A novel human glucocorticoid receptor SNP results in increased transactivation potential

Tajia L. Green, Kelly Tung, Debora Lim, Stacey M. Leventhal, Kiho Cho, David G Greenhalgh

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Glucocorticoids are one of the most widely used therapeutics in the treatment of a variety of inflammatory disorders. However, it is known that there are variable patient responses to glucocorticoid treatment; there are responders and non-responders, or those that need higher dosages. Polymorphisms in the glucocorticoid receptor (GR) have been implicated in this variability. In this study, ninety-seven volunteers were surveyed for polymorphisms in the human GR-alpha (hGRα), the accepted biologically active reference isoform. One isoform identified in our survey, named hGR DL-2, had four single nucleotide polymorphisms (SNPs), one synonymous and three non-synonymous, and a four base pair deletion resulting in a frame shift and early termination to produce a 743 amino acid putative protein. hGR DL-2 had a decrease in transactivation potential of more than 90%. Upon further analysis of the individual SNPs and deletion, one SNP, A829G, which results in a lysine to glutamic acid amino acid change at position 277, was found to increase the transactivation potential of hGR more than eight times the full-length reference. Furthermore, the hGRα-A829G isoform had a differential hyperactive response to various exogenous steroids. Increasing our knowledge as to how various SNPs affect hGR activity may help in understanding the unpredictable patient response to steroid treatment, and is a step towards personalizing patient care.

Original languageEnglish (US)
Pages (from-to)140-145
Number of pages6
JournalBiochemistry and Biophysics Reports
Volume9
DOIs
StatePublished - Mar 1 2017

Fingerprint

Glucocorticoid Receptors
Polymorphism
Transcriptional Activation
Single Nucleotide Polymorphism
Nucleotides
Protein Isoforms
Glucocorticoids
Steroids
Amino Acids
Therapeutics
Base Pairing
Lysine
Glutamic Acid
Volunteers
Patient Care
Proteins

Keywords

  • Glucocorticoid Receptor
  • Hyperactive Isoform
  • Single Nucleotide Polymorphism
  • Steroid Response
  • Stress Response

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

A novel human glucocorticoid receptor SNP results in increased transactivation potential. / Green, Tajia L.; Tung, Kelly; Lim, Debora; Leventhal, Stacey M.; Cho, Kiho; Greenhalgh, David G.

In: Biochemistry and Biophysics Reports, Vol. 9, 01.03.2017, p. 140-145.

Research output: Contribution to journalArticle

Green, Tajia L. ; Tung, Kelly ; Lim, Debora ; Leventhal, Stacey M. ; Cho, Kiho ; Greenhalgh, David G. / A novel human glucocorticoid receptor SNP results in increased transactivation potential. In: Biochemistry and Biophysics Reports. 2017 ; Vol. 9. pp. 140-145.
@article{8405b88d58164e668ac483f6a4cd14d5,
title = "A novel human glucocorticoid receptor SNP results in increased transactivation potential",
abstract = "Glucocorticoids are one of the most widely used therapeutics in the treatment of a variety of inflammatory disorders. However, it is known that there are variable patient responses to glucocorticoid treatment; there are responders and non-responders, or those that need higher dosages. Polymorphisms in the glucocorticoid receptor (GR) have been implicated in this variability. In this study, ninety-seven volunteers were surveyed for polymorphisms in the human GR-alpha (hGRα), the accepted biologically active reference isoform. One isoform identified in our survey, named hGR DL-2, had four single nucleotide polymorphisms (SNPs), one synonymous and three non-synonymous, and a four base pair deletion resulting in a frame shift and early termination to produce a 743 amino acid putative protein. hGR DL-2 had a decrease in transactivation potential of more than 90{\%}. Upon further analysis of the individual SNPs and deletion, one SNP, A829G, which results in a lysine to glutamic acid amino acid change at position 277, was found to increase the transactivation potential of hGR more than eight times the full-length reference. Furthermore, the hGRα-A829G isoform had a differential hyperactive response to various exogenous steroids. Increasing our knowledge as to how various SNPs affect hGR activity may help in understanding the unpredictable patient response to steroid treatment, and is a step towards personalizing patient care.",
keywords = "Glucocorticoid Receptor, Hyperactive Isoform, Single Nucleotide Polymorphism, Steroid Response, Stress Response",
author = "Green, {Tajia L.} and Kelly Tung and Debora Lim and Leventhal, {Stacey M.} and Kiho Cho and Greenhalgh, {David G}",
year = "2017",
month = "3",
day = "1",
doi = "10.1016/j.bbrep.2016.12.003",
language = "English (US)",
volume = "9",
pages = "140--145",
journal = "Biochemistry and Biophysics Reports",
issn = "2405-5808",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - A novel human glucocorticoid receptor SNP results in increased transactivation potential

AU - Green, Tajia L.

AU - Tung, Kelly

AU - Lim, Debora

AU - Leventhal, Stacey M.

AU - Cho, Kiho

AU - Greenhalgh, David G

PY - 2017/3/1

Y1 - 2017/3/1

N2 - Glucocorticoids are one of the most widely used therapeutics in the treatment of a variety of inflammatory disorders. However, it is known that there are variable patient responses to glucocorticoid treatment; there are responders and non-responders, or those that need higher dosages. Polymorphisms in the glucocorticoid receptor (GR) have been implicated in this variability. In this study, ninety-seven volunteers were surveyed for polymorphisms in the human GR-alpha (hGRα), the accepted biologically active reference isoform. One isoform identified in our survey, named hGR DL-2, had four single nucleotide polymorphisms (SNPs), one synonymous and three non-synonymous, and a four base pair deletion resulting in a frame shift and early termination to produce a 743 amino acid putative protein. hGR DL-2 had a decrease in transactivation potential of more than 90%. Upon further analysis of the individual SNPs and deletion, one SNP, A829G, which results in a lysine to glutamic acid amino acid change at position 277, was found to increase the transactivation potential of hGR more than eight times the full-length reference. Furthermore, the hGRα-A829G isoform had a differential hyperactive response to various exogenous steroids. Increasing our knowledge as to how various SNPs affect hGR activity may help in understanding the unpredictable patient response to steroid treatment, and is a step towards personalizing patient care.

AB - Glucocorticoids are one of the most widely used therapeutics in the treatment of a variety of inflammatory disorders. However, it is known that there are variable patient responses to glucocorticoid treatment; there are responders and non-responders, or those that need higher dosages. Polymorphisms in the glucocorticoid receptor (GR) have been implicated in this variability. In this study, ninety-seven volunteers were surveyed for polymorphisms in the human GR-alpha (hGRα), the accepted biologically active reference isoform. One isoform identified in our survey, named hGR DL-2, had four single nucleotide polymorphisms (SNPs), one synonymous and three non-synonymous, and a four base pair deletion resulting in a frame shift and early termination to produce a 743 amino acid putative protein. hGR DL-2 had a decrease in transactivation potential of more than 90%. Upon further analysis of the individual SNPs and deletion, one SNP, A829G, which results in a lysine to glutamic acid amino acid change at position 277, was found to increase the transactivation potential of hGR more than eight times the full-length reference. Furthermore, the hGRα-A829G isoform had a differential hyperactive response to various exogenous steroids. Increasing our knowledge as to how various SNPs affect hGR activity may help in understanding the unpredictable patient response to steroid treatment, and is a step towards personalizing patient care.

KW - Glucocorticoid Receptor

KW - Hyperactive Isoform

KW - Single Nucleotide Polymorphism

KW - Steroid Response

KW - Stress Response

UR - http://www.scopus.com/inward/record.url?scp=85007029624&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85007029624&partnerID=8YFLogxK

U2 - 10.1016/j.bbrep.2016.12.003

DO - 10.1016/j.bbrep.2016.12.003

M3 - Article

VL - 9

SP - 140

EP - 145

JO - Biochemistry and Biophysics Reports

JF - Biochemistry and Biophysics Reports

SN - 2405-5808

ER -