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

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 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 (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse pressure (PP). 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 9β 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′ UTR sequence element in exon 9β that destabilizes mRNA, resulting in increased production of the inactive GRβ isoform. Excess heterodimerization with the active GRα isoform may reduce GR signaling with subsequent physiological effects on blood pressure regulation.