Differing roles for TCF4 and COL8A2 in central corneal thickness and fuchs endothelial corneal dystrophy.

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

Meta-analysis for association of <i>TCF4</i> SNP rs613872 with FECD case/control status.

<p>Horizontal lines denote the 95% CI for the OR for each G allele at rs613872. The width of the squares indicating estimates of OR is proportional to the sample size in each study.</p

Summary of genotyped samples.

<p>Unless otherwise indicated, statistics are shown as mean ± SD.</p>a<p>Total includes 87 individuals with FECD grade of 1–3 in worse eye, not classified as FECD cases or controls.</p>b<p>Average of two eyes, when available.</p

Nominally significant results from association analyses for CCT.

<p>Genes <i>FOXO1, AKAP6</i> and <i>AKAP13</i> showed no significant associations, and therefore do not appear in this table. Position, physical map position (NCBI human genome build 36); Ref. All., reference (minor) allele; effect, expected µm change in CCT per copy of the reference allele (additive model) or for presence of minor allele (dominant model). <i>p</i> values in <i>italics</i> are less than 0.05; in <b>bold,</b> less than 0.001 (the Bonferroni threshold for study-wide significance at the 0.05 level). *, dominant model.</p

Association analyses for FECD case/control status.

<p>Chr., chromosome; No. SNPs, number of SNPs in or near gene passing QC; Best SNP, SNP with smallest <i>p</i> value; Position, physical map position (NCBI human genome build 36); Ref. All., reference (minor) allele; OR, odds ratio per copy of the reference allele (additive model) or for presence of minor allele (dominant model). <i>p</i> values in <i>italics</i> are less than 0.05; in <b>bold,</b> less than 0.001. *, dominant model.</p

Candidate genes for FECD and related diseases of the cornea.

<p>The columns FECD and CCT indicate whether genes have been implicated in Fuchs dystrophy and central corneal thickness, respectively. The effects on CCT are those for rare (variant) alleles; “Increased” and “Decreased” indicate that the variant (minor) allele is associated with an increase or decrease in CCT. A-R syndrome, Axenfeld-Rieger syndrome; PPCD, posterior polymorphous corneal dystrophy; POAG, primary open angle glaucoma; CHED, congenital hereditary endothelial dystrophy; CDPD, corneal dystrophy and perceptive deafness (Harboyan syndrome).</p