Differing Roles for TCF4 and COL8A2 in Central Corneal Thickness and Fuchs Endothelial Corneal Dystrophy

Abstract

Fuchs endothelial corneal dystrophy (FECD) is the most common late-onset, vision-threatening corneal dystrophy in the United States, affecting about 4% of the population. Advanced FECD involves a thickening of the cornea from stromal edema and changes in Descemet membrane. To understand the relationship between FECD and central corneal thickness (CCT), we characterized common genetic variation in COL8A2 and TCF4, genes previously implicated in CCT and/or FECD. Other genes previously associated with FECD (PITX2, ZEB1, SLC4A11), and genes only known to affect CCT (COL5A1, FOXO1, AVGR8, ZNF469) were also interrogated. FECD probands, relatives and controls were recruited from 32 clinical sites; a total of 532 cases and 204 controls were genotyped and tested for association of FECD case/control status, a 7-step FECD severity scale and CCT, adjusting for age and sex. Association of FECD grade with TCF4 was highly significant (OR = 6.01 at rs613872; p = 4.8×10−25), and remained significant when adjusted for changes in CCT (OR = 4.84; p = 2.2×10−16). Association of CCT with TCF4 was also significant (p = 6.1×10−7), but was abolished with adjustment for FECD grade (p = 0.92). After adjusting for FECD grade, markers in other genes examined were modestly associated (p ∼ 0.001) with FECD and/or CCT. Thus, common variants in TCF4 appear to influence FECD directly, and CCT secondarily via FECD. Additionally, changes in corneal thickness due to the effect of other loci may modify disease severity, age-at-onset, or other biomechanical characteristics.

Comprehensive Assessment of Genetic Variants WithinTCF4in Fuchs' Endothelial Corneal Dystrophy

“…This is the same SNV identified by Baratz et al 13 in a full genome wide association study and subsequently validated by others. [26][27][28][29][30][31][32] Importantly, we did not identify any novel SNVs that appear to be causative for FECD. In particular, none of the top 25 SNVs with the strongest association with disease status resides in the coding region of any of the 48 transcripts produced from this gene (Ensembl).…”

Collagens and proteoglycans of the cornea: importance in transparency and visual disorders

“…The Descemet's membrane, similar to other tissues, seems to contain the α1 (VIII) and α2 (VIII) chains that exist under two distinct homotrimeric molecules (Greenhill et al 2000). The gene encoding the α2 (VIII) collagen chain seems to be implicated in various corneal endotheliopathies including Fuchs' endothelial corneal dystrophy (FECD), one of the commonest indications for corneal transplantation where the principal defect is a reduction in the number of corneal endothelial cells (Igo et al 2012). The implication of the α2 (VIII) collagen chain in FECD has been demonstrated by the generation of a transgenic knock-in mouse model that carries a genetic defect on the Col8a2.…”

Polymorphisms of the Apoptosis-Related FAS and FAS Ligand Genes in Keratoconus and Fuchs Endothelial Corneal Dystrophy

“…Many case-control studies confirmed the association of genetic variability with KC and FECD (Udar et al 2006;Stabuc-Silih et al 2009;Baratz et al 2010;Burdon et al 2011;Czugala et al 2012;Guan et al 2012;Igo et al 2012). Both association and linkage studies showed that a polymorphism in the transcription factor 4 (TCF4) gene was associated with FECD (Baratz et al 2010;Li et al 2011).…”