Keratoconus (KG) is a non-inflammatory thinning disorder of the cornea with an incidence of approximately 1/2000 in the general population. As the etiology of KG is still unknown, there have been no effective therapeutic measures for the treatment of KC other than contact lenses and cornea transplantation. Association with rare genetic syndromes, observation of apparent autosomal dominant pedigrees, and results from complex segregation analysis all suggest that the genetic factors may play an important role in the susceptibility of KC. The overall goal of this application is to identify susceptibility genes for KC by (1) more clearly refining our topographic criteria for detecting subclinical KC (KC 'suspects') through longitudinal topographic analysis of our existing cohort of patients and their relatives, (2) recruiting additional KC families suitable for nonparametric linkage analysis, and (3) performing a two stage genome-wide screen with model free linkage and association methods. Specifically, all existing study subjects (-2000) will undergo ocular evaluation and videokeratography over the next 5 years to observe longitudinal and clinical topographic changes in order to examine the relationship of videokeratography variables to biomicroscopic indicators of disease status and to develop more refined criteria for 'mildly affected' (subclinical) KC family members (Aim 1). We will recruit an additional 195 keratoconus families with at least 5 family members available to be phenotyped to provide an independent set of families to confirm the linkage findings from the initial scan (Aim 2). We will employ a two stage genomewide screen approach with two sets of families (initial panel and confirmatory panel) and two levels of markers (initial screen markers and fine mapping markers) to identify chromosomal regions linked to KC. Quantitative videokeratographic indices will be used as primary phenotypes in linkage analysis. After the linked regions are confirmed in the second sample, association studies will be carried out for candidate genes in the linked regions to identify specific susceptibility alleles. Identifying genes contributing to the pathogenesis of KG may provide insights into devising medical therapy to arrest its progression and prevent the need for multiple contact lens changes and/or cornea transplantation in select hiah risk individuals.
| Perez-Straziota, Claudia; Gaster, Ronald N; Rabinowitz, Yaron S (2018) Corneal Cross-Linking for Pediatric Keratcoconus Review. Cornea 37:802-809 |
| Khaled, Mariam Lofty; Bykhovskaya, Yelena; Yablonski, Sarah E R et al. (2018) Differential Expression of Coding and Long Noncoding RNAs in Keratoconus-Affected Corneas. Invest Ophthalmol Vis Sci 59:2717-2728 |
| Bykhovskaya, Yelena; Fardaei, Majid; Khaled, Mariam Lotfy et al. (2017) TSC1 Mutations in Keratoconus Patients With or Without Tuberous Sclerosis. Invest Ophthalmol Vis Sci 58:6462-6469 |
| Bykhovskaya, Yelena; Li, Xiaohui; Taylor, Kent D et al. (2016) Linkage Analysis of High-density SNPs Confirms Keratoconus Locus at 5q Chromosomal Region. Ophthalmic Genet 37:109-10 |
| Bykhovskaya, Yelena; Gromova, Anastasia; Makarenkova, Helen P et al. (2016) Abnormal regulation of extracellular matrix and adhesion molecules in corneas of patients with keratoconus. Int J Keratoconus Ectatic Corneal Dis 5:63-70 |
| Bykhovskaya, Yelena; Margines, Benjamin; Rabinowitz, Yaron S (2016) Genetics in Keratoconus: where are we? Eye Vis (Lond) 3:16 |
| Bykhovskaya, Yelena; Caiado Canedo, Ana L; Wright, Kenneth W et al. (2015) C.57 C > T Mutation in MIR 184 is Responsible for Congenital Cataracts and Corneal Abnormalities in a Five-generation Family from Galicia, Spain. Ophthalmic Genet 36:244-7 |
| Kramerov, Andrei A; Saghizadeh, Mehrnoosh; Maguen, Ezra et al. (2015) Persistence of reduced expression of putative stem cell markers and slow wound healing in cultured diabetic limbal epithelial cells. Mol Vis 21:1357-67 |
| Bykhovskaya, Yelena; Seldin, Michael F; Liu, Yutao et al. (2015) Independent origin of c.57 C?>?T mutation in MIR184 associated with inherited corneal and lens abnormalities. Ophthalmic Genet 36:95-7 |
| Rabinowitz, Yaron S; Li, Xiaohui; Canedo, Ana Laura Caiado et al. (2014) Optical coherence tomography combined with videokeratography to differentiate mild keratoconus subtypes. J Refract Surg 30:80-7 |
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