Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes
Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes
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DOI：
10.1073/pnas.0703247104
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发表时间：
2007-09-04
影响因子：
11.1
通讯作者：
Gauguier, Dominique
中科院分区：
文献类型：
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作者：
Woon, Peng Y.;Kaisaki, Pamela J.;Gauguier, Dominique
生理学和行为的许多方面都遵循昼夜节律。脑和肌肉芳香烃受体核转位蛋白样蛋白1（BMAL1）是哺乳动物分子钟的关键组成部分，它控制着昼夜节律振荡。在大鼠中，编码Bmal1的基因位于高血压易感位点内。我们分析了与自发性高血压大鼠（SHR）高血压相关的同源区间内的单核苷酸多态性（SNP）分布模式，并且我们发现Bmal1定位在SHR与其正常血压（Wistar - Kyoto）对应物之间存在遗传差异的区域附近。对大鼠品系的Bmal1测序确定了19种多态性，包括一种SHR启动子变异体，它在瞬时转染实验中显著影响Gata - 4对转录的激活。一项旨在测试这些发现在主要因2型糖尿病而入选的424个家庭的1304名个体中的相关性的遗传关联研究表明，两种BMAL1单倍型与2型糖尿病和高血压相关。这一从小鼠和大鼠模型转化到人类的比较遗传学发现为Bmal1变异体在代谢综合征病理成分中的致病作用提供了证据。
Many aspects of physiology and behavior follow a circadian rhythm. Brain and muscle Arnt-like protein-1 (BMAL1) is a key component of the mammalian molecular clock, which controls circadian oscillations. In the rat, the gene encoding Bmal1 is located within hypertension susceptibility loci. We analyzed the SNP distribution pattern in a congenic interval associated with hypertension in the spontaneously hypertensive rat (SHR), and we show that Bmal1 maps close to a region genetically divergent between SHR and its normotensive (Wistar-Kyoto) counterpart. Bmal1 sequencing in rat strains identified 19 polymorphisms, including an SHR promoter variant that significantly affects Gata-4 activation of transcription in transient transfection experiments. A genetic association study designed to test the relevance of these findings in 1,304 individuals from 424 families primarily selected for type 2 diabetes showed that two BMAL1 haplotypes are associated with type 2 diabetes and hypertension. This comparative genetics finding translated from mouse and rat models to human provides evidence of a causative role of Bmal1 variants in pathological components of the metabolic syndrome.