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

Bykhovskaya, Yelena; Li, Xiaohui; Epifantseva, Irina; Haritunians, Talin; Siscovick, David S.; Aldave, Anthony J.; Szczotka-Flynn, Loretta; Iyengar, Sudha K.; Taylor, Kent D.; Rotter, Jerome I.; Rabinowitz, Yaron S.

doi:10.1167/iovs.11-9268

Cited by 113 publications

(116 citation statements)

References 35 publications

(33 reference statements)

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“…8 The main statistics used here (allelic test) implicitly assume codominance, and is similar to the additive models assumed in the previous reports. 8,9,13,15 Although some caution is invited in the interpretation of our findings because of the relatively small sample size, the validation of rs2956540:G4C and rs3735520:G4A showing the same effect directions as previous studies in populations of European ancestry adds weight to the existing evidence. 8,9 Although not reaching a statistically significant threshold, the higher MAF of rs1800449:C4T and rs10519694:C4T in controls compared with the KC cases in our study, was consistent with protective effects of these alleles reported in another study using Caucasian case-control panels (Supplementary Table 2).…”

Section: Discussionsupporting

confidence: 48%

“…8,9,13,15 Although some caution is invited in the interpretation of our findings because of the relatively small sample size, the validation of rs2956540:G4C and rs3735520:G4A showing the same effect directions as previous studies in populations of European ancestry adds weight to the existing evidence. 8,9 Although not reaching a statistically significant threshold, the higher MAF of rs1800449:C4T and rs10519694:C4T in controls compared with the KC cases in our study, was consistent with protective effects of these alleles reported in another study using Caucasian case-control panels (Supplementary Table 2). 9 rs1014091:G4A and rs17501108:G4T were previously also shown to have a protective effect, 8 whereas in our study their MAF was higher in KC cases that, albeit not statistically significant, indicated a tendency towards the opposite direction of the effect.…”

Section: Discussionsupporting

confidence: 48%

“…8,9 Details on previous association studies (population origin, genotyping methods used, number of KC and control samples and reported P-values) on the LOX and HGF locus are shown in Supplementary Table 2.…”

Section: Discussionmentioning

confidence: 99%

“…SNPs reported to show the strongest associations, although not reaching genome-wide significance, in GWAS 8,9 were tested (Supplementary Table 1). Genotyping was performed using custom designed Kompetitive Allele Specific PCR (KASP) assays at LGC Genomics (LGC Genomics, Hoddesdon, UK).…”

Section: Methodsmentioning

confidence: 99%

“…6,7 Single-nucleotide polymorphisms (SNPs) in two genes, lysyl oxidase (LOX; OMIM *153455) and hepatocyte growth factor (HGF; OMIM *142409), identified by a genome-wide association study (GWAS) have been reported to increase susceptibility to KC. 8,9 In this study we attempted replication for seven SNPs in LOX and HGF in a Czech case-control cohort.…”

Section: Introductionmentioning

confidence: 99%

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Validation of rs2956540:G>C and rs3735520:G>A association with keratoconus in a population of European descent

et al. 2015

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Corneal ectasias, among which keratoconus (KC) is the single most common entity, are one of the most frequent reasons for corneal grafting in developed countries and a threatening complication of laser in situ keratomileusis. Genome-wide association studies have previously found lysyl oxidase (LOX) and hepatocyte growth factor (HGF) associated with susceptibility to KC development. The aim of our study was to validate the effects of seven single-nucleotide polymorphisms (SNPs) within LOX and HGF over KC. Unrelated Czech cases with KC of European descent (108 males and 57 females, 165 cases in total) and 193 population and gender-matched controls were genotyped using Kompetitive Allele Specific PCR assays. Fisher's exact tests were used to assess the strength of associations. Evidence for association was found for both of the tested loci. It was strongest for rs3735520:G4A near HGF (allelic test odds ratio (OR) = 1.45; 95% confidence interval (CI), 1.06-1.98; P = 0.018) with A allele being a risk factor and rs2956540:G4C (OR = 0.69; 95% CI, 0.50-0.96; P = 0.024) within LOX with C allele having a protective effect. This first independent association validation of rs2956540:G4C and rs3735520:G4A suggests that these SNPs may serve as genetic risk markers for KC in individuals of European descent.

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Section: Discussionsupporting

confidence: 48%

Section: Discussionsupporting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Validation of rs2956540:G>C and rs3735520:G>A association with keratoconus in a population of European descent

et al. 2015

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Association of Genetic Variation With Keratoconus

et al. 2020

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IMPORTANCE Keratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus. OBJECTIVE To identify genetic susceptibility regions for keratoconus in the human genome. DESIGN, SETTING, AND PARTICIPANTS This study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P < 1.00 × 10 −6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019. MAIN OUTCOMES AND MEASURES Associations between keratoconus and 6 252 612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components. RESULTS The discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P < 5.00 × 10 −8), with a P value of 7.46 × 10 −9 at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 × 10 −12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00 × 10 −6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 × 10 −7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 × 10 −8). CONCLUSIONS AND RELEVANCE In this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11.

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Genetics of Keratoconus

Chaturvedi

Hansoge

2013

Encyclopedia of Life Sciences

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Keratoconus is a mysterious disease of cornea with diverse genetic complexity. Past 160 years of molecular genetics revolution has witnessed the identification of candidate genes with multiple loci through genome‐wide association studies (GWAS). This article provides key insight into the genetics of keratoconus along with diagnosis, treatment and management. Key Concepts: Keratoconus is a noninflammatory corneal progressive ectasia that is bilateral and asymmetric, characterised by steepening and deformation of the cornea, thinning of the apical cornea and corneal scarring. Patients with moderate keratoconus are observed with Fleischer ring around the cone base due to an accumulation of iron deposits. Also Vogt striae, which are fine vertical lines due to compression of Descemet membrane, can be seen. In keratoconus, the cornea's normal defence system is lost and leads to accumulation of free radicals in the tissue, which can cause structural damage. Monozygotic twins have higher concordance of keratoconus than dizygotic twins, which is shown by their phenotypic similarity. This type of evaluation can be made in situations where a clinical sign does not show a genetic pattern. As far as the age groups that get afflicted with the disease are concerned, the keratoconus‐affected individuals between 30–40 years of age are higher than the other groups. Approximately 17 genomic loci have been described from 12 studies based on linkage analysis. This propounds at large the genetic disparities in keratoconus. Further, these studies make possible to consider the mutational effects in different genes that are responsible for the disease. Visual System Homeobox 1 ( VSX1 ) is the most widely reported gene for keratoconus. This gene codes for a transcription factor that helps in ocular development and development of cornea. Mutations in the locus of this gene are reported to be pathogenic and are positive in keratoconus patients. Early signs for diagnosing include irregularity of reflex observed by retinoscopy, distortion of the corneal reflection observed by keratometry and conical contour revealed by the fit of a corneal lens. Nowadays, surgical procedures to selectively replace either the anterior or the posterior layer are used. Keratoplasty is employed to remove the damaged cornea. The distorted cornea is replaced entirely or partially by graft. Entire removal of the keratoconic cornea is called penetrating keratoplasty, whereas if a part of the cornea is removed, it is called lamellar keratoplasty.

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

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

Cited by 113 publications

References 35 publications

Validation of rs2956540:G>C and rs3735520:G>A association with keratoconus in a population of European descent

Validation of rs2956540:G>C and rs3735520:G>A association with keratoconus in a population of European descent

Association of Genetic Variation With Keratoconus

Genetics of Keratoconus

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