E2-2 protein and Fuchs's corneal dystrophy

Keith Baratz, Nirubol Tosakulwong, Euijung Ryu, William L. Brown, Kari Branham, Wei Chen, Khoa D. Tran, Katharina E. Schmid-Kubista, John R. Heckenlively, Anand Swaroop, Goncalo Abecasis, Kent R Bailey, Albert O. Edwards

Research output: Contribution to journalArticle

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Abstract

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 = 2.3×10-26). 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 = 4.0×10-7), 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.).

Original languageEnglish (US)
Pages (from-to)1016-1024
Number of pages9
JournalNew England Journal of Medicine
Volume363
Issue number11
DOIs
StatePublished - Sep 9 2010

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Fuchs' Endothelial Dystrophy
Proteins
Transcription Factors
Cornea
Endothelial Cells
National Eye Institute (U.S.)
Alleles
Genes
Corneal Endothelium
Protein Tyrosine Phosphatases
Corneal Transplantation
Homozygote
Extracellular Matrix

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Baratz, K., Tosakulwong, N., Ryu, E., Brown, W. L., Branham, K., Chen, W., ... Edwards, A. O. (2010). E2-2 protein and Fuchs's corneal dystrophy. New England Journal of Medicine, 363(11), 1016-1024. https://doi.org/10.1056/NEJMoa1007064

E2-2 protein and Fuchs's corneal dystrophy. / Baratz, Keith; Tosakulwong, Nirubol; Ryu, Euijung; Brown, William L.; Branham, Kari; Chen, Wei; Tran, Khoa D.; Schmid-Kubista, Katharina E.; Heckenlively, John R.; Swaroop, Anand; Abecasis, Goncalo; Bailey, Kent R; Edwards, Albert O.

In: New England Journal of Medicine, Vol. 363, No. 11, 09.09.2010, p. 1016-1024.

Research output: Contribution to journalArticle

Baratz, K, Tosakulwong, N, Ryu, E, Brown, WL, Branham, K, Chen, W, Tran, KD, Schmid-Kubista, KE, Heckenlively, JR, Swaroop, A, Abecasis, G, Bailey, KR & Edwards, AO 2010, 'E2-2 protein and Fuchs's corneal dystrophy', New England Journal of Medicine, vol. 363, no. 11, pp. 1016-1024. https://doi.org/10.1056/NEJMoa1007064
Baratz K, Tosakulwong N, Ryu E, Brown WL, Branham K, Chen W et al. E2-2 protein and Fuchs's corneal dystrophy. New England Journal of Medicine. 2010 Sep 9;363(11):1016-1024. https://doi.org/10.1056/NEJMoa1007064
Baratz, Keith ; Tosakulwong, Nirubol ; Ryu, Euijung ; Brown, William L. ; Branham, Kari ; Chen, Wei ; Tran, Khoa D. ; Schmid-Kubista, Katharina E. ; Heckenlively, John R. ; Swaroop, Anand ; Abecasis, Goncalo ; Bailey, Kent R ; Edwards, Albert O. / E2-2 protein and Fuchs's corneal dystrophy. In: New England Journal of Medicine. 2010 ; Vol. 363, No. 11. pp. 1016-1024.
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abstract = "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 = 2.3×10-26). 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 = 4.0×10-7), 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.).",
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T1 - E2-2 protein and Fuchs's corneal dystrophy

AU - Baratz, Keith

AU - Tosakulwong, Nirubol

AU - Ryu, Euijung

AU - Brown, William L.

AU - Branham, Kari

AU - Chen, Wei

AU - Tran, Khoa D.

AU - Schmid-Kubista, Katharina E.

AU - Heckenlively, John R.

AU - Swaroop, Anand

AU - Abecasis, Goncalo

AU - Bailey, Kent R

AU - Edwards, Albert O.

PY - 2010/9/9

Y1 - 2010/9/9

N2 - 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 = 2.3×10-26). 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 = 4.0×10-7), 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.).

AB - 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 = 2.3×10-26). 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 = 4.0×10-7), 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.).

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