ADAGESIII: Contribution of Genotype to Glaucoma Phenotype in African Americans

Glaucoma results in vision loss due to damage of the optic nerve that is irreversible if undetected or untreated. The most common form of glaucoma is primary open angle glaucoma (POAG). While glaucoma affects all races, persons of African descent are disproportionately affected; studies show African-Americans (AAs) are about four to five times more likely than Caucasian Americans to develop the disease. Glaucoma is the leading cause of irreversible blindness in Americans of African descent, and the second leading cause in all Americans. The lack of understanding about the etiology of POAG impedes our ability to identify and treat it early in its development. Evidence of genetic contribution in the pathogenesis of POAG is well established. Since POAG tends to run in families, it is critical to identify the genetic basis of the disease in order to develop effective therapies for early intervention. While genome wide association studies (GWAS) for glaucoma have been completed for Caucasian populations, evidence from other studies suggests that a GWAS of glaucoma specific genes to the African-American population will yield unique and important findings for both this population and for glaucoma in general. A better understanding of the relationship among the stage of disease, the rate of change, ancestry, and other important risk factors being tracked in the ongoing African Descent and Glaucoma Study (ADAGES) will allow us to evaluate the relationship between genetics, visual loss and structural damage in this high-risk cohort. The scientific plan for this new study focuses on glaucoma in ∼2058 African-Americans by detailed phenotyping of new subjects, acquisition of samples from both new and established previously phenotyped study subjects for a repository, establishment of a data coordinating center, and genome wide association studies. The recruitment, enrollment, and phenotyping of both established and new subjects occurs at five clinical centers, University of California (UCSD), New York Eye and Ear Infirmary (Mt Sinai) and Columbia University Medical Center, a private practice in the Atlanta area, the University of Alabama at Birmingham, and the Robert Cizik Eye Clinic in Houston, TX. UCSD is also the location for the Data Coordinating Center and the Repository with Robert N. Weinreb as Principal Investigator. LA BioMed at Harbor-UCLA did the genotyping with a GWAS panel of ∼1 million single nucleotide polymorphisms (SNPs) using the Illumina MEGA array under the direction of Jerome Rotter, Ida Chen, and Kent Taylor. ]]> Inclusion: Eligibility for inclusion as a POAG patient required glaucomatous visual field damage compatible with glaucomatous optic disc damage with no other ocular or non-ocular disease responsible for the visual field loss. Visual field damage was defined as a pattern standard deviation (PSD) or glaucoma hemifield test (GHT) outside normal limits. If good quality visual fields were not available due to advanced disease, clear documentation of glaucomatous optic disc damage by clinical examination or optic disc photography was required. Glaucomatous optic disc damage was defined as evidence of excavation, neuroretinal rim thinning or notching, localized or diffuse retinal Center of the visual field and/or optic disc damage. Progressing POAG patients as documented by structural changes, functional changes or disc hemorrhage were also recruited. Glaucomatous progression is determined centrally by the ADAGES Coordinating Center using event-based and rate-based criteria. African and European descent controls without glaucoma were also recruited. Eligibility for inclusion as a control without glaucoma was based on 1) no evidence of glaucomatous optic neuropathy based on a dilated clinical examination, and 2) an IOP < 21 mmHg. Exclusion: In order to recruit a representative sample of POAG patients, exclusion criteria were limited to 1) ocular pathology that makes it difficult to determine whether there is characteristic visual field damage, 2) closed or occluded angles, 3) secondary glaucoma, 4) history of human immunodeficiency virus or hepatitis C infection, and 5) Non-African or European descent. To ensure that progressive changes were not due to other ocular conditions, participants with other ocular pathologies were excluded if 1) VF damage or progression was due to a cause other than POAG, 2) made interpretation of visual fields or photographs uncertain or difficult, or 3) visual acuity was worse than 20/50 due to a cause other than POAG. Family history of glaucoma was an exclusion criteria for controls if the individual reported 1) more than first degree relative with glaucoma, or 2) a first degree relative that was blind from glaucoma. ]]> With sites in San Diego, New York City and Birmingham Alabama, the multicenter "African Descent and Glaucoma Evaluation Study (ADAGES): Structure and Function" was originally funded in 2002 to identify differences in optic disc structure, visual function, clinical findings, and risk factors associated with the diagnosis of glaucoma. The study was renewed in 2009 as "ADAGES II: Progression" to identify differences between individuals of African Descent and European Descent in the progression of glaucoma. "ADAGESIII: Contribution of Genotype to Glaucoma Phenotype in African Americans" was funded in 2013 to elucidate the genetics of glaucoma in individuals of African descent from 5 sites across the country. ]]>