The Genetic and Epigenetic Architecture of Keratoconus: Emerging Pathways and Clinical Implications

Keratoconus (KCN) is a progressive corneal ectasia that manifests at a young age and significantly impacts vision and quality of life. Early diagnosis allows for effective treatment with corneal collagen crosslinking, yet there is a lack of screening methods. This research aims to screen adolescents and young adults for this sight-threatening disease using quick corneal tomography mapping. This prospective cross-sectional study is being conducted at Johns Hopkins Aramco Healthcare in Saudi Arabia, focusing on subjects aged 13-23. We are presenting the data from our study as internal pilot study data. Bilateral corneal imaging with Pentacam HR (Oculus, Wetzlar, Germany), utilizing Scheimpflug corneal tomography, was performed. Historical data on allergies, eye rubbing, KCN, family history, previous eye surgery, and contact lens use were collected. The Belin Ambrosio Enhanced Ectasia Display total D value served as an objective criterion for suspect KCN (SKCN) diagnosis. In this study with 110 participants, KCN was identified in 2.75% of participants and SKCNin 11.93%. Systemic allergies or eczema were reported by 2.80%, with no cases in the KCN or SKCN groups. Eye rubbing behavior was observed in 5.50%, with the highest prevalence (33.30%) in the KCN group. A family history of KCN was found in 21.10%, with SKCN having the highest prevalence (30.80%). This restricted population study reveals a significant KCN rate of 2.75%. The condition, easily detected and treatable with corneal collagen crosslinking, highlights the need for larger population studies to determine the disease's true prevalence. Efficient screening programs tailored to regional data are essential for early detection and intervention.

BackgroundAlthough body mass index (BMI) and eye rubbing are linked to an increased risk of keratoconus (KC), the interactive effect of eye rubbing and BMI on KC is largely unknown. This study aimed to evaluate the independent and interactive effects of BMI and eye rubbing on KC and to further explore the role of environmental factors on the occurrence of KC.MethodsA total of 621 individuals (291 KC patients and 330 control individuals) were enrolled in this hospital‑based study on KC patients in Central China after individuals missing BMI data were excluded. BMI was calculated as weight in kilograms divided by the square of height in meters. Data on eye rubbing was recorded through face-to-face interviews. Generalized linear regression models were used to analyze associations among BMI, eye rubbing and KC. Interaction plots were used to describe the interactive effects of BMI and eye rubbing on KC.ResultsThe β and 95% confidence interval (CI) were 0.923 (0.112, 1.733) (p = 0.026) and 3.356 (1.953, 4.759) (p < 0.001), respectively, for the effect of each 10 kg/m2 increase in BMI and each 1 min increase in eye rubbing on KC. The interaction of BMI and eye rubbing were positively correlated with KC (p < 0.001).ConclusionThese findings suggested that a high BMI aggravated the negative effect of eye rubbing on KC, implying that individuals with a high BMI may be more susceptible to exposure to eye rubbing, which is related to an increased risk of KC.

PurposeTo evaluate the independent and interactive effects of eye rubbing and atopy on keratoconus (KC) in central China.MethodsA total of 330 KC patients and 330 controls were recruited in the case-control study. Eye rubbing and history of atopy were recorded through face-to-face interviews. The association between KC and eye rubbing, atopy, interactive effects of eye rubbing and atopy were analyzed by logistic regression, and the odds ratios (OR), relative excess risk due to interaction (RERI), attributable proportion (AP), synergy (S) index, and 95% confidence intervals (95% CI) were calculated.ResultsA total of 228 patients (69.09%) had an eye rubbing history, and 53 (16.06%) had an atopy history in the KC group, which were both higher than that in the control group (p<0.001). Eye rubbing and atopy were positively associated with KC in multivariate analysis, with ORs (95% CIs) of 15.11 (10.02, 22.80) and 5.30 (2.59, 10.84), respectively. Compared to non-eye rubbing and non-atopy eyes, the risk for eye rubbing coexisted with atopy was 52.31 (12.25, 223.35). No significant associations were found between KC and multiplicative interaction (p=0.608). The RERI, AP, and S values were 32.89 (-43.35, 109.14), 0.63 (0.05, 1.21), and 2.79 (0.56, 13.96), respectively, with no significant association between additive interaction and KC. No significant associations were found between eye rubbing, atopy and the severity of KC (p>0.05).ConclusionEye rubbing and atopy were separately positively associated with KC, and there was a strong impact of coexistent eye rubbing and atopy on KC in China. Further multi-center and cohort study need to be conducted to explore the role of eye rubbing and atopy in the occurrence and development of KC.

PurposeStudies have shown that eye rubbing is associated with increased risk of keratoconus (KC). However, the potential mediating roles between eye rubbing and KC remain largely unknown. Hence, this study aims to explore the mediating roles of two specific factors, namely, the inverse of the stiffness parameter at the first applanation (-SPA1) and maximal corneal keratometry (Kmax) values, in the relationship between eye rubbing and KC.MethodsA total of 395 patients with KC and 396 controls from the Chinese keratoconus (CKC) cohort study were included in this case–control analysis. The Spearman correlation and generalized linear regression models were used to analyze the associations between the time of eye rubbing, -SPA1, Kmax, and KC. Furthermore, three mediation models (individual, parallel multiple, and serial multiple) were utilized to investigate the mediating roles of -SPA1 and Kmax in the relationship between eye rubbing and KC.ResultsAfter adjusting for confounding factors, the odds ratio and 95% confidence interval (CI) for the time of eye rubbing, -SPA1, and Kmax in relation to KC were 1.02 (1.01, 1.04), 1.16 (1.12, 1.19), and 3.86 (2.52, 5.92), respectively. The individual mediation model indicated that the indirect effects of -SPA1 and Kmax were 0.084 and 0.056, respectively. The parallel multiple mediation model showed a total indirect effect of 0.081 for -SPA1 and Kmax. Additionally, the serial multiple mediation model (time of eye rubbing → -SPA1 → Kmax → KC) indicated that following -SPA1, Kmax partially mediated the relationship between the time of eye rubbing and KC with a total indirect effect of 0.024 (95% CI: 0.016–0.042), accounting for 14.5% of the total effect (time of eye rubbing on KC), while no significant indirect effect was found for Kmax alone.ConclusionsThe individual, parallel multiple, and serial multiple mediation analyses consistently demonstrated the mediating roles of -SPA1 and Kmax in linking the duration of eye rubbing to KC. Notably, the serial mediation pathway (time of eye rubbing → -SPA1 → Kmax → KC) exhibited a significant indirect effect. These findings confirm and complement the theoretical framework linking eye rubbing to KC, providing a reference for further exploration of the pathogenesis of KC.

BACKGROUND: Corneal transplantation in keratoconus (KC) patients is generally considered to be successful with a high grade of patient satisfaction. Long-term studies suggest a 6% to 11% probability of KC recurrence manifested by keratometric instability and progressive corneal ectasia. METHODS: We propose to review the frequency, risk factors for the development, and the surgical options for the correction of high irregular astigmatism due to late graft ectasia following penetrating keratoplasty (PK). RESULTS: Post-keratoplasty ectasia is characterized by increasing corneal steepening with myopic shift and high irregular astigmatism, developing years or decades after PK, mostly occurring in KC patients. Contact lenses may adequately improve the visual acuity; however, because these patients are often elderly and intolerant to hard contact lenses, ultimately a surgical correction is proposed to the patient. Compressive suture and corneal wedge resection may improve corneal astigmatism, but the outcomes are unpredictable and often temporary. For this reason, a larger PK graft is often proposed for surgical rehabilitation with the consequence of removing more of the recipient’s healthy endothelium and exposing the patient to a renewed immunogenic stimulus and short-term graft failure for endothelial decompensation. More recently, lamellar keratoplasty using various techniques has been proposed as an alternative to PK in order to maximize the visual outcomes and minimize the complications. CONCLUSIONS: Management of advanced corneal ectasia is a significant challenge for corneal surgeons. Many surgical approaches have been developed, so there is a large arsenal of surgical operations to correct post-PK ectasia. Among them, large-diameter anterior lamellar keratoplasty may be a viable, safer, and effective alternative to PK for the correction of post-keratoplasty ectasia.

Background and Objectives: Keratoconus (KC) is a progressive corneal ectasia with multifactorial etiology, increasingly studied for potential associations with psychiatric disorders. This systematic review aimed to evaluate recent evidence linking KC with depression and other psychiatric conditions, including psychotic disorders, personality disorders, attention deficit hyperactivity disorder (ADHD), Tourette syndrome (TS), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD). Materials and Methods: Following PRISMA guidelines, PubMed, ScienceDirect and SpringerLink were searched for English-language observational studies published since 2015 that examined psychiatric disorders in adults with keratoconus. We excluded reviews, case reports, pediatric, non-English, and inaccessible articles. Study quality was assessed using the Newcastle-Ottawa Scale and JBI Checklist. Data were narratively summarized and tabulated-without meta-analysis due to heterogeneity. Results: Twelve studies met inclusion criteria, including 41,906 KC patients and 63,267 controls. Eleven studies investigated depression and one ADHD. Findings on depression were mixed: five studies showed higher depressive symptoms among KC patients, while others found no significant association. Most were cross-sectional and of moderate-to-high quality. The single study on ADHD reported a higher prevalence of KC in males, but no evidence of casual association. Evidence on TS, ASD, and OCD was scarce and largely limited to case reports. The review was limited by heterogeneous methodologies, small sample sizes, an absence of longitudinal data, and reliance on self-report or registry data. Conclusions: Current evidence indicates increased psychological burden among some individuals with KC, particularly regarding depressive symptoms, yet casual relationships remain unproven. Male ADHD patients may have an elevated risk of KC, especially in the presence of eye rubbing. Registration: Not registered.

Aims/Purpose: The corneal stroma, is formed by fibrous connective tissue containing collagen fibrils that are super‐organized in lamellae. In keratoconus (KC), intra‐lamellar and inter‐lamellar disrupted organization causes a progressive thinning and corneal ectasia. The LUMAXIS is a new medical device specifically designed to evaluate the effects of the interaction between polarized light and corneal stroma. It identifies the orientation of collagen fibrils in the cornea, highlighting ultrastructural changes of the tissue. The purpose of this study was to employ the LUMAXIS to discriminate changes in the pattern of corneal collagen fibrils to detect keratoconus.Methods: Patients with KC and controls were included in this prospective study. Corneal tomography (Pentacam) was acquired as well as polarimetric interferometry (LUMAXIS, Phronema S.r.l., Bari, Italy). Custom software was developed to improve the visualization of the representative cross by extracting the histogram equalized luminance to provide a numerical outcome. We then fit a set of ellipses to the image in a semi‐automatic approach, aiming to capture the boundaries of the iris, pupil, each four quadrants of the cross, and eyelids. Combining this information, we are able to obtain a cross parameter. A correlation between cross outcome and Kmax was calculated.Results: A total of sixty eyes of sixty patients were included: 30 healthy subjects (including 60 eyes, mean age of 38.0 ± 13.2 years) and 30 patients with KC (60 eyes, mean age of 39.2 ± 12.9 years). Maximum keratometry value were 59.4 ± 11.2 D in the KC group and 45.3 ± 0.8 D in the healthy group. The cross parameter was 0.41 ± 0.028 in the KC group and 0.24 ± 0.055 in the healthy group. Using only measures taken from the cross resulting from the Lumaxis scan, we were able to distinguish between KC and healthy eyes.Conclusions: The interferometric analysis of diffractive and polarizing effects related to the birefringent properties provides new morphological information at corneal fibrils level. A different corneal pattern of corneal collagen fibrils can be recognized in keratoconus patients compared to healthy patients.

To describe a family segregating a novel truncating ZNF469 homozygous mutation causing brittle cornea syndrome type 1 in a male patient and associated with corneal ectasia in his two heterozygous young children. A 49-year-old affected male and his 12- and 8-year-old, apparently healthy, siblings underwent phenotypic and genetic assessment. An Oculus Pentacam Scheimpflug topographer system was employed for keratometries and central corneal thickness measurements. Exome sequencing was performed in DNA from the index case with subsequent Sanger sequencing confirmation of the ZNF469 gene causal variant in his relatives. The index case had a history of bilateral keratoglobus, corneal perforations, bilateral hypoacusia, and skeletal anomalies. His two children exhibited topographic anomalies compatible with keratoconus suspects as well as mild skeletal anomalies. Genetic analysis identified a novel homozygous c.2340delC variant in the ZNF469 gene, which predicts a p.(Arg781Glufs*19) truncated protein. Sanger sequencing identified heterozygosity for the c.2340delC variant in DNA from both siblings. Our results expand the mutational spectrum associated with brittle cornea syndrome and provide the first demonstration of early corneal anomalies in subjects carrying monoallelic ZNF469 variants.

Keratoconus (KC) is a progressive corneal thinning disorder with an uncertain aetiology. Environmental and genetic factors, including consanguinity, eye rubbing and possibly sun exposure, play a role in the aetiology of KC. Here we test for risk factors for KC in an Israeli population with particular emphasis on sun exposure. This case-control study included KC patients who were diagnosed at Care Laser Medical Group, a refractive surgery clinic with branches throughout Israel. The control group included age, sex and ethnicity matched individuals who were randomly selected from patients presenting at the clinic for refractive surgery, but without KC. Study subjects were asked to fill out a self-administered questionnaire that included demographic and geographic details, questions on ocular and general health and sun exposure. Conditional logistic regression was used to analyse univariable and multivariable data to identify risk factors for KC. Seventy-three KC patients and 146 controls participated in the study. Univariable analyses demonstrated that eye rubbing [odds ratio (OR) = 3.76], positive family history of KC (OR = 6.10) and parents' education (<12 years, OR = 0.27, 0.23 for father's and mother's education respectively) were significant risk factors for KC. Univariable analyses of sun exposure behaviour during teenage years proved equivocal with some behaviours emerging as protective for KC (wearing a hat outdoors, OR = 3.13) or as risk factors (spending time in the shade, OR = 0.45), while others showed no association [limiting time in the sun (p = 0.51), and wearing sunglasses (p = 0.20)]. Most of the factors that were significant in the univariable analyses, also emerged as statistically significant in the multivariable model (OR = 3.37, 9.68, 0.35, 5.51 for eye rubbing, family history, parental education, wearing a hat outdoors, with the exception of spending time in the shade (p = 0.88). Eye rubbing, parents' education (as a measure of socio-economic status) and having family members with KC emerged as significant risk factors for KC. The role of sun exposure in KC remains equivocal and warrants further research.

To demonstrate the correlation between excessive eye rubbing and corneal degeneration for Keratoconus patients. Keratoconus (KC) patients who regularly rub their eyes had shown a rapid degeneration rate of their affected corneas. This observation is experimentally and numerical discussed and developed based on clinical data of 8 of KC Patients with a mean age of 26.5 ± 9.4years old, and four healthy individuals with a mean age of 24.33 ± 5years old at the baseline. Corneal topography was used to measure both central corneal thickness (CCT) and its total refractive power. The registered data had been exploited to assess the progression of the disease, and the final results were embedded in a finite element model of human corneas to simulate their response to eye rubbing at different stages of the pathology. Corneal lifetime prognosis using multi-layer perceptron was then established to estimate the number of eye rubbing cycles for each stage of KC. The survey of KC patients who declared stopping eye rubbing had shown a decrease in CCT loss rate, followed by a durable stability. Mechanical stresses numerical simulations had shown different corneal behaviours in term of shape deformity, apical raise and corneal applanation between healthy and KC stages models. Apical rise ranged from 0.122 to 0.389mm for an applied intraocular pressure that equals to 15mmHg. A normal stress of 5kPa provoked a corneal applanation that ranged from 0.27mm in healthy cases to 1.173mm in severe stages of the disease. The application of 2.5kPa biaxial stress had resulted normal and tangential applanations that successively ranged from 0.152 and 0.173mm in healthy corneas to 0.446mm and 0.458mm in severe KC stages. An adopted prognosis algorithm was able to predict the current stage of the disease and to estimate the remaining number of eye rubbing cycles before failure. Eye rubbing was proven to be a considerable contributing factor in KC patient's corneal degeneration. The progression of this pathology could be decreased or halted by stopping eye rubbing at early stages.

To characterize very asymmetric keratoconus (KC) in terms of clinical demographics and risk factors in the Japanese population. We retrospectively reviewed the clinical records of patients with very asymmetric KC attending a university hospital. Patients with very asymmetric KC had defined clinical KC in one eye and normal topography in the fellow eye. All patients completed a questionnaire on potential risk factors (family history of KC, atopy, asthma, allergy, heart disease, sleep apnea, Down syndrome, eye rubbing, prone sleep position, and dominant hand). These data were compared with those of patients with clinical or topographic KC in both eyes. Subgroup analysis of very asymmetric KC eyes were performed based on the KC status: mild and severe. We retrospectively investigated 66 patients with very asymmetric KC and 505 patients with KC. Patients reported eye rubbing (53%-56%), allergy (62%-63%), and atopy (28%-29%) in both groups. There was no significant difference in terms of risk factors between the two groups. Approximately half of the 66 patients with very asymmetric KC had KC eyes ipsilateral to the dominant hand. Subgroup analysis of very asymmetric KC showed that atopy and asthma were more frequent in the mild KC group than in the severe KC group. Forty-four of 60 patients (73.3%) were using corneal, rigid, gas-permeable contact lenses (corneal GPs) for the KC eye, of which 30 patients (68.2%) were also using a corneal GP for the fellow eye. The patient-reported frequency of eye rubbing, allergy, and atopy were similar between KC and very asymmetric KC. Furthermore, we found no association between hand dominance and KC laterality.

PurposeThe multicenter studies reviewed were designed to evaluate the safety and efficacy of corneal collagen crosslinking (CXL) for the treatment of progressive keratoconus and corneal ectasia after laser refractive surgery. The results of these studies led to approval by the United States Food and Drug Agency for both conditions in 2016. This paper reviews these studies, as well as single-center substudies investigating other aspects of crosslinking outcomes.MethodsAs part of prospective, randomized, controlled clinical trials, the treatment group received standard CXL, and the sham control group received only riboflavin ophthalmic solution. The primary efficacy criterion was maximum keratometry (Kmax) 1 year after CXL. Secondary outcomes were corrected distance visual acuity (CDVA) and uncorrected distance visual acuity (UDVA). Safety and adverse events were analyzed. In single-center substudies, corneal topography, ocular aberrations, corneal haze measurements, corneal thickness, corneal biomechanics, subjective visual function, and outcomes predictors were also investigated. This paper presents a general review of the design and outcomes of crosslinking in these studies.ResultsIn the crosslinking treatment group, Kmax flattened by 1.6 diopters (D) and 0.7 D in eyes with keratoconus and ectasia, respectively. In both studies, there was continued progression in the control group. The CDVA improved by an average of 5.7 logMAR letters (LL) in the keratoconus treatment group and by 5.0 LL in the ectasia group. In both studies, corneal haze was the most frequently reported crosslinking-related adverse finding. This was most prominent at 1 month and generally returned to baseline between 3 and 12 months. In general, corneal topography, ocular aberrations, and subjective visual function improved after crosslinking.ConclusionsIn the US multicenter trials, CXL was shown to be safe and effective in stabilizing Kmax, CDVA, and UDVA in eyes with progressive keratoconus or corneal ectasia.Translational RelevanceCorneal crosslinking was originally developed in the laboratory at the University of Dresden in the late 1990s. The combination of ultraviolet-A light and riboflavin was found to be the most effective of a number of different modalities tested to increase the biomechanical strength of the cornea. The clinical study design for the US multicenter clinical trials of crosslinking demonstrated the safety and effectiveness of this technique for treatment of progressive keratoconus and corneal ectasia, bringing this important advancement to patients in the United States.

Background Concomitant corneal ectasia and posterior lamellar corneal opacification is rare, and the genetic relationship between these two conditions is unclear. We report the genetic and clinical characterization of this phenotype in three unrelated individuals. Materials and Methods One previously reported affected individual and two unreported, unrelated, affected individuals were recruited for the study. Subjects and unaffected relatives underwent slit lamp examination, refraction, and multi-modal imaging. Saliva samples were obtained from two of the three affected individuals, from which DNA was extracted. Sanger sequencing was performed to identify mutations in genes associated with posterior amorphous corneal dystrophy (PACD), brittle cornea syndrome (BCS), and posterior polymorphous corneal dystrophy (PPCD), while copy number variation (CNV) analysis was used to identify CNV in the PACD locus. Results Affected individuals demonstrated bilateral corneal steepening, stromal thinning and lamellar posterior corneal opacification. Corneal topography and tomography revealed conical or globular corneal steepening and decreased thickness. Anterior segment optical coherence tomography demonstrated hyperreflectivity of the posterior stroma in each of the affected individuals. Genetic testing did not detect a heterozygous deletion involving the PACD locus on chromosome 12 or a pathogenic mutation in the genes associated with BCS or PPCD. Conclusions Corneal ectasia may be associated with posterior lamellar stromal opacification that appears consistent with PACD. However, genetic testing for PACD as well as BCS and PPCD in affected individuals fails to reveal pathogenic deletions or mutations, indicating that other genetic factors are involved.

To investigate the association between keratoconus (KC) and allergic eye diseases, eye rubbing, and atopy. PubMed, Web of Science, Scopus, and Cochrane databases were searched for studies investigating eye allergy, atopy, and eye rubbing as risk factors for KC up to April 2021. Two authors independently screened all titles and abstracts against the predefined inclusion and exclusion criteria. The study analysed the prevalence of KC and its risk factors, including eye rubbing, family history of KC, atopy, and allergic eye diseases. The National Institutes of Health Study Quality Assessment Tool was used. Pooled data are presented as odds ratios (OR) and 95% confidence intervals (CI). The analysis was conducted using RevMan version 5.4 software. The initial search yielded 573 articles. After screening, 21 studies were identified for qualitative analysis and 15 for quantitative synthesis. A significant association was found between KC and eye rubbing (OR=5.22, 95% CI [2.80, 9.75], p < 0.00001), family history of KC (OR=6.67, 95% CI [4.77, 9.33], p < 0.00001), and allergies (OR=2.21, 95% CI [1.57, 3.13], p < 0.00001). However, no significant association was found between KC and allergic eye disease (OR=1.82, 95% CI [0.37, 8.97], p=0.46), atopy (OR=1.54, 95% CI [0.58, 4.09], p=0.39), allergic rhinitis (OR=0.85, 95% CI [0.54, 1.33], p=0.47), smoking (OR=0.96, 95% CI [0.76, 1.21], p=0.73), and asthma (OR=1.58, 95% CI [0.99, 2.53], p=0.05). Significant associations were observed between KC and eye rubbing, family history, and allergy, but not with allergic eye disease, atopy, asthma, and allergic rhinitis.

This study determined the risk factors of keratoconus (KC) among secondary school students in the West Region of Cameroon. A stratified, random sampling technique was used to select the 3015 secondary school students, 8 years and older, within the West Region of Cameroon. Selected school students completed the validated Keratoconus Risk Investigative Survey (KRIS) and a structured demographic questionnaire to determine the risk profile of KC. Descriptive analysis, logistic regression and p-values were used to provide an overview of the demographic findings and the risk factors of KC. Estimates were made as the proportion of affected school students and presented with a 95% confidence interval (CI). Multivariate logistic regression analysis was performed to explore the association between KC and the independent predictors that were found significant in the univariate analysis. The ages of the majority (93.2%) of students ranged from eight years to 18 years (mean = 13.18 ± years) and were mostly female (59.7%). Gender (OR 2.024, p < 0.001), eye rubbing (OR 3.615, p < 0.001), exposure to sunlight (OR 2.735, p < 0.001), blood relations with KC (OR 41.819, p < 0.001) and allergic experience (OR 1.070, p < 0.001) were considered. Eye rubbing was the most significant risk factor of keratoconus followed by refractive error, allergic experiences and sunlight exposure. These findings support the evidence that the etiology of KC is multifactorial, with eye rubbing being the most significant factor in this cohort. There is a need to address eye rubbing among students to minimize the risk of KC. Furthermore, 34.46% of students in Cameroon were at risk of developing KC. Hence the risk profile is that one engages in eye rubbing, has a family member with KC, spends more than eight hours per week in the sun and is prone to allergies. It will therefore be prudent for these risk factors for keratoconus to be included in the school health education programs.