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Michael A Hauser; Association of APBB2 Links Mechanisms of Neurodegeneration in Glaucoma and Alzheimer's Disease. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1183. doi: https://doi.org/.
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Primary open angle glaucoma (POAG) has a complex genetic etiology, and manifests as a health disparity that disproportionately affects individuals of African descent. In African Americans, the prevalence of POAG is 4-5 fold higher than in Caucasians. We have investigated the genetics of POAG in populations of African Ancestry.
We conducted a genome-wide association study (GWAS) in 2,320 POAG cases and 2,121 controls, including participants from Ghana, Nigeria and South Africa, as well as African Americans. We replicated these findings in 6,174 POAG cases and 14,220 controls, including both African and diaspora populations. We have also conducted immunohistochemical analysis of post-mortem retinal samples from African Americans.
Our discovery dataset shows genome-wide significant association (P=2x10-8; OR=1.33) with a single nucleotide polymorphism (rs59892895) in APBB2, a gene that is involved in the proteolytic processing of amyloid precursor protein (APP). Genotyping of this marker in replication datasets strongly corroborates our findings (P=1.5x10-7). This association is specific for African and African diaspora populations, and no association at this locus has been identified in Caucasian or Asian GWAS studies. APP is a membrane glycoprotein required for normal development of the retina; however, proteolytic processing of APP also produces amyloid beta (Aβ) peptides, which are toxic and which aggregate to form amyloid plaques, one of the neuropathological hallmarks of Alzheimer’s disease (AD). IHC analysis of African American retinas shows increased Aβ staining in the retinal ganglion cell layer of individuals carrying an APBB2 risk allele. Digestion of APP with gamma secretase (PSEN1) produces the amyloid intracellular C-terminal domain (AICD) peptide, which is a potent modulator of apoptosis. APBB2 increases production of both Aβ and AICD peptides—either of which may lead to glaucomatous retinal ganglion cell death.
Comorbidity between AD and POAG has long been suggested. Aβ is found in melanopsin retinal ganglion cells of AD patients, leading to dysfunction of the circadian rhythm. Conversely, rat models of induced ocular hypertension show retinal Aβ deposition and caspase activation. However, our findings are the first direct genetic evidence that the same mechanisms of APP processing are involved in neuronal cell death in both AD and glaucoma..
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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