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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Complex haplotypes derived from noncoding polymorphisms of the intronless alpha(2A)-adrenergic gene diversify receptor expression
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Complex haplotypes derived from noncoding polymorphisms of the intronless alpha(2A)-adrenergic gene diversify receptor expression

机译：源自非内含子α（2A）-肾上腺素基因非编码多态性的复杂单倍型使受体表达多样化

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摘要

alpha(2A)-adrenergic receptors (alpha(2A)AR) regulate multiple central nervous system, cardiovascular, and metabolic processes including neurotransmitter release, platelet aggregation, blood pressure, insulin secretion, and lipolysis. Complex diseases associated with alpha(2A)AR dysfunction display familial clustering, phenotypic heterogeneity, and interindividual variability in response to therapy targeted to alpha(2A)ARs, suggesting common, functional polymorphisms. In a multiethnic discovery cohort we identified 16 single-nucleotide polymorphisms (SNPs) in the alpha(2A)AR gene organized into 17 haplotypes of two major phylogenetic clades. In contrast to other adrenergic genes, variability of the alpha(2A)AR was primarily due to SNIPS in the promoter, 5' UTR and 3' UTR, as opposed to the coding block. Marked ethnic variability in the frequency of SNIPS and haplotypes was observed: one haplotype represented 70% of Caucasians, whereas Africans and Asians had a wide distribution of less common haplotypes, with the highest haplotype frequencies being 16% and 35%, respectively. Despite the compact nature of this intronless gene, local linkage disequilibrium between a number of SNIPS was low and ethnic-dependent. Whole-gene transfections into BE(2)-C human neuronal cells using vectors containing the entire approximate to 5.3-kb gene without exogenous promoters were used to ascertain the effects of haplotypes on alpha(2A)AR expression. Substantial differences (P < 0.001) in transcript and cell-surface protein expression, by as much as approximate to 5-fold, was observed between haplotypes, including those with common frequencies. Thus, signaling by this virtually ubiquitous receptor is under major genetic influence, which may be the basis for highly divergent phenotypes in complex diseases such as systemic and pulmonary hypertension, heart failure, diabetes, and obesity.
机译：α（2A）-肾上腺素能受体（α（2A）AR）调节多个中枢神经系统，心血管和代谢过程，包括神经递质释放，血小板聚集，血压，胰岛素分泌和脂解。与α（2A）AR功能障碍相关的复杂疾病在针对α（2A）AR的治疗反应中表现出家族聚集，表型异质性和个体差异，表明常见的功能性多态性。在一个多民族的研究队列中，我们在alpha（2A）AR基因中鉴定出16个单核苷酸多态性（SNP），这些基因被组织成两个主要系统进化进化枝的17个单倍型。与其他肾上腺素基因相反，α（2A）AR的变异性主要是由于启动子中的SNIPS，5'UTR和3'UTR，而不是编码块。观察到SNIPS和单倍型的频率存在明显的种族差异：一种单倍型代表了70％的白种人，而非洲人和亚洲人则分布较不常见的单倍型，最高的单倍型频率分别为16％和35％。尽管该无内含子基因具有紧凑的性质，但许多SNIPS之间的局部连锁不平衡程度较低，并且具有种族依赖性。使用含有完整的大约5.3-kb基因且不含外源启动子的载体对BE（2）-C人神经元细胞进行全基因转染，以确定单倍型对alpha（2A）AR表达的影响。在单倍型之间，包括在那些具有共同频率的单倍型之间，在转录本和细胞表面蛋白表达上存在显着差异（P <0.001），约为5倍。因此，这种几乎普遍存在的受体发出的信号受主要的遗传影响，这可能是复杂疾病（如系统性和肺动脉高压，心力衰竭，糖尿病和肥胖症）中高度分化表型的基础。

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