Glucocorticoid Receptor Gene Variant in the 3′ Untranslated Region Is Associated with Multiple Measures of Blood Pressure
Glucocorticoid Receptor Gene Variant in the 3′ Untranslated Region Is Associated with Multiple Measures of Blood Pressure
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DOI：
10.1210/jc.2008-1089
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发表时间：
2009-01-01
影响因子：
5.8
通讯作者：
Hixson, James E.
中科院分区：
文献类型：
--
作者：
Chung, Charles C.;Shimmin, Lawrence;Hixson, James E.
内容：糖皮质激素受体（GR）是下丘脑-垂体-肾上腺轴中的一种关键激素，调节包括血压稳态在内的许多途径。因此，GR基因变异可能会影响个体间的差异，血压在human population.Objective：我们重新测序个别GR等位基因的全面发现GR变异及其染色体相位在三个主要的美国种族群体。我们研究了GR变异体对血压的影响，在大量的家庭使用家庭为基础的association methods.Design和参与者：对于协会研究，我们基因型GR变异体在家庭成员的遗传流行病学网络动脉病（GENOA）的研究，测量多个血压性状。GENOA家族包括非洲裔美国人，墨西哥裔美国人，和欧洲裔American.Main测量：血压测量的关联研究包括收缩压，舒张压，平均动脉压，和pulse pressure.Results：单核苷酸多态性（SNPs）通过重新测序确定了与GENOA家族血压测量的关联进行了测试。个体SNPs分析发现，在欧裔美国人中，外显子9 β中的rs6198 A/G与多种血压指标显著相关。GR单倍型的分析发现显着协会的单倍型，是由rs6198 A/G的区别。结论：血压与rs6198 A/G的显着协会可能反映GR信号的等位基因效应。这种SNP破坏外显子9 β中的3'非翻译区序列元件，使mRNA不稳定，导致无活性GR β同种型的产生增加。与活性GR α亚型的过度异二聚化可能会减少GR信号传导，随后对血压调节产生生理影响。（J Clin Endocrinol Metab 94：268-276，2009）
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 9 beta 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 9 beta that destabilizes mRNA, resulting in increased production of the inactive GR beta isoform. Excess heterodimerization with the active GR alpha isoform may reduce GR signaling with subsequent physiological effects on blood pressure regulation. (J Clin Endocrinol Metab 94: 268-276, 2009)