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


OBJECTIVE
The aim of the study was to identify and determine the functional implications of common genetic variation in NR3C1.


METHODS
We resequenced the NR3C1 gene using 240 DNA samples from four ethnic groups, followed by functional characterization of the effects of selected polymorphisms.


RESULTS
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.


CONCLUSIONS
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.
Niu
Nifang
N
Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Manickam
Venkatraman
V
Kalari
Krishna R
KR
Moon
Irene
I
Pelleymounter
Linda L
LL
Eckloff
Bruce W
BW
Wieben
Eric D
ED
Schaid
Daniel J
DJ
Wang
Liewei
L
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D023281:Genomics; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D017422:Sequence Analysis, DNA
C497713:NR3C1 protein, human; D011965:Receptors, Glucocorticoid