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Editors Selection IGR 11-4

Basic Research: SNPs in glucocorticoid responders

Comment by Subhabrata Chakrabarti on:

25860 Assessment of SNPs associated with the human glucocorticoid receptor in primary open-angle glaucoma and steroid responders, Fingeret JH; Alward WL; Wang K et al., Molecular Vision, 2010; 16: 596-601

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There is growing evidence that glucocorticoid receptors (GR) play a major role in steroid response and POAG. Fingeret et al. (776) explored the potential involvement of variants in GR-associated genes by genotyping 48 single nucleotide polymophisms (SNPs) spanning six genes (FKBP4, FKBP5, SRFS3, SFRS5, SFRS9 and NR3C1) in a cohort of POAG (n = 197), steroid responders (n = 104) and normal control (n = 400) subjects.The authors hypothesize that SNP-based genotyping may implicate some risk alleles in these genes that may be responsible for GR-induced ocular hypertension and POAG. All the SNPs were selected from the HAPMAP database and genotyped on the Sequenom platform that uses a mass-spectroscopy-based allele detection. The data was analyzed for allelic and genotypic association but none of the SNPs were significant following Bonferroni correction.

While the data is sound, non-association of SNPs within these genes does not completely rule out their possible involvement with the disease phenotype. As opposed to the selective screening of tag SNPs, a resequencing approach covering the entire promoter, coding and non-coding regions of these genes would have been more convincing. The authors could have also considered comparing the expression levels of these genes across these subjects. Additionally, as has been pointed out, it would have been appropriate to include a separate group of 'steroid non-responders' or at least a cohort of 'non-responder controls only' for a valid comparison. The vagaries of inappropriate sample sizes under different phenotype categories coupled with screening of selected SNPs are unlikely to yield positive associations, unless these are large effect alleles. Thus, a comprehensive screening of these genes along with their functional characterization would be necessary to draw further insights into their underlying role as predictive markers for steroid-induced ocular hypertension and POAG.

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