    Molecular vision 04/2013; 19:845-851. · 1.99 Impact Factor
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    • "Despite a suggestive linkage in a familial KC panel to the 5q23.2 region where LOX is located (Bisceglia et al. 2009), no pathogenic sequence variants have so far been identified (Bykhovskaya et al. 2012; De Bonis et al. 2011). Although LOX expression was found to be higher in KC corneas compared to normal ones (Nielsen et al. 2003), we have recently found lower LOX activity in tissue culture medium in which KC corneal fibroblasts were cultured. "
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    ABSTRACT: Keratoconus (KC) is an eye disease characterized by the progressive thinning and protrusion of the cornea, which results in the loss of visual acuity. This disorder remains poorly understood, although recent studies indicate the involvement of genetic and environmental factors. Recently, we have found that the distribution of the cross-linking enzyme lysyl oxidase (LOX) is markedly decreased in about 63 % of keratoconic specimens. Similarly, LOX activity is significantly reduced by 38 % compared to control tissue. Nearly 70 systemic disorders have been reported in association with KC, most of them affecting the extracellular matrix. In this review we attempted to ascertain whether any KC-associated diseases exhibit signs that may reflect LOX impairment. We hypothesized that very similar changes in the extracellular matrix, particularly at the level of collagen metabolism, including LOX impairment in mitral leaflets, may reflect an association between KC and mitral valve prolapse. Moreover, this putative association is supported by the high frequency of Down syndrome in both diseases. Among other disorders that have been found to coincide with KC, we did not find any in which the LOX enzyme may be directly or indirectly impaired. On the other hand, in cases where KC is present along with other connective tissue disorders (Marfan syndrome, Ehlers-Danlos syndrome and others), KC may not arise as a localized manifestation, but rather may be induced as the result of a more complex connective tissue disorder.
    Journal of Neural Transmission 02/2013; 120(6). DOI:10.1007/s00702-013-0993-1 · 2.40 Impact Factor
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