Document Detail

An association between the calpastatin (CAST) gene and keratoconus.
MedLine Citation:
PMID:  23449483     Owner:  NLM     Status:  MEDLINE    
PURPOSE: Keratoconus (KC) is a genetically heterogeneous corneal dystrophy. Previously, we performed 2 genome-wide linkage scans in a 4-generation autosomal dominant pedigree and repeatedly mapped a KC locus to a genomic region located on chromosome 5q overlapping the gene encoding the inhibitor of calpains, calpastatin (CAST). To test whether variants in CAST gene are involved in genetic susceptibility to KC, we performed genetic testing of polymorphic markers in CAST gene in family and case-control panels of patients with KC.
METHODS: We genotyped single-nucleotide polymorphisms (SNPs) located in CAST gene in 262 patients in 40 white KC families and in a white case-control panel with 304 cases and 518 controls. Generalized estimating equation models accounting for familial correlations implemented in GWAF program were used for association testing in families. Logistic regression models implemented in PLINK were performed to test the associations in case-control samples.
RESULTS: Genetic testing of the first set of 7 SNPs in familial samples revealed 2 tentative nominally significant markers (rs4869307, P = 0.03; rs27654, P = 0.07). Additional genotyping of 12 tightly spaced SNPs identified CAST SNP rs4434401 to be associated with KC in both familial and case-control panels with P values of 0.005 and 0.05, respectively, and with combined meta P value of familial and case-control cohorts of 0.002 or after Bonferroni correction of 0.04.
CONCLUSIONS: Linkage analysis and genetic association support involvement of CAST gene in the genetic susceptibility to KC. In silico analysis of CAST expression suggests differential regulation of calpain/calpastatin system in cornea as a potential mechanism of functional defect.
Xiaohui Li; Yelena Bykhovskaya; Yongming G Tang; Yoana Picornell; Talin Haritunians; Anthony J Aldave; Loretta Szczotka-Flynn; Sudha K Iyengar; Jerome I Rotter; Kent D Taylor; Yaron S Rabinowitz
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cornea     Volume:  32     ISSN:  1536-4798     ISO Abbreviation:  Cornea     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-04-09     Completed Date:  2013-08-07     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  8216186     Medline TA:  Cornea     Country:  United States    
Other Details:
Languages:  eng     Pagination:  696-701     Citation Subset:  IM    
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MeSH Terms
Calcium-Binding Proteins / genetics*
Case-Control Studies
Chromosome Mapping
Cysteine Proteinase Inhibitors / genetics*
Genetic Association Studies
Genetic Linkage
Genetic Predisposition to Disease
Genotyping Techniques
Keratoconus / genetics*
Microsatellite Repeats
Middle Aged
Polymorphism, Single Nucleotide*
Grant Support
Reg. No./Substance:
0/Calcium-Binding Proteins; 0/Cysteine Proteinase Inhibitors; 79079-11-1/calpastatin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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