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Subhabrata Chakrabarti, Srujana Nagireddy, Kollu N. Rao, Sirisha Senthi, Harsha B. Rao, Anil K. Mandal, Garudadri Chandrasekhar, Inderjeet Kaur; Whole Genome Expression and Candidate Gene Analysis Reveals the Involvement of Novel Genes in Primary Open Angle Glaucoma. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4599. doi: https://doi.org/.
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To assess the involvement of genes causing primary open angle glaucoma (POAG) through whole genome expression analysis of 45,000 genes followed by validation through customized genotyping of 40 candidate genes involved in inflammation and extracellular matrix (ECM) remodelling and ascertainment of their expression levels in the aqueous humor.
Whole genome expression was carried out by microarray analysis using the Illumina chip containing 45,000 transcripts in clinically well characterized POAG cases (n=6) with elevated intraocular pressure (IOP>22 mm Hg) and ethnically matched senile cataract patients as normal controls (n=6). A subset of genes (n=40) involved in two distinct pathways of inflammation and ECM remodelling and exhibiting differential expression were validated through customized genotyping of variants (n=384) spanning these genes in a larger cohort of POAG (n=200) and control (n=200) subjects. Further, the expression levels of these genes in the aqueous humor of a subset of these subjects were analyzed by multiplex Elisa to assess the concordance between the gene expression and genetic association data.
Whole genome microarray analysis followed by stringent quality control and multiple statistical corrections (Benjamini Hochberg) revealed differential expressions of ~200 genes. Case-control-based analysis using 384 variants of 40 candidate genes revealed associations in 5 ECM-related genes of which, only one withstood Bonferroni correction for multiple testing (p=1.30 x 10-4) that also revealed strong allelic associations (p<10-4) and a risk haplotype (p=2.0x10-4). The mean concentrations of the ECM proteins were significantly higher in the aqueous humor of POAG subjects compared to unaffected subjects.
The present study highlights novel genes based on their genetic involvement and expression levels in POAG.
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