Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy.

Yi-Ju Li,S Amer Riazuddin,Simon G Gregory,Bei Zhao,Mollie A Minear,R Rand Allingham,Allen O Eghrari,John D Gottsch,Michael A Hauser,Jacqueline Rimmler,Elmer Balajonda,Gordon K Klintworth,Natalie A Afshari,Nicholas Katsanis

doi:10.1371/journal.pone.0018044

Abstract

Fuchs endothelial corneal dystrophy (FECD) is a common, late-onset disorder of the corneal endothelium. Although progress has been made in understanding the genetic basis of FECD by studying large families in which the phenotype is transmitted in an autosomal dominant fashion, a recently reported genome-wide association study identified common alleles at a locus on chromosome 18 near TCF4 which confer susceptibility to FECD. Here, we report the findings of our independent validation study for TCF4 using the largest FECD dataset to date (450 FECD cases and 340 normal controls). Logistic regression with sex as a covariate was performed for three genetic models: dominant (DOM), additive (ADD), and recessive (REC). We found significant association with rs613872, the target marker reported by Baratz et al.(2010), for all three genetic models (DOM: P = 9.33×10−35; ADD: P = 7.48×10−30; REC: P = 5.27×10−6). To strengthen the association study, we also conducted a genome-wide linkage scan on 64 multiplex families, composed primarily of affected sibling pairs (ASPs), using both parametric and non-parametric two-point and multipoint analyses. The most significant linkage region localizes to chromosome 18 from 69.94cM to 85.29cM, with a peak multipoint HLOD = 2.5 at rs1145315 (75.58cM) under the DOM model, mapping 1.5 Mb proximal to rs613872. In summary, our study presents evidence to support the role of the intronic TCF4 single nucleotide polymorphism rs613872 in late-onset FECD through both association and linkage studies.

Highlights

Fuchs endothelial corneal dystrophy (FECD), first described by Ernst Fuchs [1], is a common progressive disorder of the corneal endothelium that typically becomes symptomatic during the fifth or sixth decade of life [2,3], corneal endothelial abnormalities can be clinically detected several years before patients become symptomatic [4]
We report the results from an expansion of our previous linkage study, as well as an association study analyzing the association of rs613872 with FECD in a dataset containing 450 unrelated FECD cases and 340 unaffected controls, the largest sample of FECD patients interrogated to date
Variable No of families (DUEC, JHU)a No of samples (No of affected) No of ASPsb Male, Female Mean (SDc) of aged in years No of samples Male, Female Mean (SD) of age in years aDUEC: Duke University Eye Center; JHU, Johns Hopkins University. bASPs: affected sibpairs (ASP) count is based on n-1 for n siblings per familycSD: standard deviation. dAge: age at the time of study enrollment

Summary

Introduction

Fuchs endothelial corneal dystrophy (FECD), first described by Ernst Fuchs [1], is a common progressive disorder of the corneal endothelium that typically becomes symptomatic during the fifth or sixth decade of life [2,3], corneal endothelial abnormalities can be clinically detected several years before patients become symptomatic [4]. The disorder affects as much as 4% of the United States population over the age of 40 years [5,6,7] and occurs predominantly in women, who comprise approximately 75% of cases [8]. This debilitating disorder leads to corneal edema with a loss of corneal clarity, painful episodes of recurrent corneal erosions, severe impairment of visual acuity, and sometimes even blindness. Mutations in TCF8 (MIM: 609141), whose loss of function causes posterior polymorphous corneal dystrophy (PPCD, MIM: 609141) [22], were recently reported in late-onset Caucasian [23] but not in Chinese FECD patients [24]

Methods

Results

Discussion

Conclusion