title: 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.
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Igo
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Kopplin
authors.forename: Peronne
authors.initials: P
authors.lastname: Joseph
authors.forename: Barbara
authors.initials: B
authors.lastname: Truitt
authors.forename: Jeremy
authors.initials: J
authors.lastname: Fondran
authors.forename: David
authors.initials: D
authors.lastname: Bardenstein
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Aldave
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Croasdale
authors.forename: Marianne O
authors.initials: MO
authors.lastname: Price
authors.forename: Miriam
authors.initials: M
authors.lastname: Rosenwasser
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Lass
authors.forename: Sudha K
authors.initials: SK
authors.lastname: Iyengar
mesh_terms: D000368:Aged; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D024102:Collagen Type VIII / Q000235:genetics*; D003315:Cornea / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005642:Fuchs' Endothelial Dystrophy / Q000235:genetics* / Q000473:pathology*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C443712:COL8A2 protein, human; D024102:Collagen Type VIII; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors