The role of genetic variants in TCF4 and LOXHD1 in Fuchs Endothelial Dystrophy in a UK Cohort

Abstract

Purpose: Fuchs endothelial corneal dystrophy (FECD) is a late-onset progressive condition which occurs primarily in the absence of family history, but familial forms with dominant inheritance have been documented. Mendelian mutations in 6 genes have been described to date, together with 4 loci for which the mutations have yet to be found. The aim of this study was to determine the relative contributions of genetic variants at the FECD3 locus in a UK cohort. A 9.3mb region of chromosome 18 overlaps this locus and encompasses the TCF4 and LOXHD1 genes, both implicated in FECD in previous studies.

Methods: Genomic DNA from 56 unrelated FECD patients was genotyped for TCF4 variant rs613872 and tested for the presence of expanded repeat allele CTG18.1. DNA from the same cohort was also Sanger sequenced for the 42 coding exons encompassing the documented transcript isoforms of LOXHD1 to look for rare pathogenic variants. Results were compared to control populations of the same ethnicity documented in previous studies and in data downloaded from the 1000 genomes database.

Results: The G allele of rs613872 and the trinucleotide expansion of CTG18.1 were both strongly associated with FECD (p-value for rs613872 allele G in cases vs controls 6.06 x 10^-10, OR 5.70 [95% CI 3.23 -10.05], p-value for CTG18.1 in cases vs controls 2.63 x 10^-14, OR 14.4 [95% CI 6.44- 32.18]). Rare pathogenic LOXHD1 variants were identified in 14.3% cases compared to 7.5% in the controls revealing a modest but non-significant enrichment of LOXHD1 alleles in the FECD cases (p-value 0.12).

Conclusions: The trinucleotide expansion in TCF4 appears to be an allele with a major effect, significantly increasing FECD risk in the UK Caucasian population, consistent with previous published observations. By contrast, the contribution of LOXHD1 variants to FECD risk is inconclusive and requires further replication.