title: An association between the calpastatin (CAST) gene and keratoconus.
abstract: OBJECTIVE
  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.
authors: Cornea Genetic Eye Institute, Los Angeles, CA, USA.
authors: Xiaohui
authors: X
authors: Li
authors: Yelena
authors: Y
authors: Bykhovskaya
authors: Yongming G
authors: YG
authors: Tang
authors: Yoana
authors: Y
authors: Picornell
authors: Talin
authors: T
authors: Haritunians
authors: Anthony J
authors: AJ
authors: Aldave
authors: Loretta
authors: L
authors: Szczotka-Flynn
authors: Sudha K
authors: SK
authors: Iyengar
authors: Jerome I
authors: JI
authors: Rotter
authors: Kent D
authors: KD
authors: Taylor
authors: Yaron S
authors: YS
authors: Rabinowitz
mesh_terms: D002135:Calcium-Binding Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D015853:Cysteine Proteinase Inhibitors / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D060005:Genotyping Techniques; D006801:Humans; D007640:Keratoconus / Q000235:genetics*; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: D002135:Calcium-Binding Proteins; D015853:Cysteine Proteinase Inhibitors; C033668:calpastatin