The purpose of this grant is to identify susceptibility genes involved in the pathogenesis of keratoconus (KC). We will achieve our goal by: 1) refining criteria for the early detection of KC using videokeratography and wavefront Zernike variables;2) comprehensively testing genes under newly identified linkage peaks generated through genome wide linkage scans of KC families, and performing comprehensive positional candidate gene association studies;and 3) characterizing specific genetic variants that predispose an individual to developing KC. We will study a cohort comprising: normal controls, patients with 'early'KC, KC 'suspect', and KC relatives with videokeratography and aberrometry in order to determine the best combination of variables that discriminate KC 'suspects'from normals. Study subjects will be followed longitudinally to determine which combination of variables is predictive of progression to KC, and thus define subclinical KC (Aim 1). After genome-wide linkage scan of multiplex KC families, we identified regions with significant or suggestive linkage on chromosomes 4, 5, 9, 11, 12, and 14, confirmed by subsequent fine mapping studies. To follow-up these positive linkage findings, we will conduct a comprehensive positional candidate gene association study by testing all genes in these regions with tagSNPs. Any positive association results will be tested in an independent sample for confirmation (Aim 2). Additionally, using newly identified criteria for defining subclinical markers for KC (combination of videokeratography and aberrometry), we will refine our linkage analysis on families with KC in an attempt identify new linkage peaks which may encompass new potential candidate genes for study. Genes identified by both genetic association studies and expression studies published in the literature to date will be prioritized for further study to identify specific genetic variants that contribute to the susceptibility of KC (Aim 3). Refining criteria for early detection of KC will provide the tools to prevent many patients from under- going unnecessary surgery and developing post-lasik ectasia, a significant public health issue. It will also facilitate identification of susceptibility genes for KC, which may provide an understanding of the mechanisms contributing to corneal thinning in KC. Ultimately, this work may improve our ability to treat KC and/or prevent the development of KC.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY009052-18
Application #
8215705
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
1993-01-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
18
Fiscal Year
2012
Total Cost
$672,532
Indirect Cost
$258,666
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Bykhovskaya, Yelena; Li, Xiaohui; Taylor, Kent D et al. (2015) Linkage Analysis of High-density SNPs Confirms Keratoconus Locus at 5q Chromosomal Region. Ophthalmic Genet :2-Jan
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
Rabinowitz, Yaron S (2013) INTACS for keratoconus and ectasia after LASIK. Int Ophthalmol Clin 53:27-39
Li, Xiaohui; Bykhovskaya, Yelena; Tang, Yongming G et al. (2013) An association between the calpastatin (CAST) gene and keratoconus. Cornea 32:696-701
Tang, Yongming G; Picornell, Yoana; Su, Xiaowen et al. (2008) Three VSX1 gene mutations, L159M, R166W, and H244R, are not associated with keratoconus. Cornea 27:189-92
Rabinowitz, Yaron S (2007) Intacs for keratoconus. Curr Opin Ophthalmol 18:279-83
Li, Xiaohui; Rabinowitz, Yaron S; Tang, Yongming G et al. (2006) Two-stage genome-wide linkage scan in keratoconus sib pair families. Invest Ophthalmol Vis Sci 47:3791-5
Rabinowitz, Yaron S (2006) INTACS for keratoconus. Int Ophthalmol Clin 46:91-103
Rasheed, K; Rabinowitz, Y S (2000) Surgical treatment of advanced pellucid marginal degeneration. Ophthalmology 107:1836-40
Kim, W J; Rabinowitz, Y S; Meisler, D M et al. (1999) Keratocyte apoptosis associated with keratoconus. Exp Eye Res 69:475-81

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