In order to identify the risk loci for primary open angle glaucoma (POAG), a large multi-ethnic meta-analysis of genome-wide association studies (GWAS) was conducted. The study involved a total of 34,179 POAG patients and 344,321 controls.
This unique study was performed across African, Asian and European ancestries. Previous studies have focused on European descent only. However, Africans, Latinos and Asians have the highest prevalence of POAG and are at high risk to develop POAG. Therefore, this study has greater significance.
The study identified 127 risk loci for POAG, of which 44 were not previously reported.
The study concluded that several genes contributed to the development of POAG. Among these genes are the following: SVEP1, RERE, VCAM1, ZNF638, CLIC5, SLC2A12, YAP1, MXRA5 and SMAD6.
The identified risk loci were found to have broadly consistent effects across the African, Asian and European ancestries.
Among Europeans, the study found 66 independent genome-wide significant single nucleotide polymorphisms (SNPs), of which 16 were novel SNPs.
In Asians, 10 loci were identified, all of which were previously known.
In Africans, one locus (rs 16944405 within IQGAP1) was of genome-wide significance level. This locus was not previously reported for POAG and was not associated with POAG in Europeans and Asians.
24 of the 32 SNPs had a clear effect on VCDR (vertical cup:disc ratio).
8 of the POAG loci did not appear to have a clear effect on intra-ocular pressure (IOP) or VCDR.
16 loci were associated with retinal nerve fiber layer (RNFL).
3 POAG loci (MAPT, CADM2, APP) have been implicated previously in the development of Alzheimer’s disease (AD) and dementia.
A previously unknown association of a human leukocyte antigen (HLA-G/HLA-H) with POAG was also identified.
The gene-sets for the risk loci identified two major pathogenic mechanisms for POAG: (1) Vascular system defects (e.g. blood vessel morphogenesis, vasculature development and regulation of endothelial cell proliferation). (2) Lipid binding and transportation (e.g. intracellular lipid transport, apolipoprotein binding, negative regulation of lipid storage and positive regulation of cholesterol efflux).
The study found enrichment of the expression of POAG risk genes in arteries and vessels.
MXRA5 and SMAD6 are involved in transforming growth factor (TGF) beta-mediated extracellular matrix remodeling, a process known to contribute to risk of POAG.
SVEP1 missense allele was associated with POAG risk (rs 61751937). This gene (SVEP1) encodes an extracellular matrix protein essential for the lymphangiogenesis in mice. Lymphangiogenesis is required for the development of Schlemm’s canal. Two other genes necessary for lymphangiogenesis and Schlemm’s canal development (TEK, ANGPT1) are involved in the development of childhood glaucoma.
VCAM1 is an extracellular matrix cell adhesion molecule involved in angiogenesis and regulation of fluid outflow.
RERE is associated with VCDR.
CLIC5 encodes a chloride channel, that functions in mitochondria and could have a role in ocular fluid dynamics.
ZNF638 is a zinc finger protein that regulates adipose differentiation and has been implicated in genetic regulation of height.
SLCA12 is a glucose transporter involved in fat metabolism.
YAP1 is an oncogene and main effector of the HIPPO tumor suppressor pathway and apoptosis inhibitor. Thus, it could influence RGC survival.
Several proteins encoded by genes within the identified POAG risk loci are targets of currently approved drugs.
COL4A1 is targeted by ocriplasmin (a collagen hydrolytic enzyme) being used to treat vitreo-macular adhesion.
Acitretin (a retinoid receptor agonist targeting RARAB) is being considered for AD.
Dipyridamole (a 3’,5’-cyclic phosphodiesterase inhibitor) is undergoing trials for the treatment of stroke, coronary heart disease, ischemia reperfusion injury and internal carotid artery stenosis. It could be a potential therapy for POAG, through modulation of blood flow.
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