Replication of the TCF4 intronic variant in late-onset Fuchs corneal dystrophy and evidence of independence from the FCD2 locus.
OBJECTIVE
Fuchs corneal dystrophy (FCD) is an autosomal dominant disease of the corneal endothelium with variable penetrance and expressivity. Recently, rs613872, an intronic variation of TCF4 associated with late-onset FCD, was reported. The present study was undertaken to examine this association in our cohort of FCD patients, to assess the significance of this finding, and to investigate the candidacy of TCF4 in the context of the mapped FCD2 locus.


METHODS
The authors recruited 170 patients with late-onset FCD and 180 age-matched controls. Blood samples were collected, and genomic DNA was extracted. A panel of nine SNPs spanning the entire TCF4 locus was genotyped both on this cohort and on three previously reported FCD2-linked families. The association of an individual SNP with late-onset FCD was evaluated with the Fisher exact test, and the coding exons and exon-intron boundaries of TCF4 were sequenced in 96 affected persons.


RESULTS
The risk allele G of rs613872 is associated significantly with late-onset FCD (odds ratio, 4.2; P = 4.28 x 10⁻¹⁵) and was present in male and female affected persons without any sex bias, replicating recent findings, though the authors found no apparent correlation with the severity of the disease phenotype. Moreover, the risk allele did not cosegregate with the disease phenotype in any of the three FCD2-linked families. The authors did not identify any pathogenic variants in the coding region of TCF4.


CONCLUSIONS
The authors report the first independent replication of rs613872 conferring risk of late-onset FCD. Their data suggest that this risk factor is likely independent of the FCD2 locus, whose causality remains unknown.
Wilmer Eye Institute, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
S Amer
SA
Riazuddin
Elyse J
EJ
McGlumphy
William S
WS
Yeo
Jiangxia
J
Wang
Nicholas
N
Katsanis
John D
JD
Gottsch
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D004247:DNA / Q000235:genetics; D004261:DNA Replication; D005260:Female; D005642:Fuchs' Endothelial Dystrophy / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D004247:DNA
Invest Ophthalmol Vis Sci. 2006 Sep;47(9):3919-26
16936105
Hum Mutat. 2010 Nov;31(11):1261-8
20848555
Am J Ophthalmol. 1967 Dec;64(6):1155-8
6072991
Cell. 1993 Dec 3;75(5):827-30
8252617
Ophthalmic Physiol Opt. 1999 May;19(3):210-22
10627840
Mol Cell Biol. 1996 Jun;16(6):2898-905
8649400
Hum Mol Genet. 2008 Mar 1;17(5):656-66
18024964
Am J Hum Genet. 2007 Sep;81(3):559-75
17701901
J Cell Sci. 2009 Apr 1;122(Pt 7):1014-24
19295128
Invest Ophthalmol Vis Sci. 2005 Jun;46(6):1934-9
15914606
Am J Hum Genet. 2010 Jan;86(1):45-53
20036349
Arch Ophthalmol. 1978 Nov;96(11):2036-9
309758
Cell. 1989 Aug 11;58(3):537-44
2503252
J Exp Med. 1997 Apr 21;185(8):1467-79
9126927
N Engl J Med. 2010 Sep 9;363(11):1016-24
20825314
Mol Cell Biol. 1999 May;19(5):3600-6
10207083
Am J Hum Genet. 2007 May;80(5):988-93
17436254
Invest Ophthalmol Vis Sci. 2005 Dec;46(12):4504-11
16303941
Invest Ophthalmol Vis Sci. 2006 Jan;47(1):140-5
16384955