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Ekaterina Yonova, Abhishek Nag, Cristina Venturini, Pirro Hysi, Katie Williams, Tim Spector, Christopher Hammond; Role of ephrin genes in cortical cataract pathogenesis. Invest. Ophthalmol. Vis. Sci. 2013;54(15):899.
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Although both common and rare variants in the EPHA2 gene were previously implicated in age-related cortical cataract pathogenesis, little is known about the role of other genetic factors in cortical cataract. The purpose of the study was to perform a genome wide association study (GWAS) of cortical cataract to detect common variants, and to analyze rare variants in any genes identified in the GWAS from sequence data.
Cortical cataract was measured in sample of 2265 twins over 50 years of age from the TwinsUK registry using retroilumination images, and all individuals with lens opacity covering more than 5% of the lens area were considered affected. Genotypes were obtained using Illumina 610k and Illumina 317K platforms, which were later imputed against the 1000 genomes SNP panel. We performed a genome-wide logistic regression association analysis of cortical cataract and common Single Nucleotide Polymorphisms (SNPs), adjusting for age and family structure using (Linkage and Association Modeling in Pedigrees) LAMP. Additionally, we looked at association between rare variants in associated genes using the SNP-set kernel association test (SKAT) burden test on sequencing data.
Variants near one of the ephrin (EPH) genes, EPHA4 on chromosome 2q36.1, were highly associated with cortical cataract. The most associated SNP was rs10932912 (p=1.5e-07), 46kb form the end of the gene and is in a region predicted to harbour many transcription factor binding sites. EPHA4 is a EPH-binding receptor important for development of various tissues. Additionally, the SKAT burden test for the same region gave p=0.0007. Examination of associations in other EPH genes showed an association of nominal significance for rs6669666 in the EPHB2 gene (p=0.012). The rare variants burden test for this gene was not statistically significant. EPHB2 gene is important for calcium signalling and cell guidance.
Our study provides further evidence that EPH genes play a role in cortical cataract, EPHA4 and probably EPHB2 in particular. Both these genes are expressed in lens epithelia and Ephb2 -/- murine knockouts develop early cortical cataract. These results require replication, but suggest that further investigation of the roles of EPH genes in maintenance of lens transparency should be further investigated.
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