Glucocorticoid Receptor Gene Variant in the 3 ' Untranslated Region Is Associated with Multiple Measures of Blood Pressure

Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, 1200 Hermann Pressler, Houston, Texas 77030, USA.
Molecular Endocrinology (Impact Factor: 4.2). 02/2009; 23(1):124-5. DOI: 10.1210/jc.2008-1089
Source: PubMed

ABSTRACT The glucocorticoid receptor (GR) is a key hormone in the hypothalamus-pituitary-adrenal axis that regulates many pathways including blood pressure homeostasis. Thus, GR gene variation may influence interindividual differences in blood pressure in human populations.
We resequenced individual GR alleles for comprehensive discovery of GR variants and their chromosomal phase in three major American ethnic groups. We examined the influence of GR variants on blood pressure in large numbers of families using family-based association methods.
For association studies, we genotyped GR variants in family members from the Genetic Epidemiology Network of Arteriopathy (GENOA) study that were measured for multiple blood pressure traits. The GENOA families consisted of African-Americans, Mexican-Americans, and European-Americans.
The blood pressure measurements for association studies included systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure.
Single-nucleotide polymorphisms (SNPs) identified by resequencing were tested for associations with blood pressure measures in GENOA families. Analysis of individual SNPs identified significant associations of rs6198 A/G in exon 9beta with multiple blood pressure measures in European-Americans. Analysis of GR haplotypes found significant associations of a haplotype that is distinguished by rs6198 A/G.
Significant associations of blood pressure with rs6198 A/G likely reflect allelic effects on GR signaling. This SNP disrupts a 3' untranslated region sequence element in exon 9beta that destabilizes mRNA, resulting in increased production of the inactive GRbeta isoform. Excess heterodimerization with the active GRalpha isoform may reduce GR signaling with subsequent physiological effects on blood pressure regulation.

Download full-text


Available from: Charles C Chung, Jul 22, 2015
  • Source
    • "The EPR has a large minority population that consists of 24.7% African Americans and 5.3% Hispanics or Latinos. Minorities were targeted in the hGR study because of a lack of relevant data in these populations (Chung et al. 2009; Hawkins et al. 2004). The EPR is monitored for racial diversity and recruitment is targeted toward under represented groups as needed. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dissecting complex disease has become more feasible because of the availability of large-scale DNA resources and advances in high-throughput genomic technology. Although these tools help scientists identify potential susceptibility loci, subjects with relevant genotypes are needed for clinical phenotyping and toxicity studies.Objective: We have developed a resource of subjects and their DNA to use for translational research of environmental disease. More than 15,000 individuals of diverse sex, age, race, and ethnicity were recruited from North Carolina. DNA was isolated from their blood and coded with personal identification numbers linked to their identities. This linked resource of subjects and their DNA-the Environmental Polymorphism Registry (EPR)-allows scientists to screen for individuals with genotypes of interest and invite them to participate in follow-up studies. The EPR is a phenotype-by-genotype resource designed to facilitate translational studies of environmental disease. Based on their genotypes, subjects are invited to participate at all levels of research, from basic laboratory ex vivo cell phenotyping experiments that require viable tissue to in vivo observational studies and clinical trials. Here we report on progress of the EPR since 2008. We also describe a major effort at the National Institute of Environmental Health Sciences (NIEHS) to investigate susceptibility loci in 87 environmental response genes and gene × environment interactions using EPR resources. The EPR is a unique and novel resource and is ideal for genotype-driven translational research of environmental disease. We expect that it will serve as a model for future resources. Such tools help scientists attain their ultimate goals: to identify at-risk populations and develop strategies for preventing and treating human disease.
    Environmental Health Perspectives 06/2011; 119(11):1523-7. DOI:10.1289/ehp.1003348 · 7.03 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The glucocorticoid receptor (GR), a member of the nuclear receptor superfamily, mediates most of the known biologic effects of glucocorticoids. The human GR gene consists of 9 exons and expresses 2 alternative splicing isoforms, the GRα and GRβ. GRα is the classic receptor that binds to glucocorticoids and mediates most of the known actions of glucocorticoids, while GRβ does not bind to these hormones and exerts a dominant negative effect upon the GRα-induced transcriptional activity. Each of the two GR splice isoforms has 8 translational variants with specific transcriptional activity and tissue distribution. GRα consists of three subdomains, translocates from the cytoplasm into the nucleus upon binding to glucocorticoids, and regulates the transcriptional activity of numerous glucocorticoid-responsive genes either by binding to its cognate DNA sequences or by interacting with other transcription factors. In addition to these genomic actions, the GR also exerts rapid, non-genomic effects, which are possibly mediated by membrane-localised receptors or by translocation into the mitochondria. All these actions of the GR appear to play an important role in the regulation of the immune system. Specifically, the splicing variant GRβ may be involved in the pathogenesis of rheumatic diseases, while the circadian regulation of the GR activity via acetylation by the Clock transcription factor may have therapeutic implications for the preferential timing of glucocorticoid administration in autoimmune inflammatory disorders.
    Clinical and experimental rheumatology 01/2011; 29(5 Suppl 68):S32-41. · 2.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    The Journal of Clinical Endocrinology and Metabolism 05/2009; 94(8):3072-84. DOI:10.1210/jc.2008-2109 · 6.31 Impact Factor
Show more