Glucocorticoid receptor gene variant in the 3' untranslated region is associated with multiple measures of blood pressure.

TitleGlucocorticoid receptor gene variant in the 3' untranslated region is associated with multiple measures of blood pressure.
Publication TypeJournal Article
Year of Publication2009
AuthorsChung, CC, Shimmin, L, Natarajan, S, Hanis, CL, Boerwinkle, E, Hixson, JE
JournalJ Clin Endocrinol Metab
Volume94
Issue1
Pagination268-76
Date Published2009 Jan
ISSN0021-972X
Keywords3' Untranslated Regions, Blood Pressure, Cell Line, Haplotypes, Humans, Polymorphism, Single Nucleotide, Protein Isoforms, Receptors, Glucocorticoid
Abstract

CONTEXT: 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.OBJECTIVE: 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.DESIGN AND PARTICIPANTS: 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.MAIN MEASUREMENTS: The blood pressure measurements for association studies included systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure.RESULTS: 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.CONCLUSIONS: 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.

DOI10.1210/jc.2008-1089
Alternate JournalJ Clin Endocrinol Metab
PubMed ID18854398
PubMed Central IDPMC2630865
Grant ListHL54505 / HL / NHLBI NIH HHS / United States
R01 HL039107 / HL / NHLBI NIH HHS / United States
HL051021 / HL / NHLBI NIH HHS / United States
HL039107 / HL / NHLBI NIH HHS / United States
P01 HD047609 / HD / NICHD NIH HHS / United States
HD047609 / HD / NICHD NIH HHS / United States
U10 HL054457 / HL / NHLBI NIH HHS / United States
U01 HL054457 / HL / NHLBI NIH HHS / United States
HL054457 / HL / NHLBI NIH HHS / United States
R37 HL051021 / HL / NHLBI NIH HHS / United States