calpastatin and Keratoconus

To investigate whether calpastatin (CAST) gene polymorphisms are in association with keratoconus (KC) in Han Chinese population.. Four SNPs (rs4434401, rs7704167, rs26504, and rs10053056) in CAST gene were genotyped in 120 unrelated Han Chinese KC patients and 305 age and gender matched healthy controls, using TaqMan SNP genotyping method. PLINK and LDmatrix software was used for data analysis.. SNP rs4434401, whose contribution to KC susceptibility has been established in Caucasians, still kept its effect in our population. The C allele frequency of rs4434401 was markedly higher in cases (27.7%) than in the controls (20.7%, P = 0.03654, OR = 1.47, 95%CI = 1.02-2.11). The genotype distribution of rs4434401 showed marginal difference between KC cases and controls. The allelic and genotype frequencies of other three tested SNPs showed no significant difference between cases and controls.. We confirmed previous report that SNP(s) in CAST gene conferred risk for KC susceptibility in Han Chinese population, suggesting the potential contribution of CAST gene to KC development.

Topics: Adolescent; Adult; Alleles; Asian People; Calcium-Binding Proteins; Case-Control Studies; China; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Keratoconus; Male; Polymorphism, Single Nucleotide; Sequence Analysis, DNA; Sex Factors; Young Adult

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.. 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.. 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.. 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.

Topics: Calcium-Binding Proteins; Case-Control Studies; Chromosome Mapping; Cysteine Proteinase Inhibitors; Female; Genetic Association Studies; Genetic Linkage; Genetic Predisposition to Disease; Genotype; Genotyping Techniques; Humans; Keratoconus; Male; Microsatellite Repeats; Middle Aged; Pedigree; Polymorphism, Single Nucleotide