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Dongseok Choi, William O Cepurna, John C Morrison, Elaine C Johnson; Statistical Analysis of Age and Elevated Intraocular Pressure (IOP) Dependent Gene Expression Changes in the Rat Optic Nerve Head (ONH). Invest. Ophthalmol. Vis. Sci. 2014;55(13):2401.
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© ARVO (1962-2015); The Authors (2016-present)
Aging is a top risk factor in glaucoma, yet little is known about its effect on ONH responses in glaucoma models. Previously, we reported ONH gene expression responses to experimentally elevated IOP in 8 month old, adult rats with both early (PMID 20847120) and extensive (PMID 17591886) nerve injury. Because we found that elevated IOP produces more injury in elderly (28 month old) rats, we have conducted a parallel array study using elderly rat ONH. This report directly compares these array sets.
Arrays (N=30) were within-array normalized by a modified Lowess procedure followed by an adapted quantile normalization for across-array and batch effects. Modified F- and t-tests were used to identify differentially expressed genes using the LIMMA package for R language. Fold changes ≥1.3 and false discovery rates adjusted to p<0.05 were considered differentially expressed. DAVID analysis tools were used to functionally categorize affected genes.
Compared to age-matched controls, extensive injury in elderly ONH was associated with far fewer differentially expressed genes (275) than seen earlier in glaucomatous adult ONH (1980). Cell cycle, translation and immune responses were not upregulated. Similarly, early injury in elderly ONH produced only 282 regulated genes and, unlike in adult ONH, affected few cell cycle genes. A control group comparison revealed differential regulation of 2712 genes, with aging primarily downregulating proteolytic processes and upregulating cell cycle genes. Interestingly, over 50% of these 2712 genes were similarly up- or downregulated by elevated IOP in adults, suggesting that aging and IOP-induced injury may affect similar cell functions. Direct comparison of the two extensive injury groups revealed 2113 regulated genes. Elderly glaucomatous ONH failed to upregulate translation, transcription and cell cycle genes, compared to adult glaucomatous ONH.
For both early and extensive injury, ONH expression responses were greatly attenuated in elderly ONH. Additionally, after adjustment for potential batch effects, aging appeared to have a dramatic effect on both normal and glaucomatous ONH gene expression, compared to parallel adult ONH groups. These observations suggest that age-induced changes in gene expression may provide a genomic basis for the increased susceptibility to glaucoma with aging.
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