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

Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas 77030

Address all correspondence and requests for reprints to: James E. Hixson, Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, 1200 Hermann Pressler, Houston, Texas 77030. E-mail: James.E.Hixson{at}uth.tmc.edu.

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 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.

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 9β that destabilizes mRNA, resulting in increased production of the inactive GRβ isoform. Excess heterodimerization with the active GR isoform may reduce GR signaling with subsequent physiological effects on blood pressure regulation.