Human glucocorticoid receptor alpha gene (NR3C1) pharmacogenomics: gene resequencing and functional genomics

Nifang Niu; Venkatraman Manickam; Krishna R Kalari; Irene Moon; Linda L Pelleymounter; Bruce W Eckloff; Eric D Wieben; Daniel J Schaid; Liewei Wang

doi:10.1210/jc.2008-2109

Back

Human glucocorticoid receptor alpha gene (NR3C1) pharmacogenomics: gene resequencing and functional genomics

Journal article

Open access

Peer reviewed

Human glucocorticoid receptor alpha gene (NR3C1) pharmacogenomics: gene resequencing and functional genomics

Nifang Niu, Venkatraman Manickam, Krishna R Kalari, Irene Moon, Linda L Pelleymounter, Bruce W Eckloff, Eric D Wieben, Daniel J Schaid and Liewei Wang

The journal of clinical endocrinology and metabolism, Vol.94(8), pp.3072-3084

08/01/2009

DOI: 10.1210/jc.2008-2109

PMCID: PMC2730876

PMID: 19435830

Files and links (1)

url

https://doi.org/10.1210/jc.2008-2109View

Published (Version of record) Open Access

Abstract

The human glucocorticoid receptor alpha (GRalpha) is a nuclear hormone receptor that regulates multiple physiological and pathophysiological processes. There are large variations in both physiological and therapeutic response to glucocorticoids. Multiple previous studies suggested that genetic polymorphisms in GRalpha (NR3C1) might play an important role. The aim of the study was to identify and determine the functional implications of common genetic variation in NR3C1. We resequenced the NR3C1 gene using 240 DNA samples from four ethnic groups, followed by functional characterization of the effects of selected polymorphisms. A total of 108 polymorphisms were identified in GRalpha, including nine nonsynonymous coding single nucleotide polymorphisms (cSNPs) and four synonymous cSNPs with a minor allele frequency greater than 5%. Functional studies showed that SNPs encoding Phe(65)Val and Asp(687)Glu displayed slightly increased levels of protein compared with WT, and Asp(687)Glu also caused increased GRalpha receptor number. In addition, Ala(229)Thr and Ile(292)Val showed slightly decreased ligand binding affinity in COS-1 cells. A genotype-phenotype association study of NR3C1 gene expression in 240 lymphoblastoid cell lines identified one SNP, Cm746T>C, located 5'-upstream of noncoding exon 1C, and one haplotype, Cm237delC/Cm238C>T/Cm240G>C in exon 1C of the gene that were associated with GRalpha mRNA expression and a trend with GRalpha number. These results represent a step toward understanding the functional role of common sequence variation in the GRalpha gene (NR3C1) and the potential application of those SNPs in translational studies.

Animals

Cercopithecus aethiops

COS Cells

Genomics

Genotype

Haplotypes

Humans

Linkage Disequilibrium

Pharmacogenetics

Polymorphism, Single Nucleotide

Receptors, Glucocorticoid - genetics

Sequence Analysis, DNA

Details

Title: Subtitle: Human glucocorticoid receptor alpha gene (NR3C1) pharmacogenomics: gene resequencing and functional genomics
Creators: Nifang Niu - Mayo Clinic
Venkatraman Manickam - Mayo Clinic
Krishna R Kalari - Mayo Clinic in Florida
Irene Moon - Mayo Clinic
Linda L Pelleymounter - Mayo Clinic
Bruce W Eckloff - Mayo Clinic
Eric D Wieben - Mayo Clinic
Daniel J Schaid - Mayo Clinic
Liewei Wang - Mayo Clinic
Resource Type: Journal article
Publication Details: The journal of clinical endocrinology and metabolism, Vol.94(8), pp.3072-3084
DOI: 10.1210/jc.2008-2109
PMID: 19435830
PMCID: PMC2730876
ISSN: 0021-972X
eISSN: 1945-7197
Grant note: U01 GM061388 / NIGMS NIH HHS K22 CA130828-01A1 / NCI NIH HHS U01 GM61388 / NIGMS NIH HHS R01 CA138461-01 / NCI NIH HHS K22 CA130828 / NCI NIH HHS R01 CA138461 / NCI NIH HHS
Language: English
Date published: 08/01/2009
Academic Unit: Stead Family Department of Pediatrics; Medical Genetics and Genomics
Record Identifier: 9984701646102771

Metrics

4 Record Views

33 Times Cited - Web of Science