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An association between the calpastatin (CAST) gene and keratoconus.

ABSTRACT: 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.

SUBMITTER: Li X

PROVIDER: S-EPMC3653445 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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An association between the calpastatin (CAST) gene and keratoconus.

Li Xiaohui X Bykhovskaya Yelena Y Tang Yongming G YG Picornell Yoana Y Haritunians Talin T Aldave Anthony J AJ Szczotka-Flynn Loretta L Iyengar Sudha K SK Rotter Jerome I JI Taylor Kent D KD Rabinowitz Yaron S YS

Cornea 20130501 5

<h4>Purpose</h4>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 ...[more]

PMID: 23449483

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Project description:ObjectiveThe study aimed to evaluate the character of corneal stiffness parameter at the first applanation (SP-A1) in normal and keratoconus eyes and explore the association between SP-A1 and keratoconus severity indicators.MethodsA total of 351 normal and 351 keratoconus eyes were included in the current study. Keratoconus was diagnosed according to the corneal topography map and slit-lamp examination. The severity of keratoconus was classified to mild (steep keratometry (Ks) < 48D), moderate (48 ≤ Ks < 55D), and severe (Ks ≥ 55D). The SP-A1 was measured using the Corvis ST software. The correlation analyses and receiver operating characteristic (ROC) curve were performed in the current analysis.ResultsThe SP-A1 values of keratoconus were lower than that of normal eyes (72.11 (57.02, 83.08) mmHg/mm vs 110.89 (100.45, 122.47) mmHg/mm, P < 0.001). With the severity of keratoconus increasing, the SP-A1 decreased and the value of SP-A1 was 79.54 (70.30, 90.93) mmHg/mm, 65.11 (53.14, 77.46) mmHg/mm, and 47.59 (37.50, 62.14) mmHg/mm in mild, moderate, and severe keratoconus eyes, respectively (P < 0.001). The negative association between SP-A1 and Ks was found in mild, moderate, and severe keratoconus eyes (r mild = -0.171, r moderate = -0.317, r severe = -0.288, all P < 0.05). A positive association between SP-A1 and the thinnest corneal thickness (TCT) was found in all eyes (rnormal = 0.687, r mild = 0.519, r moderate = 0.488, r severe = 0.382, all P < 0.05). SP-A1 was found to be statistically positively associated with intraocular pressure (IOP), biomechanical corrected IOP (bIOP), time from the initiation of air puff until the first applanation (A1T), corneal velocity at the second applanation (A2V), and negatively associated with deformation amplitude (DA), peak distance (PD), corneal velocity at the first applanation (A1V), time from the initiation of air puff until the second applanation (A2T), and DA Ratio Max [2 mm] both in normal and keratoconus eyes (all P < 0.05). The ROC analysis indicated that the AUC (95% CI) of SP-A1 was 0.952 (0.934-0.967) and 0.930 (0.904-0.951) in detecting keratoconus eyes and mild keratoconus eyes from normal eyes, respectively.ConclusionsThe SP-A1 value decreased while the keratoconus severity increased. It was lower in keratoconus than that in normal eyes and could be helpful in identifying keratoconus eyes from normal eyes. Further researches would be warranted to expand the clinical utility of SP-A1.

Project description:BackgroundKeratoconus (KC) is the most common primary ectatic disease of the cornea and a major indication for corneal transplant. To date, limited KC-associated-risk loci have been identified. Association has recently been suggested between KC and 8 single nucleotide polymorphisms (SNPs) in the genomic regions of FNDC3B, COL4A3, MPDZ-NF1B, RXRA-COL5A1, LCN12-PTGDS, FOXO1, and BANP-ZNF469. These SNPs are associated with central corneal thickness (CCT), a known risk factor to KC. We are questioning whether these SNPs are significantly associated with KC in a Saudi Arabian population. The study included 108 unrelated KC cases and 300 controls. Patients were diagnosed with KC according to the Schimpff-flow based elevation map of the cornea. DNA genotyping was done using probe-based allelic discrimination TaqMan assays. Allele frequencies were compared between the cases and controls.ResultsAll SNPs were successfully genotyped with high efficiency (>95 %). The SNPs had no significant deviation in cases or controls from Hardy-Weinberg Equilibrium (HWE, p value > 0.05). None of the selected SNPs were significantly associated with KC in the Saudi Arabian population. However, we replicated the same trend of minor allele frequency (MAF) between cases and controls reported by a recent GWAS regarding the 5 SNPs rs4894535 (FNDC3B, chr3: 171995605), rs1536482 (RXRA-COL5A1, chr9: 137440528), rs7044529 (COL5A1, chr9: 137568051), rs11145951 (LCN12-PTGDS, chr9: 139860264), and rs2721051 (FOXO1, chr13: 41110884).ConclusionsThis is the first study investigating the association of these SNPs with KC in a population from Saudi Arabia. We replicated the same trend of MAF alteration of the association between the SNPs rs4894535 (FNDC3B, chr3: 171995605), rs7044529 (COL5A1, chr9: 137568051), rs11145951 (LCN12-PTGDS, chr9: 139860264) and rs2721051 (FOXO1, chr13: 41110884) and KC-risk as reported by a recently published GWAS. Consistently replicated population-based studies are necessary to identify and/or confirm genetic susceptibility for certain diseases. We acknowledge that the lack of significance in our study is due to our small sample size and insufficient statistical power; however our data still add to the body of evidence of potential KC-candidate SNPs. This report aims at supporting the possible association between CCT-associated SNPs and KC susceptibility.

Dataset Information

An association between the calpastatin (CAST) gene and keratoconus.

Publications

An association between the calpastatin (CAST) gene and keratoconus.

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