E2-2 protein and Fuchs's corneal dystrophy.
BACKGROUND
Fuchs's corneal dystrophy (FCD) is a leading cause of corneal transplantation and affects 5% of persons in the United States who are over the age of 40 years. Clinically visible deposits called guttae develop under the corneal endothelium in patients with FCD. A loss of endothelial cells and deposition of an abnormal extracellular matrix are observed microscopically. In advanced disease, the cornea swells and becomes cloudy because the remaining endothelial cells are not sufficient to keep the cornea dehydrated and clear. Although rare genetic variation that contributes to both early-onset and typical late-onset forms of FCD has been identified, to our knowledge, no common variants have been reported.


METHODS
We performed a genomewide association study and replicated the most significant observations in a second, independent group of subjects.


RESULTS
Alleles in the transcription factor 4 gene (TCF4), encoding a member of the E-protein family (E2-2), were associated with typical FCD (P=2.3x10(-26)). The association increased the odds of having FCD by a factor of 30 for persons with two copies of the disease variants (homozygotes) and discriminated between case subjects and control subjects with about 76% accuracy. At least two regions of the TCF4 locus were associated independently with FCD. Alleles in the gene encoding protein tyrosine phosphatase receptor type G (PTPRG) were associated with FCD (P=4.0x10(-7)), but the association did not reach genomewide significance.


CONCLUSIONS
Genetic variation in TCF4 contributes to the development of FCD. (Funded by the National Eye Institute and others.)
Baratz
Keith H
KH
Department of Ophthalmology, Mayo Clinic, Rochester, MN, USA.
Tosakulwong
Nirubol
N
Ryu
Euijung
E
Brown
William L
WL
Branham
Kari
K
Chen
Wei
W
Tran
Khoa D
KD
Schmid-Kubista
Katharina E
KE
Heckenlively
John R
JR
Swaroop
Anand
A
Abecasis
Goncalo
G
Bailey
Kent R
KR
Edwards
Albert O
AO
D000483:Alleles; D002882:Chromosomes, Human, Pair 13; D003315:Cornea / Q000473:pathology; D005642:Fuchs' Endothelial Dystrophy / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein
D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein