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


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.


METHODS
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.
Chung
Charles C
CC
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, 1200 Hermann Pressler, Houston, Texas 77030, USA.
Shimmin
Lawrence
L
Natarajan
Sivamani
S
Hanis
Craig L
CL
Boerwinkle
Eric
E
Hixson
James E
JE
D020413:3' Untranslated Regions / Q000235:genetics*; D001794:Blood Pressure / Q000502:physiology*; D002460:Cell Line; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms; D011965:Receptors, Glucocorticoid / Q000235:genetics*
D020413:3' Untranslated Regions; D020033:Protein Isoforms; D011965:Receptors, Glucocorticoid