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Arup Das, Sampathkumar Rangasamy, Marcus Naymik, Finny Monickaraj, Christophe Legendre, Chris Balak, David Duggan, Nicholas Schork, Paul McGuire; Novel Genetic Variants in Extreme Phenotypes of Diabetic Retinopathy: DRGen Study. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1911.
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© ARVO (1962-2015); The Authors (2016-present)
The genetic risk factors play an important role in the development and progression of diabetic retinopathy independent of HBA1c and lipid control. In this study, using a well-defined, clinical phenotype, we seek to understand better the role of rare genetic variants in DR progression, or protection by undertaking whole exome sequencing (WES).
We performed WES analysis on two cohorts of patients selected from Diabetic Retinopathy Genetic (DRGen) study population established at University of New Mexico. Group 1 had “extreme” phenotype (No DR in spite of >25 years of diabetes) (n=6), while Group 2 had “advanced” DR (PDR within 15 years of diabetes) (n=6). All the subjects were matched for gender and age. After obtaining informed consent, DNA was isolated from white blood cells and the WES was performed using SureSelect All Human XT v5 exome kits, on Illumina NovaSeq platform. This was followed by an in-house downstream analysis pipeline to align sequence reads and complete variant calling and annotation.
Analysis of rare coding variants using MAF cutoff revealed an interesting pattern of gene list with heterozygous missense mutations in the two cohorts. Among the variants predicted to be disease-causing, variants in four gene (CD33, COL18A1, ZNF395, PLEKHG5) with MAF<0.5%, while variant in a gene (NKX2-3) with MAF<0.5% was shared among the cohort 1 (extreme phenotype), which is a protective factor. One of the variants in the gene ZNF395 in DR group is a private variant compared to other rare variants whose MAF was <0.35. In addition we also found that the genetic variation. Interestingly, in a separate RNA sequence analysis of human retinal endothelial cells treated with high glucose or monocyte conditional media, we observed an increased expression of one of the listed genes, COL18A1 (p<0.0001). This gene encodes the alpha chain of type XVIII collagen, one of the extracellular matrix proteins that when proteolytic processed results in production of endostatin, a potent antiangiogenic protein that is able to inhibit angiogenesis and tumor growth.
We identified coding sequence variants in a novel set of genes involved in the angiogenesis/inflammatory pathway that contributes to DR progression, or protection. Future functional validation of the identified variants in disease pathogenesis could potentially lead to the identification of a new molecular target for treating DR.
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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