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Association of rs613872 and Trinucleotide Repeat Expansion in the TCF4 Gene of German Patients With Fuchs Endothelial Corneal Dystrophy

Okumura, Naoki, MD, PhD*; Hayashi, Ryousuke, BS, MS*; Nakano, Masakazu, PhD; Tashiro, Kei, MD, PhD; Yoshii, Kengo, PhD; Aleff, Ross, BS§; Butz, Malinda, BS; Highsmith, Edward W., PhD; Wieben, Eric D., PhD§; Fautsch, Michael P., PhD; Baratz, Keith H., MD; Komori, Yuya, BS*; Ueda, Emi, BS*; Nakahara, Makiko, PhD*; Weller, Julia, MD**; Tourtas, Theofilos, MD, PhD**; Schlötzer-Schrehardt, Ursula, PhD**; Kruse, Friedrich, MD, PhD**; Koizumi, Noriko, MD, PhD*

doi: 10.1097/ICO.0000000000001952
Clinical Science

Purpose: To investigate single nucleotide polymorphisms (SNPs) and trinucleotide repeat (TNR) expansion in the transcription factor 4 (TCF4) gene in a large cohort of German patients with Fuchs endothelial corneal dystrophy (FECD).

Methods: Genomic DNA was obtained from 398 patients with FECD and from 58 non-FECD controls. Thirty-seven previously reported SNPs were evaluated by genotyping. The 398 FECD samples were analyzed for TNR expansions by short tandem repeat assays and Southern blotting. The possible associations between the TNR length and clinical parameters (age, sex, visual acuity, and central corneal thickness) were analyzed in 132 patients.

Results: The SNPs in COL8A2, TCF8, LOXHD1, and AGBL1 showed no heterogeneity in 36 cases, although SLCA411 showed 3 nonsense mutations. SNPs were detected for TCF4 (rs613872, rs2123392, rs17089887, rs1452787, and rs1348047), but only rs613872 showed a significant association with FECD (P = 9.93 × 10−12). Overall, 315/398 (79%) patients harbored TNR lengths >50, whereas no non-FECD controls harbored TNR lengths >50. The TCF4 SNP rs613872 genotype was TT: 39 (67%), TG: 18 (31%), and GG: 1 (2%) in non-FECD controls; TT: 39 (47%), TG: 38 (46%), and GG: 6 (7%) in FECD cases harboring TNR <50; and TT: 23 (8%), TG: 224 (79%), and GG: 38 (13%) in FECD cases harboring TNR >50 (P = 2.93 × 10−25). No significant association was detected between the TNR length and clinical parameters.

Conclusions: Our large German cohort demonstrated a significant association between the risk allele G in rs613872 and FECD, irrespective of TNR expansion, although this risk allele was more frequent in FECD cases with TNR expansion than without.

*Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan;

Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan;

Department of Mathematics and Statistics in Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan;

§Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN;

Departments of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN;

Ophthalmology, Mayo Clinic, Rochester, MN; and

**Department of Ophthalmology, University of Erlangen-Nürnberg, Erlangen, Germany.

Correspondence: Noriko Koizumi, MD, PhD, Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe 610-0321, Japan (e-mail:

Supported by the Program for the Strategic Research Foundation at Private Universities from MEXT (N. Koizumi and N. Okumura); NEI grants EY25071 (K. H. Baratz and E. D. Wieben) and EY26490 (M. P. Fautsch); and the Mayo Foundation.

The authors have no conflicts of interest to disclose.

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Received September 07, 2018

Received in revised form February 01, 2019

Accepted February 20, 2019

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