Keratoconus International Consortium (KIC)- advancing keratoconus research.

CLINICAL RELEVANCE: The Keratoconus International Consortium (KIC) will allow better understanding of keratoconus. BACKGROUND: Keratoconus is a disorder characterised by corneal elevation and thinning, leading to reduced vision. The current gaps in understanding of this disease will be discussed and the need for a multi-pronged and multi-centre engagement to enhance our understanding of keratoconus will be highlighted. DESIGN: KIC has been established to address the gaps in our understanding of keratoconus with the aim of collecting baseline as well as longitudinal data on several fields. PARTICIPANTS: Keratoconus and control (no corneal condition) subjects from different sites globally will be recruited in the study. METHODS: KIC collects data using an online, secure database, which enables standardised data collection at member sites. Data fields collected include medical history, clinical features, quality of life and economic burden questionnaires and possible genetic sample collection from patients of different ethnicities across different geographical locations. RESULTS: There are currently 40 Australian and international clinics or hospital departments who have joined the KIC. Baseline data has so far been collected on 1130 keratoconus patients and indicates a median age of 29.70 years with 61% being male. A total of 15.3% report a positive family history of keratoconus and 57.7% self-report a history of frequent eye rubbing. CONCLUSION: The strength of this consortium is its international, collaborative design and use of a common data collection tool. Inclusion and analyses of cross-sectional and longitudinal data will help answer many questions that remain in keratoconus, including factors affecting progression and treatment outcomes.

Eye rubbing in the aetiology of keratoconus: a systematic review and meta-analysis.

PURPOSE: Keratoconus is a potentially blinding condition that slowly deforms the cornea in young people. Despite the increasing prevalence of keratoconus, the exact aetiology of the condition is unknown. This first systematic review examines the evidence of eye rubbing and its association with keratoconus and presents the findings of the meta-analysis. METHODS: Two independent reviewers searched the electronic databases for all potential articles published from 1st of January 1900 to 31st of July 2020 on eye rubbing and keratoconus. The researchers assessed the methodological quality of the studies using the Newcastle-Ottawa scale for observational studies. The assessment for statistical heterogeneity was estimated using chi-square and I-square (I2) tests. A p value of < 0.05 was considered as statistically significant and I2 < 30% as homogenous. Begg funnel plot was used to interpret the asymmetry or small study effects. RESULTS: Eight case-control studies were included in this systematic review. Two studies assessed eye rubbing without odds ratios and thus were excluded. The pooled odds ratios for the six remaining studies included in the meta-analysis was 6.46 (95% CI 4.12-10.1). The study results were heterogenous (I2 = 71.69 [95% CI 35.14-87.88]). All the studies scored moderate quality methodology on the Newcastle-Ottawa scale. Begg funnel plot showed asymmetry supporting heterogeneity. CONCLUSION: Eye rubbing showed consistent association with keratoconus. However, the current evidence is limited to only a small number of case-control studies which present as heterogeneous and of sub-optimal methodological quality. Additionally, the cause-effect temporal relationship cannot be determined. Further studies are needed to address this intricate relationship of eye rubbing and its induction, ongoing progression, and severity of keratoconus.

Risk factors and association with severity of keratoconus: the Australian study of Keratoconus.

SIGNIFICANCE: Our results show that asthmatic patients tend to have more severe KC and thus close monitoring for disease progression would be advised, and appropriate treatment strategies may be actioned stabilise the condition that may reduce the need for future corneal transplantation. PURPOSE: To explore a wide range of risk factors associated with the severity of keratoconus (KC). METHODS: A cross-sectional study of KC patients was undertaken in Melbourne, Australia. A questionnaire addressing age, gender, educational background, ocular and medical history, smoking and alcohol consumption, and physical examination comprising anthropometric measurements was collected; eye examination was undertaken. The associations between a range of risk factors and the severity of KC were determined using univariate and multivariable linear regression analyses. RESULTS: A total of 260 KC subjects were included in this study. Mean age of subject was 35.5 (SD = 14.8) years and the majority of the subjects were European 171 (68.2%). Initial univariate regression analysis identified the following risk factors at the p < 0.1 level with KC: higher body mass index, smoking cigarettes, diabetes, rheumatoid arthritis and asthma were associated with increased severity of KC, whereas eczema was associated with less severe KC. Following multivariable regression analysis, only asthma remained as a significant risk factor associated with 2.2 diopters (D) steeper average mean keratometry compared to KC subjects having no asthma [p = 0.03; ß = 2.18; 95% confidence intervals: 1.22, 4.14]. CONCLUSION: Our study describes the comprehensive assessment of all the known risk factors in a large KC cohort recruited in Australia. Our study has reported asthma as the only risk factor found to be significantly associated with the severity of KC. The results of this study allow us to better understand the aetiology of KC and such knowledge could be useful in instigate systemic management of patients to slow or prevent KC.

Economic impact of keratoconus using a health expenditure questionnaire: A patient perspective.

IMPORTANCE: This is the first study to estimate the lifetime costs associated with keratoconus based on a questionnaire completed by patients and highlights the significant economic burden of the disease. As keratoconus affects individuals from a young age, the study highlights keratoconus as a public health concern. BACKGROUND: Keratoconus is a disorder characterized by corneal steepening and thinning, leading to reduced visual acuity. To date, there have been no studies evaluating the economic costs of keratoconus from a patient's perspective. DESIGN: A randomized cross-sectional study undertaken in Australia where keratoconus subjects were recruited from public and private ophthalmology and optometry clinics. PARTICIPANTS: A total of 100 participants completed the questionnaire: median age was 31 years and 57% were males. METHODS: A keratoconus health expenditure questionnaire was designed to assess direct and indirect expenditures for each individual. MAIN OUTCOME MEASURES: Total direct and indirect costs associated with the condition were calculated along with the estimated lifetime per capita costs. RESULTS: The total cost related to direct and indirect care was estimated to be AUD 3365. By applying our cost data to keratoconus prevalence data for the Australian population, the total cost is estimated to be approximately AUD 44.7 million per year in Australia. CONCLUSIONS AND RELEVANCE: Our results show that the costs associated with the diagnosis and management of keratoconus represent a significant cost to patients. An understanding of this is important not only to individuals and their families, but also health care providers, health insurers and the wider health system.

Pooled genome wide association detects association upstream of FCRL3 with Graves' disease.

BACKGROUND: Graves' disease is an autoimmune thyroid disease of complex inheritance. Multiple genetic susceptibility loci are thought to be involved in Graves' disease and it is therefore likely that these can be identified by genome wide association studies. This study aimed to determine if a genome wide association study, using a pooling methodology, could detect genomic loci associated with Graves' disease. RESULTS: Nineteen of the top ranking single nucleotide polymorphisms including HLA-DQA1 and C6orf10, were clustered within the Major Histo-compatibility Complex region on chromosome 6p21, with rs1613056 reaching genome wide significance (p = 5 × 10-8). Technical validation of top ranking non-Major Histo-compatablity complex single nucleotide polymorphisms with individual genotyping in the discovery cohort revealed four single nucleotide polymorphisms with p ≤ 10-4. Rs17676303 on chromosome 1q23.1, located upstream of FCRL3, showed evidence of association with Graves' disease across the discovery, replication and combined cohorts. A second single nucleotide polymorphism rs9644119 downstream of DPYSL2 showed some evidence of association supported by finding in the replication cohort that warrants further study. CONCLUSIONS: Pooled genome wide association study identified a genetic variant upstream of FCRL3 as a susceptibility locus for Graves' disease in addition to those identified in the Major Histo-compatibility Complex. A second locus downstream of DPYSL2 is potentially a novel genetic variant in Graves' disease that requires further confirmation.

Assessment of anterior segment parameters of keratoconus eyes in an Australian population.

PURPOSE: To assess anterior segment parameters of eyes with keratoconus (KC) at different clinical stages of disease. METHODS: KC and non-KC patients were recruited from public and private clinics in Melbourne, Australia. Axial length (AL), mean front corneal curvature (Front Km), mean back corneal curvature (Back Km), central corneal thickness (CCT), corneal thickness at the apex (CTA), corneal thickness at the thinnest point (CTT), anterior chamber depth (ACD), and corneal volume were noted for all the eyes. RESULTS: A total of 181 individuals comprising 44 (24.3%) subclinical KC, 118 (65.2%) clinical KC, and 19 (10.5%) control subjects were analyzed. Significant differences were noticed between the subclinical KC and control group for ACD and CTT, whereas between clinical and control groups, significant differences were obtained for AL, CCT, CTA, CTT, and ACD (p < 0.05). In the case of mild, moderate, and severe KC groups, Back Km, CCT, CTA, and CTT were significantly associated (p < 0.001) with increasing disease severity. We further did receiver operating characteristic analysis to confirm the importance of pachymetric parameters in differentiating between control and KC eyes. The area under the receiver operating characteristic curve value of CTT for subclinical and clinical KC was 0.68 and 0.82, which showed that it may be a potential marker for the early detection and prevention of KC. CONCLUSIONS: This study identified the anterior chamber parameters that differ between subclinical and clinical KC as well as the severity of KC. There is a significant reduction in CTT between control and subclinical eyes, although there are no significant alterations in Front and Back Km or AL between the two groups. Also, a progressive reduction in the pachymetric readings at the pupil center, apex, and thinnest corneal point was identified when comparing mild to severe KC groups. Thus, corneal thickness represents an important parameter that needs to be considered in monitoring KC disease severity.

Vision-Related Quality of Life and Ocular Parameters in End-Stage Renal Disease Patients Undergoing Hemodialysis.

Purpose: To evaluate the vision-related quality of life (VRQoL) of patients receiving hemodialysis through the assessment of the impact of vision impairment (IVI) questionnaire and ocular parameters, including best-corrected visual acuity (BCVA), intraocular pressure (IOP), and refraction as calculated by spherical equivalent (SE) of each eye. Methods: Fifty-one patients with end-stage renal disease undergoing hemodialysis at a single center were recruited, and a total of 77 eyes were evaluated. BCVA, IOP, and SE were evaluated before and after hemodialysis (within 30 min). Results: Of the 51 patients recruited, 13 (25%) were female, 37 (73%) were male, and one (2%) chose not to specify gender. The mean age was 61.85 ± 32 years. The mobility IVI score was correlated significantly with the presence of hypertension (P = 0.01), eye drop usage (P = 0.04), and gender (P = 0.04). Emotional IVI scores were correlated significantly with diabetes (P = 0.03) and hypertension (P < 0.01). IOP significantly correlated with the IVI overall score (P = 0.02), including the reading IVI subscale and the emotional IVI subscale. Several factors were associated with posthemodialysis ocular parameters, including predialysis ocular parameters, age, and hypertension (P < 0.05 for all). Conclusions: IOP significantly correlated with VRQoL in hemodialysis patients. Demographic variables such as diabetes status, hypertension, eye drop usage, and gender also significantly correlated with subsections of the IVI questionnaire. This study investigated the relationship between ocular parameters and VRQoL in hemodialysis patients, and future longitudinal research is needed to further elucidate the mechanisms.

Non-genetic risk factors for keratoconus.

Keratoconus is a complex and multifactorial disease and its exact aetiology remains unknown. This current study examined the important environmental risk factors and their association with keratoconus. This study was registered in the PROSPERO International Prospective Register of systematic reviews under registration number CRD42021256792 in 2021. Scopus, Web of Science, PubMed, and Cochrane CENTRAL databases were searched for all relevant articles published from 1 January 1900 to 31 July 2021. National Institutes of Health Quality Assessment Tool was used to assess the methodological quality of the studies. The assessment for statistical heterogeneity was assessed using the Z-statistics on RevMan v5.4. P-value of <0.05 was considered as statistically significant and I2 < 25% as homogenous. Thirty studies were included in this meta-analysis. Pooled odds ratio was calculated with 95% CI. The pooled odds ratio (OR) of eye rubbing, atopy, asthma, and eczema was 3.64 (95% CI, 2.02, 6.57), 1.90 (95% CI, 1.22, 2.94), 1.36 (95% CI, 1.15, 1.61) and 1.90 (95% CI, 1.22, 2.94), respectively. The OR for diabetes was 0.86 (95% CI 0.73, 1.02), and use of sunglasses, contact lens, allergic conjunctivitis, side sleep position and prone sleep position was 0.40 (95% CI, 0.16, 0.99), 1.68 (0.70, 4.00), 2.24 (95% CI, 0.68, 7.36), 3.81 (95% CI, 0.31, 46.23), 12.76 (95% CI, 0.27, 598.58), respectively. Twenty studies were considered to be of high quality, nine to be moderate and one to be low. Environmental risk factors have been identified to play a role in the susceptibility of keratoconus. However, further large-scale longitudinal studies are needed to understand the mechanisms between environmental risk factors and keratoconus.

Accuracy of Machine Learning Assisted Detection of Keratoconus: A Systematic Review and Meta-Analysis.

(1) Background: The objective of this review was to synthesize available data on the use of machine learning to evaluate its accuracy (as determined by pooled sensitivity and specificity) in detecting keratoconus (KC), and measure reporting completeness of machine learning models in KC based on TRIPOD (the transparent reporting of multivariable prediction models for individual prognosis or diagnosis) statement. (2) Methods: Two independent reviewers searched the electronic databases for all potential articles on machine learning and KC published prior to 2021. The TRIPOD 29-item checklist was used to evaluate the adherence to reporting guidelines of the studies, and the adherence rate to each item was computed. We conducted a meta-analysis to determine the pooled sensitivity and specificity of machine learning models for detecting KC. (3) Results: Thirty-five studies were included in this review. Thirty studies evaluated machine learning models for detecting KC eyes from controls and 14 studies evaluated machine learning models for detecting early KC eyes from controls. The pooled sensitivity for detecting KC was 0.970 (95% CI 0.949-0.982), with a pooled specificity of 0.985 (95% CI 0.971-0.993), whereas the pooled sensitivity of detecting early KC was 0.882 (95% CI 0.822-0.923), with a pooled specificity of 0.947 (95% CI 0.914-0.967). Between 3% and 48% of TRIPOD items were adhered to in studies, and the average (median) adherence rate for a single TRIPOD item was 23% across all studies. (4) Conclusions: Application of machine learning model has the potential to make the diagnosis and monitoring of KC more efficient, resulting in reduced vision loss to the patients. This review provides current information on the machine learning models that have been developed for detecting KC and early KC. Presently, the machine learning models performed poorly in identifying early KC from control eyes and many of these research studies did not follow established reporting standards, thus resulting in the failure of these clinical translation of these machine learning models. We present possible approaches for future studies for improvement in studies related to both KC and early KC models to more efficiently and widely utilize machine learning models for diagnostic process.

Diagnosis and Management of Keratoconus-A Narrative Review of Clinicians' Perspectives.

This review discusses the current practices, attitudes, and trends in diagnosing and managing keratoconus (KC) in adults and children by optometrists and ophthalmologists in order to highlight the differences on a global scale. Two independent reviewers searched the electronic databases and grey literature for all potential articles published from 1 January 2000 to 1 June 2022 on management of KC. Keywords used in searches included "keratoconus", "diagnosis", "management", "treatment", "attitude", "practices", "opinion", "optometrist", "ophthalmologist", "consensus", and "protocol". A total of 19 articles was included in this review-12 from the database search and seven from the grey literature. Although a common stepwise approach of non-surgical management was noted, there were differences in the rates of prescribing rigid gas permeable lenses. Furthermore, while clinicians agreed on the need for early diagnosis, the timeline and type of referral varied significantly. A similar discordance was found in the milestones for surgical intervention and preferred surgical techniques. Practice patterns in keratoconus diagnosis and management vary throughout the world. Multiple recommendations and suggestions to minimise the differences have been provided in the literature, with the main themes being improvement in education, interdisciplinary patient care, and further research to reach consensus.

Keratoconus in pre-teen children: Demographics and clinical profile.

Purpose: To study the demographics and clinical profile of keratoconus (KC) presenting in pre-teen children in India. Methods: This was a retrospective case series conducted as a single-institutional study at a tertiary eye center in India. A total of 586 eyes from 294 KC patients (aged 12 years or less) without any active comorbid conditions of the eye were included in the study. Slit-lamp biomicroscopy was used to document the clinical signs of KC. Information on age; gender; reason for consultation; family history; history of allergy, atopy, and eye rubbing; manifest refraction; uncorrected and best-corrected distance visual acuity (UCVA and BCVA, respectively); clinical presentation; and contact lens usage were also analyzed, along with data on types of medical and surgical treatments for KC and their outcomes. Results: The mean age of this pediatric KC patient cohort was 9.3 ± 1.8 years, and there was a male (70%) preponderance. Baseline mean UCVA, BCVA, steep keratometry, and flat keratometry were 0.86 ± 0.58 logMAR, 0.44 ± 0.38 logMAR, 54.82 ± 8.4 D, and 48.21 ± 9.5 D, respectively. Progression, necessitating collagen crosslinking (CXL), was noted in 12.7% eyes. Post-CXL, visual and topographic parameters remained stable without any complications till 6 months posttreatment. However, in eyes that did not undergo CXL, significant progression over time (P < 0.001) was observed. A keratoplasty was required in 2.3% eyes. Conclusion: KC was present at an advanced stage in 25% of the pre-teens in our series, and therefore, it is an important diagnostic entity when a refractive error is diagnosed, even in very young children.

Cross-Linking Improves the Quality of Life of People With Keratoconus: A Cross-Sectional and Longitudinal Study From the Save Sight Keratoconus Registry.

PURPOSE: The purpose of this study was to comprehensively evaluate the patient-reported quality-of-life (QoL) outcomes after corneal cross-linking for keratoconus. METHODS: This Save Sight Keratoconus Registry study used cross-sectional and longitudinal designs. For the cross-sectional study, 532 patients with keratoconus (mean age 30.9 ± 11.9 years; 31.6% female) completed the Keratoconus Outcomes Research Questionnaire (KORQ) and 343 patients with keratoconus (mean age 28.3 ± 10.7 years; 32.7% female) completed the Impact of Vision Impairment (IVI) questionnaires. Similarly, for the longitudinal study, 39 patients (mean age 24.2 ± 8.4 years; 23.1% female) completed the KORQ and 16 patients (mean age 27.9 ± 17.1 years; 50.0% female) completed the IVI questionnaire before and after 6 months of cross-linking. The QoL data were analyzed using the Andrich Rating Scale Model of Rasch analysis. RESULTS: For both cross-sectional and longitudinal studies, the KORQ and IVI scales demonstrated satisfactory psychometric properties [ordered and well-spaced categories, variance explained by the measure 52%-73%, person separation index 2.4-3.9, and fit statistics <1.3 (most cases)]. The patients who had not undergone corneal cross-linking had worse mean activity limitation than those with cross-linking (P = 0.008). However, the differences in symptoms and emotional scores between the groups were not statistically significant (both P > 0.05). The longitudinal study showed that cross-linking was associated with improved activity limitation, symptoms, and emotional scores. CONCLUSIONS: The KORQ and IVI are psychometrically robust tools to evaluate the QoL outcomes of corneal cross-linking. Cross-linking is associated with improved activity limitation, symptoms, and emotional status.

The M4 muscarinic antagonist MT-3 inhibits myopia in chick: evidence for site of action.

PURPOSE: It is well established that the broad-band muscarinic antagonist, atropine is effective at inhibiting the progression of myopia and does so by preventing the elongation of the vitreous chamber of the eye. However, uncertainty remains as to whether this effect occurs through a receptoral mechanism and, if so, which muscarinic receptor subtype mediates this effect. Previous work, in avian and mammalian models of myopia, implicates the M1 and M4 receptors as potential targets. The current study used physiologically relevant concentrations of highly selective muscarinic antagonists (MT-3 and MT-7) to further characterise the role of the M4 receptor in the control of myopia in the chick model of refractive development. METHODS: Nine groups of week-old chicks underwent 5 days of monocular deprivation, with a translucent occluder, to induce myopia. These animals had either no injection, scleral puncture with a needle, or daily intravitreal injections of MT-3 (M4-selective), MT-7 (M1-selective) or vehicle. Three concentrations of each antagonist were delivered (250 nm, 2.5 µm and 10 µm). After the treatment period, keratometry, retinoscopy and A-Scan ultrasound were used to assess ocular biometry. RESULTS: MT-3 treatment produced a significant dose-dependent reduction in relative myopia (treated-control eye) compared to vehicle treatment (vehicle -10.1 ± 1.1 D vs 10 µm MT-3 -4.0 ± 1.5 D, p < 0.01). The majority of this effect was due to reduced relative vitreous chamber elongation in drug treated eyes (vehicle +0.26 ± 0.04 mm, 10 µm MT-3 +0.08 ± 0.07 mm, p < 0.05). In contrast, MT-7 had no significant effect on the development of myopia (MT-7 10 µm: myopia, -12.1 ± 0.8 D and vitreous chamber depth, +0.23 ± 0.07 mm). Calculations indicate that the experimentally achieved concentrations of MT-3 at intraocular receptors necessary to inhibit 50% of myopia development (between 5 and 50 nm) were consistent with published in vitro affinity constants for the M4 receptor and below those for the M1 receptor. Histology demonstrated that MT-3 at the doses used had no gross effects on the retina, indicating a non-toxic mode of action. CONCLUSIONS: In the chick, which lacks a homologue of the mammalian M1 receptor, the above findings represent compelling evidence that muscarinic antagonists prevent myopia progression through an M4-receptor mediated mechanism, most likely located in the retina.

Machine learning with a reduced dimensionality representation of comprehensive Pentacam tomography parameters to identify subclinical keratoconus.

PURPOSE: To investigate the performance of a machine learning model based on a reduced dimensionality parameter space derived from complete Pentacam parameters to identify subclinical keratoconus (KC). METHODS: All 1692 available parameters were obtained from the Pentacam imaging machine on 145 subclinical KC and 122 control eyes. We applied a principal component analysis (PCA) to the complete Pentacam dataset to reduce its parameter dimensionality. Subsequently, we investigated machine learning performance of the random forest algorithm with increasing numbers of components to identify their optimal number for detecting subclinical KC from control eyes. RESULTS: The dimensionality of the complete set of 1692 Pentacam parameters was reduced to 267 principal components using PCA. Subsequent selection of 15 of these principal components explained over 85% of the variance of the original Pentacam-derived parameters and input to train a random forest machine learning model to achieve the best accuracy of 98% in detecting subclinical KC eyes. The model established also reached a high sensitivity of 97% in identification of subclinical KC and a specificity of 98% in recognizing control eyes. CONCLUSIONS: A random forest-based model trained using a modest number of components derived from a reduced dimensionality representation of complete Pentacam system parameters allowed for high accuracy of subclinical KC identification.

A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus.

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

Evaluating the Performance of Various Machine Learning Algorithms to Detect Subclinical Keratoconus.

Purpose: Keratoconus (KC) represents one of the leading causes of corneal transplantation worldwide. Detecting subclinical KC would lead to better management to avoid the need for corneal grafts, but the condition is clinically challenging to diagnose. We wished to compare eight commonly used machine learning algorithms using a range of parameter combinations by applying them to our KC dataset and build models to better differentiate subclinical KC from non-KC eyes. Methods: Oculus Pentacam was used to obtain corneal parameters on 49 subclinical KC and 39 control eyes, along with clinical and demographic parameters. Eight machine learning methods were applied to build models to differentiate subclinical KC from control eyes. Dominant algorithms were trained with all combinations of the considered parameters to select important parameter combinations. The performance of each model was evaluated and compared. Results: Using a total of eleven parameters, random forest, support vector machine and k-nearest neighbors had better performance in detecting subclinical KC. The highest area under the curve of 0.97 for detecting subclinical KC was achieved using five parameters by the random forest method. The highest sensitivity (0.94) and specificity (0.90) were obtained by the support vector machine and the k-nearest neighbor model, respectively. Conclusions: This study showed machine learning algorithms can be applied to identify subclinical KC using a minimal parameter set that are routinely collected during clinical eye examination. Translational Relevance: Machine learning algorithms can be built using routinely collected clinical parameters that will assist in the objective detection of subclinical KC.

Association of Genetic Variation With Keratoconus.

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.

Genome-wide association meta-analysis of corneal curvature identifies novel loci and shared genetic influences across axial length and refractive error.

Corneal curvature, a highly heritable trait, is a key clinical endophenotype for myopia - a major cause of visual impairment and blindness in the world. Here we present a trans-ethnic meta-analysis of corneal curvature GWAS in 44,042 individuals of Caucasian and Asian with replication in 88,218 UK Biobank data. We identified 47 loci (of which 26 are novel), with population-specific signals as well as shared signals across ethnicities. Some identified variants showed precise scaling in corneal curvature and eye elongation (i.e. axial length) to maintain eyes in emmetropia (i.e. HDAC11/FBLN2 rs2630445, RBP3 rs11204213); others exhibited association with myopia with little pleiotropic effects on eye elongation. Implicated genes are involved in extracellular matrix organization, developmental process for body and eye, connective tissue cartilage and glycosylation protein activities. Our study provides insights into population-specific novel genes for corneal curvature, and their pleiotropic effect in regulating eye size or conferring susceptibility to myopia.

Do age-related macular degeneration genes show association with keratoconus?

BACKGROUND: Keratoconus (KC) is a common corneal condition with an unknown gender predominance. Although numerous studies have investigated the genetic component of KC, no specific genes have yet been attributed to the condition. We recently reported posterior segment changes occurring in the eyes of KC patients. However, it is not clear whether these changes are part of KC pathogenesis or reflect changes in anatomical features of the eye manifested by changes at the cornea. Given retinal changes represent the main characteristics observed in age-related macular degeneration (AMD) and that pleiotropy has been demonstrated between different eye diseases, we wished to assess if known AMD associated genes were also associated with KC. METHODS: A total of 248 KC subjects and 366 non-KC (control) subjects were recruited from public and private clinics in Melbourne for this analysis. Nineteen single nucleotide polymorphisms (SNPs) previously associated with AMD, including rs10490924 (ARMS2/HTRA1), rs10737680 (CFH), rs13278062 (TNFRSF10A), rs1864163 (CETP), rs2230199 (C3), rs3130783 (IER3/DDR1), rs334353 (TGFBR1), rs3812111 (COL10A1), rs429608 (C2/CFB), rs4420638 (APOE), rs4698775 (CFI), rs5749482 (TIMP3), rs6795735 (ADAMTS9), rs8017304 (RAD51B), rs8135665 (SLC16A8), rs920915 (LIPC), rs943080 (VEGFA), rs9542236 (B3GALTL) and rs13081855 (COL8A1/FILIP1L), were genotyped in this cohort. Logistic regression was applied to evaluate the association between these SNPs and KC on both genders together, as well as each gender separately. Linear regression was also applied to assess the association between SNPs and corneal curvature. Bonferroni correction was applied to adjust for multiple testing. RESULTS: Genotyping data were available for 18 SNPs. The SNP, rs6795735 (ADAMTS9) was significantly associated with KC (p = 3.5 × 10- 4) when both genders were assessed, whereas rs5749482 (TIMP3) was only associated in males (p = 7.7 × 10- 4) following Bonferroni multiple correction. However, when the covariates of age and gender were included, the associations became non-significant. In addition, none of the SNPs appeared significant for corneal curvature. CONCLUSIONS: Our study suggested a potential association of rs6795735 in the ADAMTS9 gene and rs5749482 in the TIMP3 gene in KC and that different associations may be gender specific. Overall, SNPs initially identified as associated with AMD following multiple correction may be further impacted by other factors such as age or gender and further studies are needed to resolve this issue.