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.
Highlights
The curvature, thickness, and function of the cornea are controlled by the fine structure of its five layers
Association results for Fuchs endothelial corneal dystrophy (FECD) case/control status and FECD grade We found a highly significant association between FECD case/
We observed two other nominally significant associations with the binary FECD trait, one SNP each in pituitary homeobox 2 (PITX2) and autogenous vein graft remodeling associated protein 8 (AVGR8), with p values of 0.028 and 0.015, respectively, for FECD status adjusted for central corneal thickness (CCT) (Table 3 and Table S1)
Summary
The curvature, thickness, and function of the cornea are controlled by the fine structure of its five layers. Fuchs endothelial corneal dystrophy (FECD), which results in loss of vision associated with progressive corneal edema and loss of corneal transparency, is estimated to have a prevalence of approximately 4% in the United States [1,2], where it is one of the most common indications for corneal transplantation [3]. The principal defect in FECD is a decline in the number of functional corneal endothelial cells, with compensatory abnormalities, such as thickening of Descemet membrane, and subsequent thickening of the cornea due to edema. In the initial stages of the disease, excrescences form on Descemet membrane along with deposition of abnormal, excess collagen posterior to the membrane (the ‘‘posterior collagenous layer’’), resulting in the clinical and pathologic appearance of guttae [4]. Compromise of endothelial function may result in corneal stromal edema, epithelial edema, and painful bullous keratopathy. Penetrating or endothelial keratoplasty is the only definitive treatment, with palliative care the only option prior to surgery
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