Association of rs613872 and trinucleotide repeat expansion in the TCF4 gene in Fuchs endothelial corneal dystrophy in Germany

Abstract

Purpose : Single nucleotide polymorphisms (SNPs) in several genes have been associated with Fuchs endothelial corneal dystrophy (FECD). Among those SNPs, rs613872 in transcription factor 4 (TCF4) showed strong association, and accumulating evidence indicates that intronic CTG trinucleotide repeat expansion is frequently found in TCF4. The purpose of this study was to investigate SNPs and trinucleotide repeat expansion in TCF4 in the large cohort of German patients with FECD.

Methods : Genomic DNA was obtained from the peripheral blood of 398 German patients with FECD. The genomic DNA of 57 non-FECD controls was obtained from donor corneas of healthy individuals. Previously reported 37 SNPs in COL8A2, SLCA411, TCF8, LOXHD1, AGBL1, and TCF4 was evaluated in 36 randomly selected samples of FECD by genotyping. The expansion of a CTG trinucleotide repeat was analyzed by STR assay and Southern blotting in 398 FECD samples.

Results : No heterogeneity was found in SNPs in COL8A2, TCF8, LOXHD1 and AGBL1 in 36 cases, though 3 nonsense mutations were detected in SLCA411. In contrast, SNPs of TCF4; rs613872, rs2123392, rs17089887, rs1452787, and rs1348047 were detected. Only rs613872 showed significant association with FECD in comparison to non-FECD control (P<7.08×10^-12). STR assay and Southern blotting demonstrated that 315 (homozygous 8, heterozygous 307) /398 patients (79.1%) harbored CTG trinucleotide repeat lengths > 50. Genotype of TCF4 SNP rs613872 was TT:38 (68%), TG:17 (30%), and GG:1 (2%) in non-FECD controls TT:39 (47%), TG: 38 (46%), and GG:6 (7%) in FECD harboring trinucleotide repeat lengths < 50, and TT:23 (7%), TG: 224 (71%), and GG:68 (22%) in FECD harboring trinucleotide repeat lengths > 50 (P<1.42×10^-29).

Conclusions : CTG repeat expansion was found in 79% of German FECD patients, similar to the findings in other Caucasian cohorts. Among previously reported SNPs, only variation in rs613872 in TCF4 showed a strong correlation with FECD in this study group. Our large cohort demonstrated that risk allele G was associated with FECD with or without trinucleotide repeat expansion, though this risk allele was more frequently found in FECD harboring repeat expansion than in FECD without repeat expansion.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.