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John D. Gottsch, S. Amer Riazuddin, Elyse J. McGlumphy, William S. Yeo, Jiangxia Wang, Nicholas Katsanis; Replication of The TCF4 Intronic Variant In Late-onset Fuchs Corneal Dystrophy and Evidence of Independence From The FCD2 Locus. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1106.
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Fuchs Corneal Dystrophy (FCD) is an autosomal dominant disease of the corneal endothelium with variable penetrance and expressivity. Recently, Baratz and colleagues reported rs613872, an intronic variation of TCF4 associated with late-onset FCD. The present study was undertaken to examine this association in our cohort of FCD patients and to assess the significance of this finding and to investigate the candidacy of TCF4 in the context of the mapped FCD2 locus.
We recruited 170 late-onset FCD cases and 180 age-matched controls. Blood samples were collected and genomic DNAs were extracted. A panel of 9 SNPs spanning the entire TCF4 locus was genotyped on both this cohort and on three previously-reported FCD2-linked families. The association of individual SNP with late-onset FCD was evaluated with the Fisher exact test, while the coding exons and exon-intron boundaries of TCF4 were sequenced in 96 affected individuals.
The risk allele G of rs613872 is associated significantly with late-onset FCD (OR=4.2, p=4.28 x 10-15) and was present in male and female affecteds without any gender bias, replicating recent findings, although we find no apparent correlation with the severity of the disease phenotype. Moreover, the risk allele did not co-segregate with the disease phenotype in any of the three FCD2-linked families. Furthermore, we did not identify any pathogenic variants in the coding region of TCF4.
Herein, we report the first independent replication of rs613872 conferring risk of late-onset FCD. Our data suggest that this risk factor is likely independent of the FCD2 locus, whose causality remains unknown.
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