Assessment of SNPs associated with the human glucocorticoid receptor in primary open-angle glaucoma and steroid responders

John H. Fingert, Wallace L. Alward, Kai Wang, Thomas Yorio, Abbot Clark

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23 Citations (Scopus)

Abstract

Purpose: While chronic glucocorticoid (GC) therapy leads to ocular hypertension in about one third of individuals, almost all primary open-angle glaucoma (POAG) patients show this response and are called "steroid responders." Two differentially spliced isoforms of the glucocorticoid receptor (GR), GRα and GRβ, regulate GC responsiveness in trabecular meshwork (TM) cells. GRβ acts as a dominant negative regulator of GC activity and is expressed at lower levels in glaucomatous TM cells, making them more sensitive to GCs. Several arginine/serine-rich splicing factor (SR) proteins have been implicated in alternative splicing of the GR. We have previously demonstrated that immunophilins FKBP5 and FKBP4 are required for GRα and GRβ translocation into the nucleus, which is essential for their biologic activity. The purpose of the present study was to use single nucleotide polymorphism (SNP) genotyping to determine whether there are any allele frequency differences in GR, FKBP4/5, or SR genes between normal control, POAG, and steroid responder populations. Methods: Clinically characterized individuals (400 normal controls, 197 POAG, and 107 steroid responders) were recruited from the U. Iowa Ophthalmology Clinics after IRB approved consent. Genotyping of DNA samples for 48 SNPs in SFRS3, SFRS5, SFRS9, FKBP4, FKBP5, and NR3C1 was done at GeneSeek using a mass spectroscopy based system. Results: All 48 SNPs displayed high call rates (99%). There were no significant differences in allele frequencies or genotypes in SNPs for SFRS5, SFRS9, FKBP4, FKBP5, and NR3C1 between the 3 groups. Up to three SNPs in SFRS3 had p-values <0.05 when comparing controls to POAG or steroid responders, but this statistical significance was lost when the p values were adjusted for multiple measures. Conclusions: Although these 6 genes may be involved in the pathogenesis of GC-induced ocular hypertension, it does not appear that major heritable risk alleles in these genes are responsible for the development of GC-induced ocular hypertension or POAG.

Original languageEnglish
Pages (from-to)596-601
Number of pages6
JournalMolecular Vision
Volume16
StatePublished - 23 Aug 2010

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Glucocorticoid Receptors
Single Nucleotide Polymorphism
Steroids
Glucocorticoids
Ocular Hypertension
Trabecular Meshwork
Gene Frequency
Immunophilins
Genes
Primary Open Angle Glaucoma
Research Ethics Committees
Alternative Splicing
Ophthalmology
Mass Spectrometry
Protein Isoforms
Alleles
Genotype
tacrolimus binding protein 4
DNA
Population

Cite this

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title = "Assessment of SNPs associated with the human glucocorticoid receptor in primary open-angle glaucoma and steroid responders",
abstract = "Purpose: While chronic glucocorticoid (GC) therapy leads to ocular hypertension in about one third of individuals, almost all primary open-angle glaucoma (POAG) patients show this response and are called {"}steroid responders.{"} Two differentially spliced isoforms of the glucocorticoid receptor (GR), GRα and GRβ, regulate GC responsiveness in trabecular meshwork (TM) cells. GRβ acts as a dominant negative regulator of GC activity and is expressed at lower levels in glaucomatous TM cells, making them more sensitive to GCs. Several arginine/serine-rich splicing factor (SR) proteins have been implicated in alternative splicing of the GR. We have previously demonstrated that immunophilins FKBP5 and FKBP4 are required for GRα and GRβ translocation into the nucleus, which is essential for their biologic activity. The purpose of the present study was to use single nucleotide polymorphism (SNP) genotyping to determine whether there are any allele frequency differences in GR, FKBP4/5, or SR genes between normal control, POAG, and steroid responder populations. Methods: Clinically characterized individuals (400 normal controls, 197 POAG, and 107 steroid responders) were recruited from the U. Iowa Ophthalmology Clinics after IRB approved consent. Genotyping of DNA samples for 48 SNPs in SFRS3, SFRS5, SFRS9, FKBP4, FKBP5, and NR3C1 was done at GeneSeek using a mass spectroscopy based system. Results: All 48 SNPs displayed high call rates (99{\%}). There were no significant differences in allele frequencies or genotypes in SNPs for SFRS5, SFRS9, FKBP4, FKBP5, and NR3C1 between the 3 groups. Up to three SNPs in SFRS3 had p-values <0.05 when comparing controls to POAG or steroid responders, but this statistical significance was lost when the p values were adjusted for multiple measures. Conclusions: Although these 6 genes may be involved in the pathogenesis of GC-induced ocular hypertension, it does not appear that major heritable risk alleles in these genes are responsible for the development of GC-induced ocular hypertension or POAG.",
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Assessment of SNPs associated with the human glucocorticoid receptor in primary open-angle glaucoma and steroid responders. / Fingert, John H.; Alward, Wallace L.; Wang, Kai; Yorio, Thomas; Clark, Abbot.

In: Molecular Vision, Vol. 16, 23.08.2010, p. 596-601.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Assessment of SNPs associated with the human glucocorticoid receptor in primary open-angle glaucoma and steroid responders

AU - Fingert, John H.

AU - Alward, Wallace L.

AU - Wang, Kai

AU - Yorio, Thomas

AU - Clark, Abbot

PY - 2010/8/23

Y1 - 2010/8/23

N2 - Purpose: While chronic glucocorticoid (GC) therapy leads to ocular hypertension in about one third of individuals, almost all primary open-angle glaucoma (POAG) patients show this response and are called "steroid responders." Two differentially spliced isoforms of the glucocorticoid receptor (GR), GRα and GRβ, regulate GC responsiveness in trabecular meshwork (TM) cells. GRβ acts as a dominant negative regulator of GC activity and is expressed at lower levels in glaucomatous TM cells, making them more sensitive to GCs. Several arginine/serine-rich splicing factor (SR) proteins have been implicated in alternative splicing of the GR. We have previously demonstrated that immunophilins FKBP5 and FKBP4 are required for GRα and GRβ translocation into the nucleus, which is essential for their biologic activity. The purpose of the present study was to use single nucleotide polymorphism (SNP) genotyping to determine whether there are any allele frequency differences in GR, FKBP4/5, or SR genes between normal control, POAG, and steroid responder populations. Methods: Clinically characterized individuals (400 normal controls, 197 POAG, and 107 steroid responders) were recruited from the U. Iowa Ophthalmology Clinics after IRB approved consent. Genotyping of DNA samples for 48 SNPs in SFRS3, SFRS5, SFRS9, FKBP4, FKBP5, and NR3C1 was done at GeneSeek using a mass spectroscopy based system. Results: All 48 SNPs displayed high call rates (99%). There were no significant differences in allele frequencies or genotypes in SNPs for SFRS5, SFRS9, FKBP4, FKBP5, and NR3C1 between the 3 groups. Up to three SNPs in SFRS3 had p-values <0.05 when comparing controls to POAG or steroid responders, but this statistical significance was lost when the p values were adjusted for multiple measures. Conclusions: Although these 6 genes may be involved in the pathogenesis of GC-induced ocular hypertension, it does not appear that major heritable risk alleles in these genes are responsible for the development of GC-induced ocular hypertension or POAG.

AB - Purpose: While chronic glucocorticoid (GC) therapy leads to ocular hypertension in about one third of individuals, almost all primary open-angle glaucoma (POAG) patients show this response and are called "steroid responders." Two differentially spliced isoforms of the glucocorticoid receptor (GR), GRα and GRβ, regulate GC responsiveness in trabecular meshwork (TM) cells. GRβ acts as a dominant negative regulator of GC activity and is expressed at lower levels in glaucomatous TM cells, making them more sensitive to GCs. Several arginine/serine-rich splicing factor (SR) proteins have been implicated in alternative splicing of the GR. We have previously demonstrated that immunophilins FKBP5 and FKBP4 are required for GRα and GRβ translocation into the nucleus, which is essential for their biologic activity. The purpose of the present study was to use single nucleotide polymorphism (SNP) genotyping to determine whether there are any allele frequency differences in GR, FKBP4/5, or SR genes between normal control, POAG, and steroid responder populations. Methods: Clinically characterized individuals (400 normal controls, 197 POAG, and 107 steroid responders) were recruited from the U. Iowa Ophthalmology Clinics after IRB approved consent. Genotyping of DNA samples for 48 SNPs in SFRS3, SFRS5, SFRS9, FKBP4, FKBP5, and NR3C1 was done at GeneSeek using a mass spectroscopy based system. Results: All 48 SNPs displayed high call rates (99%). There were no significant differences in allele frequencies or genotypes in SNPs for SFRS5, SFRS9, FKBP4, FKBP5, and NR3C1 between the 3 groups. Up to three SNPs in SFRS3 had p-values <0.05 when comparing controls to POAG or steroid responders, but this statistical significance was lost when the p values were adjusted for multiple measures. Conclusions: Although these 6 genes may be involved in the pathogenesis of GC-induced ocular hypertension, it does not appear that major heritable risk alleles in these genes are responsible for the development of GC-induced ocular hypertension or POAG.

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SN - 1090-0535

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