A Genome-Wide Association Study of Fuchs' Endothelial Corneal Dystrophy (FECD)

Fuchs' Endothelial Corneal Dystrophy (FECD) is a common disease that results in loss of vision associated with progressive corneal edema and loss of corneal transparency. In the initial stages of the disease, excrescences on Descemet's membrane with the appearance of an abnormal posterior collagenous layer, result in the clinical and pathologic appearance of guttae. Corneal edema ensues as endothelial function is compromised that may result in 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. The pathophysiology underlying FECD, particularly in the common cases that affect older individuals, remains unknown, with a genetic predisposition being reported as the single best predictor of disease. Three independent groups funded by the National Eye Institute (NEI), with well-established programs in the genetics of FECD, conducted a genome-wide association study of FECD. The collaboration comprised investigators from Case Western University (CWRU), Duke University (DUEC), and Johns Hopkins University (JHU). CWRU and DUEC contributed samples that were genotyped at CIDR for the GWAS. Johns Hopkins University (JHU) provided samples for the replication phase of the study, where their data are not listed in dbGaP. Cohorts of FECD cases and controls were assembled. Synchronization of clinical and coded data was performed to unify the information across centers. The family history, clinical, demographic information, and genome-wide genotype data for samples from CWRU and DUEC were deposited in dbGaP.]]>
All three sites used a modified Krachmer scale for assessing disease severity in cases. Because each group modified Krachmer's grading scheme slightly differently, but otherwise had cornea fellowship trained observers using similar instrumentation (slit lamp biomicroscopy) to grade the corneal phenotype, the consortium was able to make adjustments to equalize grading across ascertainment sites. The following grading scheme was used: FECD Consortium Grading Scheme GradeFindings 0No central cornea guttae 1Scattered central cornea guttae 21 or 2 mm of central cornea guttae 3>2 to 5 mm of grouped central cornea guttae 4>5 mm of grouped central cornea guttae 5Cornea guttae with corneal edema There was no age restriction of cases. Based on discussions between investigators at all three centers, the following inclusion criteria for controls were established: 60 years of age or older Normal cornea with no epithelial, stromal, or endothelial abnormalities with the exceptions of: Arcus senilis and Vogt's limbal girdle Cornea scar from subepithelial zone Previous cataract, glaucoma or retina-vitreous surgery, as long as the preoperative record indicated no evidence by slit lamp examination of guttae or FECD and postoperative exam also showed no evidence Previous intraocular surgery (such as iridotomy, trabeculoplasty, or pan retinal photocoagulation with same caveats as intraocular surgery) ]]>
CWRU initiated its genetics studies on FECD with the commencement of the FECD Genetics Multi-center Study funded by the National Eye Institute in 2005. The study involved the recruitment of probands, family members and unrelated controls from 29 sites throughout United States from the practices of private practice or university based cornea fellowship trained specialists. All sites underwent rigorous training on acquiring phenotypic disease severity for FECD using a modified grading scale of Krachmer and also detailed personal and family history pertinent to the disease. The probands were defined not only by the severity of the phenotype clinically, but also either by pathologic confirmation of the excised corneal tissue following keratoplasty or by enrolling additional severely affected siblings or avuncular relatives. Recruitment began in March 2005 and was concluded in December 2010. Duke University initiated its study of FECD in 2002 and the team was granted an NIH award in 2007. The Duke dataset has over 1200 study subjects. Initially a linkage study was performed using 22 families (Afshari, et al., IOVS 2009). Since then the team has focused on both recruitment and genetic studies of FECD. A recent study with a combination of association and linkage studies (Li et al., 2011) was able to replicate TCF4 gene reported by Baratz et al. (2010). In our study, a set of 450 cases and 340 normal controls was used for association study, and revealed significant association with rs613872, the target marker of Baratz et al.(2010). In addition, the genome-wide linkage scan on 64 multiplex families composed primarily of affected sibling pairs (ASPs), a larger dataset than our first linkage scan, led to a promising linkage region localizing to chromosome 18 from 69.94cM to 85.29cM, with a peak multipoint HLOD = 2.5. The peak marker, rs1145315 (75.58cM) under the DOM model maps 1.5 Mb proximal to rs613872, which provides strong supporting evidence for the association finding at TCF4 marker. Both recruitment and genetic studies of FECD are still ongoing at Duke University Eye Center.]]>