Risk Of Keratoconus Research Articles

Effect of Allergic Diseases on Keratoconus Severity

ABSTRACTPurpose: To investigate the association between keratoconus (KC) and allergic diseases.Methods: In a prospective age- and sex-matched case–-control study clinical data of 885 KC patients and 1526 controls were evaluated regarding the presence of various allergic diseases. Severity of KC and ophthalmic parameters of KC patients were compared between KC patients with and without allergic diseases.Results: The prevalence of allergic diseases was significantly higher in KC patients. KC patients with vernal keratoconjunctivitis (VKC) or allergic conjunctivitis (AC) had significantly thinner and steeper corneas in comparison with non-allergic KC patients. Only VKC and AC were significantly associated with KC severity.Conclusions: Patients with VKC or AC were at increased risk of KC. They had more severe KC and should be closely followed up and intensively treated.

Subclinical keratoconus detection by pattern analysis of corneal and epithelial thickness maps with optical coherence tomography

To screen for subclinical keratoconus by analyzing corneal, epithelial, and stromal thickness map patterns with Fourier-domain optical coherence tomography (OCT). Four centers in the United States. Cross-sectional observational study. Eyes of normal subjects, subclinical keratoconus eyes, and the topographically normal eye of a unilateral keratoconus patient were studied. Corneas were scanned using a 26,000 Hz Fourier-domain OCT system (RTVue). Normal subjects were divided into training and evaluation groups. Corneal, epithelial, and stromal thickness maps and derived diagnostic indices, including pattern standard deviation (PSD) variables and pachymetric map-based keratoconus risk scores, were calculated from the OCT data. Area under the receiver operating characteristic curve (AUC) analysis was used to evaluate the diagnostic accuracy of the indices. The study comprised 150 eyes of 83 normal subjects, 50 subclinical keratoconus eyes of 32 patients, and 1 topographically normal eye of a unilateral keratoconus patient. Subclinical keratoconus was characterized by inferotemporal thinning of the cornea, epithelium, and stroma. The PSD values for corneal (P < .001), epithelial (P < .001), and stromal (P = .049) thickness maps were all significantly higher in subclinical keratoconic eyes than in the normal group. The diagnostic accuracy was significantly higher for PSD variables (pachymetric PSD, AUC = 0.941; epithelial PSD, AUC = 0.985; stromal PSD, AUC = 0.924) than for the pachymetric map-based keratoconus risk score (AUC = 0.735). High-resolution Fourier-domain OCT could map corneal, epithelial, and stromal thicknesses. Corneal and sublayer thickness changes in subclinical keratoconus could be detected with high accuracy using PSD variables. These new diagnostic variables might be useful in the detection of early keratoconus. Oregon Health and Science University (OHSU) and Drs. Li, Tan, and Huang have a significant financial interest in Optovue, Inc. These potential conflicts have been reviewed and managed by OHSU. Dr. Brass receives research grants from Optovue, Inc. Drs. Chamberlain and Weiss have no financial or proprietary interest in any material or method mentioned.

Lack of association between polymorphisms of the DNA base excision repair genes MUTYH and hOGG1 and keratoconus in a Polish subpopulation.

IntroductionKeratoconus (KC) is a non-inflammatory thinning of the cornea and a leading indication for corneal transplantation. Oxidative stress plays a role in the pathogenesis of this disease. The products of the hOGG1 and MUTYH genes play an important role in the repair of oxidatively modified DNA in the base excision repair pathway. We hypothesized that variability in these genes may change susceptibility to oxidative stress and predispose individuals to the development of KC. We investigated the possible association between the c.977C>G polymorphism of the hOGG1 gene (rs1052133) and the c.972G>C polymorphism of the MUTYH gene (rs3219489) and KC occurrence as well as the modulation of this association by some KC risk factors.Material and methodsA total of 205 patients with KC and 220 controls were included in this study. The polymorphisms were genotyped with polymerase chain reaction (PCR) restriction fragment length polymorphism and PCR-confronting two-pair primer techniques. Differences in genotype and allele frequency distributions were evaluated using the χ2 test, and KC risk was estimated with an unconditional multiple logistic regression with and without adjustment for co-occurrence of visual impairment, allergies, sex and family history for KC.ResultsWe did not find any association between the genotypes and combined genotypes of the c.977C>G polymorphism of the hOGG1 gene and the c.972G>C polymorphism of the MUTYH gene and the occurrence of KC.ConclusionsOur findings suggest that the c.977C>G-hOGG1 polymorphism and the c.972G>C-MUTYH polymorphism may not be linked with KC occurrence in this Polish subpopulation.

Keratoconus in Inflammatory Bowel Disease Patients: A Cross-sectional Study

Increasing evidence suggests that keratoconus may have an inflammatory component. The possible association of keratoconus with inflammatory bowel disease (IBD) has yet to be determined. The aim of this study was to determine the prevalence of keratoconus and suspect keratoconus in patients with IBD. All consecutive adult IBD patients seen in the Department of Gastroenterology, Nancy, University Hospital, France, between March 2014 and June 2014 were included. Pregnant women, rigid lens wearers, patients with a family history of keratoconus and patients with a history of refractive surgery were excluded. A control group of healthy subjects was included. All included patients underwent a corneal topography (OPD-Scan III, Nidek) to detect keratoconus or suspect keratoconus. Rabinowitz videokeratographic indices were the basis of corneal topography interpretation. Two hundred and one IBD patients were included, 150 with Crohn's disease and 51 with ulcerative colitis. Mean age was 38.7 years and 121 were women. Mean disease duration was 10.8 years. Two IBD patients were diagnosed with keratoconus (1%) and 38 with suspect keratoconus (18.9%). Overall prevalence of keratoconus and suspect keratoconus was 19.9% (95% confidence interval [CI] 17.5-22.0). None of the 100 healthy subjects had keratoconus, while three were diagnosed with suspect keratoconus (p = 0.0002 versus IBD patients). Only smoking was identified as a risk factor (p = 0.029), especially in Crohn's disease. Inflammatory bowel disease patients may carry an increased risk of keratoconus and suspect keratoconus, smoking further increasing this risk. This supports the hypothesis of an inflammatory origin of keratoconus.

Association of Interleukin-1 Gene Single Nucleotide Polymorphisms with Keratoconus in Chinese Han Population

ABSTRACTPurpose: To investigate whether interleukin-1 alpha (IL1A) and interleukin-1 beta (IL1B) polymorphisms are associated with keratoconus (KC) in unrelated Chinese Han patients.Methods: The IL1A (rs2071376) and IL1B (rs1143627, rs16944) polymorphisms were genotyped in 115 unrelated Chinese Han KC patients and 101 healthy Chinese Han volunteers with the Sequenom MassARRAY RS1000. Sequenom Typer 4.0 software, PLINK 1.07, Haploview 4.0 software platform were used to analyze the allelic variants of IL1A and IL1B genes, and their association with KC risk factors were assessed.Results: Among the variants, the three SNPs (rs2071376 in IL1A, rs1143627 and rs16944 in the promoter region of IL1B) were different between the two groups. The A allele of rs2071376 (A > C, p = 0.017, OR = 1.968, 95% C.I. 1.313–3.425), the C allele of rs1143627 (C > T, p < 0.001, OR = 2.864, 95% C.I. 1.631–4.968) and the A allele of rs16944 (A > G, p = 0.002, OR = 2.401, 95% C.I. 1.396–4.161) were associated with a increased risk of KC in Chinese Han patients. This study showed that rs2071376, rs1143627 and rs16944 had significant differences in associations between KC patients and the control group when different genotypes were analyzed in three models (dominant, recessive, and additive). In the haplotype analysis, the two single nucleotide polymorphisms (SNPs), rs1143627 and rs16944 showed strong linkage disequilibrium. In addition, Haplotype “ACA” was found to be associated with a higher risk of developing KC (OR = 12.91, p < 0.001).Conclusion: Keratocyte apoptosis is an initiating event in the pathogenesis of KC which could be induced by the altered levels of IL1 gene. These findings confirmed that polymorphisms in IL1 genes were associated with risk of KC in the Chinese Han population, which help us to gain insight into the pathogenesis of KC.

WNT10A exonic variant increases the risk of keratoconus by decreasing corneal thickness.

Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross-linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a sample of 1029 individuals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 × 10(-10)) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent samples from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a sample of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41 × 10(-5)).

Evaluation of possible relationship between COL4A4 gene polymorphisms and risk of keratoconus.

Keratoconus (KC) is a genetically heterogeneous corneal dystrophy with unknown etiology that causes loss of visual acuity. Evidence has shown that corneas from patients with KC contain reduced amounts of total collagen proteins, and collagen type IV has been suggested as a candidate gene in KC pathogenesis. This study aimed to evaluate the possible associations between collagen type IV alpha-4 chain (COL4A4) polymorphisms (rs2229813 G/A, M1327V and rs2228555 A/G, V1516V) and susceptibility to KC. A total of 262 Iranian subjects including 112 patients with KC and 150 healthy individuals as controls were recruited in this case-control study. Diagnosis was based on clinical examination, electronic refractometry, and keratometry. Genotyping for the COL4A4 rs2229813 and rs2228555 variants was executed using allele-specific polymerase chain reaction and Tetra-ARMS polymerase chain reaction, respectively. A significant difference was found between the 2 groups regarding allelic and genotyping distribution of COL4A4 polymorphism at position rs2229813 G>A. The COL4A4 rs2229813 AA and GA+AA genotypes were risk factors for developing KC (odds ratio [OR] = 2.1, P = 0.036 and OR = 1.7, P = 0.042, for the AA and GA+AA genotypes, respectively). The COL4A4 rs2229813 A allele was also associated with an increased risk for KC (OR = 1.5, 95% confidence intervals: 1.1-2.2, P = 0.018). However, in our study, we found no association between COL4A4 rs2228555 polymorphism and the risk of KC. We suggest that the COL4A4 rs2229813 AA and GA+AA genotypes as well as the A allele play roles as risk factors for developing KC in our population.

Brittle cornea syndrome ZNF469 mutation carrier phenotype and segregation analysis of rare ZNF469 variants in familial keratoconus.

Brittle cornea syndrome 1 (BCS1) is a rare recessive condition characterized by extreme thinning of the cornea and sclera, caused by mutations in ZNF469. Keratoconus is a relatively common disease characterized by progressive thinning and ectasia of the cornea. The etiology of keratoconus is complex and not yet understood, but rare ZNF469 variants have recently been associated with disease. We investigated the phenotype of BCS1 carriers with known pathogenic ZNF469 mutations, and recruited families in which aggregation of keratoconus was observed to establish if rare variants in ZNF469 segregated with disease. Patients and family members were recruited and underwent comprehensive anterior segment examination, including corneal topography. Blood samples were donated and genomic DNA was extracted. The coding sequence and splice sites of ZNF469 were PCR amplified and Sanger sequenced. Four carriers of three BCS1-associated ZNF469 loss-of-function mutations (p.[Glu1392Ter], p.[Gln1930Argfs*6], p.[Gln1930fs*133]) were examined and none had keratoconus. One carrier had partially penetrant features of BCS1, including joint hypermobility. ZNF469 sequencing in 11 keratoconus families identified 9 rare (minor allele frequency [MAF] ≤ 0.025) variants predicted to be potentially damaging. However, in each instance the rare variant(s) identified, including two previously reported as potentially keratoconus-associated, did not segregate with the disease. The presence of heterozygous loss-of-function alleles in the ZNF469 gene did not cause keratoconus in the individuals examined. None of the rare nonsynonymous ZNF469 variants identified in the familial cohort conferred a high risk of keratoconus; therefore, genetic variants contributing to disease pathogenesis in these 11 families remain to be identified.

Polymorphism of the flap endonuclease 1 gene in keratoconus and Fuchs endothelial corneal dystrophy.

Oxidative stress is implicated in the pathogenesis of many diseases, including serious ocular diseases, keratoconus (KC) and Fuchs endothelial corneal dystrophy (FECD). Flap endonuclease 1 (FEN1) plays an important role in the repair of oxidative DNA damage in the base excision repair pathway. We determined the association between two single nucleotide polymorphisms (SNPs), c.–441G>A (rs174538) and g.61564299G>T (rs4246215), in the FEN1 gene and the occurrence of KC and FECD. This study involved 279 patients with KC, 225 patients with FECD and 322 control individuals. Polymerase chain reaction (PCR) and length polymorphism restriction fragment analysis (RFLP) were applied. The T/T genotype of the g.61564299G>T polymorphism was associated with an increased occurrence of KC and FECD. There was no association between the c.–441G>A polymorphism and either disease. However, the GG haplotype of both polymorphisms was observed more frequently and the GT haplotype less frequently in the KC group than the control. The AG haplotype was associated with increased FECD occurrence. Our findings suggest that the g.61564299G>T and c.–441G>A polymorphisms in the FEN1 gene may modulate the risk of keratoconus and Fuchs endothelial corneal dystrophy.

Polymorphism Analysis of COL4A3 and COL4A4 Genes in Greek Patients with Keratoconus

Background: In this study, we conducted the genotyping of D326Y in COL4A3 and M1327V, as well as F1644F in COL4A4 polymorphisms, in a case–control sample panel of Greek origin population.Materials and Methods: A case–control panel, with 45 keratoconus (KC) patients and 78 healthy controls, were surveyed. DNA from each individual was tested for the D326Y in COL4A3 and M1327V, as well as F1644F in COL4A4 polymorphisms by direct sequencing.Results: When analyzing the Hardy-Weinberg equilibrium, we observed no significant deviation from expected numbers in both KC patients and controls. The genotype frequencies in the polymorphisms tested were not found to be significantly associated with KC development risk. The M1327V AA and F1644F TT genotypes were significantly over-represented in healthy individuals.Conclusions: We could hypothesize that mutations in COL4A3 and COL4A4 genes are not involved in KC risk in Greek population. Nevertheless, the M1327V AA and F1644F TT genotypes were significantly over-represented in healthy individuals, suggesting a protective role of these genotypes in KC development risk in our population.

Ethnic Variation in Central Corneal Refractive Power and Steep Cornea in Asians

Purpose: To describe ethnic differences in the distribution of central corneal refractive power and steep cornea in a multiethnic Asian population.Methods: A total of 2968 Chinese, 2957 Indian and 2928 Malay participants aged over 40 years were included in this study. Each subject underwent standardized systematic and ocular examinations, interviewer-administered questionnaires, and blood investigations for risk factor assessment. Central corneal refractive power was measured using an autorefractor. Steep cornea was defined as central corneal refractive power exceeding 48 diopters (D) measured by keratometry.Results: Mean keratometry readings were 43.9 ± 1.5 D in Malays, 44.2 ± 1.5 D in Indians and 43.9 ± 1.5 D in Chinese. The prevalence of steep cornea was 0.6% (95% confidence interval, CI, 0.3–0.9%) in Malays, 1.0% (95% CI 0.7–1.4%) in Indians and 0.5% (95% CI 0.3–0.8%) in Chinese. In multivariate analysis, increasing central corneal refractive power was associated with Indian race, shorter body height, non-smokers, absence of pterygium, shorter axial length, thinner corneas and greater anterior chamber depth, while the presence of steep cornea was significantly associated with Indian race, shorter axial length and thinner corneas.Conclusions: Indian participants had the steepest corneas among the three major ethnic groups in Singapore. Central corneal refractive power was related to several ocular parameters including anterior chamber depth, axial length and central corneal thickness. These data have important clinical implications for understanding the risk of keratoconus.

Polymorphisms of the apoptosis-related FAS and FAS ligand genes in keratoconus and Fuchs endothelial corneal dystrophy.

Keratoconus (KC) is a non-inflammatory eye disease characterized by progressive corneal thinning and asymmetrical conical protrusion of the cornea. Fuchs endothelial corneal dystrophy (FECD) is a degenerative, slowly progressive disease of the corneal endothelium that is characterized by alteration in corneal endothelial cell morphology and progressive loss of these cells. They are unrelated eye diseases that may ultimately lead to vision loss. Their pathogenesis is largely unknown, although impaired apoptosis has been suggested to be responsible for both diseases. Therefore, we studied the frequency of the c.-671A>G polymorphism of the apoptosis-related FAS gene and the c.-844T>C polymorphism of the FAS ligand (FASLG) gene in patients with FECD (221 individuals) or KC (264) and controls (300). Each polymorphism is located within the putative cis-acting element of the respective promoter. Risk of KC or FECD was estimated with unconditional multiple logistic regression with adjustment for various factors, including age, sex, allergies, and family history. The T/T genotype and the T allele of the c.-844T>C polymorphism were associated with increased occurrence of KC, while the C allele was associated with decreased KC occurrence. The G allele of the c.-671A>G polymorphism was associated with increased occurrence of FECD, while the A allele was associated with decreased FECD occurrence. The C/C-A/A combined genotype was associated with reduced risk of FECD, whereas the T/T-G/A combined genotype increased risk of KC. In conclusion, variability in the expression of the FAS and FASLG genes may be involved in the pathogenesis of KC and FECD.

Evaluating the Association Between Keratoconus and the Corneal Thickness Genes in an Independent Australian Population

A recent genome-wide association study (GWAS) identified six loci associated with central corneal thickness that also conferred associated risk of keratoconus (KC). We aimed to assess whether genetic associations existed for these loci with KC or corneal curvature in an independent cohort of European ancestry. In total, 157 patients with KC were recruited from public and private clinics in Melbourne, Australia, and 673 individuals without KC were identified through the Genes in Myopia study from Australia. The following six single-nucleotide polymorphisms (SNPs) that showed a statistically significant association with KC in a recent GWAS study were selected for genotyping in our cohort: rs4894535 (FNDC3B), rs1324183 (MPDZ-NF1B), rs1536482 (RXRA-COL5A1), rs7044529 (COL5A), rs2721051 (FOXO1), and rs9938149 (BANP-ZNF469). The SNPs were assessed for their association with KC or corneal curvature using logistic or linear regression methods, with age and sex included as covariates. Bonferroni corrections were applied to account for multiple testing. Genotyping data were available for five of the SNPs. Statistically significant associations with KC were found for the SNPs rs1324183 (P = 0.001; odds ratio [OR], 1.68) and rs9938149 (P = 0.010; OR, 1.47). Meta-analysis of previous studies yielded genome-wide significant evidence of an association for rs1324183, firmly establishing it as a KC risk variant. None of the SNPs were significantly associated with corneal curvature. The SNPs rs1324183 in the MPDZ-NF1B gene and rs9938149 (between BANP and ZNF4659) were associated with KC in this independent cohort, but their association was via a non-corneal curvature route.

Keratoconus diagnosis with optical coherence tomography–based pachymetric scoring system

To develop an optical coherence tomography (OCT) pachymetry map–based keratoconus risk scoring system. Doheny Eye Institute, University of Southern California, Los Angeles, California, and Brass Eye Center, New York, New York, USA; Department of Ophthalmology, Affiliated Eye Hospital of Wenzhou Medical College, Wenzhou, China. Cross-sectional study. Fourier-domain OCT was used to acquire corneal pachymetry maps in normal and keratoconus subjects. Pachymetric variables were minimum, minimum−median, superior–inferior (S–I), superonasal–inferotemporal (SN–IT), and the vertical location of the thinnest cornea (Ymin). A logistic regression formula and a scoring system were developed based on these variables. Keratoconus diagnostic accuracy was measured by the area under the receiver operating characteristic (ROC) curve. One hundred thirty-three eyes of 67 normal subjects and 82 eyes from 52 keratoconus subjects were recruited. The keratoconus logistic regression formula = 0.543 × minimum + 0.541 × (S–I) − 0.886 × (SN–IT) + 0.886 × (minimum–median) + 0.0198 × Ymin. The formula gave better diagnostic power with the area under the ROC than the best single variable (formula = 0.975, minimum = 0.942; P<.01). The diagnostic power with the area under the ROC of the keratoconus risk score (0.949) was similar to that of the formula (P=.08). The OCT corneal pachymetry map–based logistic regression formula and the keratoconus risk scoring system provided high accuracy in keratoconus detection. These methods may be useful in keratoconus screening.

Variability of oxidative stress‐related genes in keratoconus and Fuchs endothelial corneal dystrophy

AbstractPurpose In the present work we investigated polymorphism in nuclear genes encoding proteins important for the cellular reaction to oxidative stress and mutations in mitochondrial DNA in two eye diseases with established role of oxidative stress in their pathology: keratoconus (KC) and Fuchs endothelial corneal dystrophy (FECD).Methods Over 200 FECD and KC patients as well as more than 300 sex‐ and age‐matched controls were enrolled in this study. Genetic variation in nuclear DNA was determined in peripheral blood lymphocytes by allele‐specific and restriction length fragment polymorphism PCR. Quantitative real‐time PCR with TaqMan probes was employed to study mutagenesis in mitochondrial DNA (mtDNA).Results Genotypes of polymorphisms of genes encoding catalase and superoxide dismutase, glutathione transferase, enzymes neutralizing reactive oxygen species, were associated with the increased risk of AMD, FECD and KC. Polymorphism of numerous DNA repair genes, including hOGG1, MUTYH, UNG and SMUG1 was associated with AMD and KC. Finally, we found some associations between the occurrence of FECD and mtDNA mutagenesis, expressed by the number of mtDNA copies and specific deletions and point mutations, including 4977 bp deletion in mtDNA encoding 5 tRNAs and 7 proteins of respiratory chain as well as the 414T&gt;G transversion.Conclusion Polymorphism in nuclear genes encoding oxidative stress‐related proteins and mutations in mitochondrial DNA may contribute to the risk of occurrence and development of KC and FECD by modulating the cellular reaction to the stress.

Common Single Nucleotide Polymorphisms and Keratoconus in the Han Chinese Population

ABSTRACTObjective: To investigate whether the tag single nucleotide polymorphisms (tSNPs) in VSX1, COL4A3, COL4A4, IL1A and IL1B genes were associated with keratoconus (KTCN) in the Han Chinese population.Methods: Ninety-seven KTCN patients and 101 healthy controls were enrolled in this study. All cases were diagnosed on the basis of clinical examination. Twenty-one tSNPs were selected for association study in five genes. SNP genotyping was performed by Sequenom MassARRAY RS1000. Sequenom Typer 4.0 Software, PLINK, Haploview and SHEsis software platform were used to perform data management and analyses.Results: Three tSNPs in the VSX1 gene were observed to be associated with KTCN risk at a 5% level by χ2 test (rs56157240 and rs12480307, p = 0.0499, OR: 6.42, 95% CI: 0.77–53.78; rs6050307, p = 1.22 × 10−7, OR: 0.05, 95% CI: 0.01–0.23). Rs2071376 in the IL1A gene was also associated with KTCN (p = 0.0487, OR: 1.51, 95% CI: 1.00–2.26). Three haplotypes in the VSX1 gene were found to be associated with risk of KTCN (p < 0.05).Conclusions: Our findings confirmed previous reports that polymorphisms of VSX1 and IL1A genes were associated with risk of KTCN in the Chinese population, suggesting an important determinant of KTCN development by VSX1 and IL1A genes.

Polymorphism of the transferrin gene in eye diseases: keratoconus and Fuchs endothelial corneal dystrophy.

Oxidative stress may play a role in the pathogenesis of keratoconus (KC) and Fuchs endothelial corneal dystrophy (FECD). Iron may promote the stress by the Fenton reaction, so its homeostasis should be strictly controlled. Transferrin is essential for iron homeostasis because it transports iron from plasma into cells. The malfunction of transferrin, which may be caused by variation in its gene (TF) variation, may contribute to oxidative stress and change KC and FECD risk. To verify this hypothesis we investigated the association between three polymorphisms of the TF gene, g.3296G>A (rs8177178), g.3481A>G (rs8177179), and c.–2G>A (rs1130459), and KC and FECD occurrence. Genotyping was performed in blood lymphocytes in 216 patients with KC, 130 patients with FECD and 228 controls by PCR-RFLP. We studied also the influence of other risk factors. The A/A genotype and the A allele of the g.3296G>A polymorphism were associated with KC occurrence, while the G allele was negatively correlated with it. We observed a decrease in KC occurrence associated with the A/G genotype of the g.3481A>G polymorphism. We did not find any association between the c.–2G>A polymorphism and KC. No association was found between all three polymorphisms and FECD occurrence.

Association of visual system homeobox gene polymorphisms with the risk of sporadic keratoconus

Background Keratoconus is a bilateral,noninflammatory,gradually progressive corneal disorder characterized by progressive thinning and steepening of the central cornea.It is significant to investigate keratoconusrelated pathogenic gene for elaborating the pathogenesis and establishing early diagnosis standard and taking clinical measurement.Objective The aim of the study was to explore the relationship of visual system homeobox gene (VSX1) polymorphism and the risk of sporadic keratoconus.Methods This study was approved by Ethic Commission of First Hospital of Xi' an.Written informed consent was obtained from each subject prior to enrollment.A case-controlled study was conducted.One hundred and one Han nationality patients with sporadic keratoconus were included in this study.These keratoconus patients were clinically diagnosed by slit lamp examination and corneal tomography.Single nucleolide polymorphism (SNP) of VSX1 gene was assayed and classified using the MassARRAY SNP technique.Demography and relevant risk factors were collected from each subject by questionnaire.Eighty healthy volunteers served as controls.Chi-square test and Binary logistic regression were used to evaluate the difference in the distribution of allele frequency and genotype frequency and to analyze the association with keratoconus risks.Results SNP of two genes was found in the Chinese Han population (rs743018 (c.843+140 C＞T) and rs6138482(R217H C＞T)).There were no significant differences in the genotype frequency and allele frequency of the SNP of two genes in the keratoconus group in comparison with the normal control group (P＞0.05).After adjustment by age and sex,SNP of two genes was not significantly associated with the risk of keratoconus (regression model:rs743018 (C＞T) adjusted:P=0.35,OR=0.72,95％ CI:0.37-1.43 ;rs6138482 (C＞T) adjusted:P =0.48,OR=0.76,95％ CI:0.35-1.64).Conclusions Gene polymorphisms of rs743018(c.843+140 C＞T) and rs6138482(R217H C＞T) in the Chinese Han population is not associated with the risk of keratoconus.Due to the racial difference in genotype and allele frequency,the role of the VSX1 gene in the pathogenesis of keratoconus still remains controversial,and further study needs to be developed. Key words: Keratoconus; Visual system homeobox gene; Gene polymorphism

Corneal Descriptive Indices in the Fellow Eye of Unilateral Keratoconus

To determine whether indices derived from corneal topography could be used to differentiate between three populations at varying degrees of risk for presenting keratoconus, but otherwise unremarkable clinical appearance. Eighty subjects lacking clinical signs of keratoconus were divided into three groups according to their background. Fifty refractive surgery candidates were used as controls, to be compared with 15 clinically normal fellow eyes of subjects with unilateral keratoconus, and 15 eyes from first and second degree relatives of the former keratoconic patients. Corneal topography indices (curvature, wavefront, and thickness) were obtained from Placido disc (Keratron) and scanning-slit (Orbscan) devices. Receiver operator characteristic curve analysis (sensitivity, specificity, and area under the curve) was performed to highlight the ability of any single index to discriminate between groups, and cutoff values for a fixed 0.80 specificity were determined. Corneal wavefront indices (root mean square and vertical coma) exhibited the best performance for discriminating between controls and the fellow eye of unilateral keratoconus patients. Corneal curvature and thickness indices showed poor capability to differentiate between the groups. Relatives and controls were distinguishable by a single thickness parameter. The proposed cutoff values between controls and patients at risk for keratoconus may prove useful for screening purposes.

VSX1 gene variants are associated with keratoconus in unrelated Korean patients

Keratoconus is a bilateral ectatic disorder characterized by the central thinning of corneal tissue leading to visual impairment. To investigate the possibility of visual system homeobox 1 (VSXI) as a candidate susceptibility gene for Korean patients with keratoconus, we performed a mutation screening of the VSXI gene in 249 unrelated patients with keratoconus and 208 control subjects without the ocular disorder. We found two heterozygous novel missense mutations in exon 2: N151S and G160V. The G160V mutation was identified in 13 keratoconus patients (5.3%), and the N151S mutation was found in only one keratoconus patient (0.4%). We also detected three synonymous polymorphisms and four intragenic polymorphisms. The IVS1-11*a allele was associated with a significantly increased risk of keratoconus in Korean patients [3.6 vs. 0.5%, p = 0.001, odds ratio (OR) = 7.76, 95% confidence interval (CI) 1.989-30.241). Other polymorphisms did not show an association with keratoconus risk. Our data is the first reported VSX1 mutation screening in Korean keratoconus patients. We detected two novel missense mutations and one intragenic polymorphism in the VSX1 gene, which show a strong statistical association with unrelated keratoconus patients. Consequently, our study suggests that VSX1 gene variants seem to be significant genetic variants for keratoconus predisposition in unrelated Korean patients.