CTG18.1 Expansion in TCF4 Increases Likelihood of Transplantation in Fuchs Corneal Dystrophy

Abstract

Purpose: Fuchs dystrophy is the leading indication of corneal transplantation in the United States. A CTG18.1 trinucleotide repeat in TCF4 correlates with increased severity in Fuchs dystrophy; however, quantitative estimates of increased transplantation risk, including effects of age and sex, are unclear.

Methods: In a tertiary institution clinical practice, 574 participants were enrolled in a longitudinal study of Fuchs dystrophy after slit-lamp biomicroscopy confirmed significant central guttae and/or corneal transplantation in both eyes. We documented clinical history, examination findings, and demographic information. We acquired blood samples, extracted DNA, and sequenced the CTG18.1 trinucleotide repeat in TCF4. In this retrospective case-control study, the number of participants with triplet expansion, defined as greater than 40 CTG repeats, and transplantation status were assessed. Kaplan-Meier estimates of timing and transplantation events were produced. The Cox proportional hazard regression model was used to assess the relationship between age, sex, triplet expansion, and surgery.

Results: A total of 106 participants (18.5%) previously underwent corneal transplantation in at least 1 eye at the time of initial evaluation. A higher proportion of individuals harboring allele expansion had undergone transplantation (78/357, 21.8%) compared with those without the expanded allele (28/217, 12.9%), a significant association (P = 0.007). The log-rank test demonstrates a significant difference in survival function over time (P = 0.027), with a hazard ratio of 1.64 (95% confidence interval, 1.05-2.55).

Conclusions: Expansion of the TCF4 CTG trinucleotide repeat was associated with 1.64 times higher likelihood of corneal transplantation at a given age in patients with Fuchs dystrophy.

Figure 1

Proportion of subjects who had undergone corneal transplantation at time of enrollment in a longitudinal study of Fuchs Corneal Dystrophy, by repeat expansion status. The number of trinucleotide repeats, listed on the x-axis, represents the designated number of repeats up to the following interval (e.g. “30” includes participants with repeat sizes from 30 to 39).

Figure 2

Estimated survival curves depicting relative differences in age of surgery between patients with less than 40 repeats (NN) vs. greater than 40 repeats in either allele (NX/XX), constructed from clinical data. Cox proportional hazard regression model demonstrates a significant difference in survival function (p=0.027), with hazard ratio of 1.64 (95% CI, 1.05 to 2.55) but without significant association with gender (p=0.747).