Sequence variation in the human angiotensin converting enzyme
Sequence variation in the human angiotensin converting enzyme
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DOI：
10.1038/8760
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发表时间：
1999-05-01
期刊：
影响因子：
30.8
通讯作者：
Nickerson, DA
中科院分区：
文献类型：
--
作者：
Rieder, MJ;Taylor, SL;Nickerson, DA
血管紧张素转换酶（由基因DCP1编码，也称为ACE）催化血管紧张素I转化为具有生理活性的肽——血管紧张素II，后者控制着体液 - 电解质平衡和全身血压。由于其在肾素 - 血管紧张素系统中的关键作用，人们对DCP1进行了许多关联研究。几乎所有研究都将内含子16中一个287bp的Alu重复元件的存在（插入，I）或缺失（缺失，D）与循环酶水平或心血管病理生理状况相关联（1 - 3）。许多流行病学研究表明，DCP1*D等位基因会增加心血管疾病的易感性；然而，其他报告却未发现这种关联，甚至发现有有益影响（参考文献4 - 7）。在此，我们展示了来自11个人的DCP1的完整基因组序列，这代表了对人类DNA序列变异最长的连续扫描（24kb）。我们在22条染色体上确定了78个变异位点，这些位点可归结为13种不同的单倍型。在这些变异位点中，有17个与通常所检测的Alu插入/缺失多态性处于绝对连锁不平衡状态，产生了两个不同且远缘相关的分支。我们还在Alu缺失分支中确定了一个主要的细分，这使得能够进一步分析与该基因相关的性状。在DCP1中发现的多样性与人类基因组其他区域所描述的相当（8 - 11）。DCP1中高度相关的结构为确定基因内功能性DNA变异以及基于标记关联的人类遗传学研究提出了重要问题。
Angiotensin converting enzyme (encoded by the gene DCP1, also known as ACE) catalyses the conversion of angiotensin I to the physiologically active peptide angiotensin II, which controls fluid-electrolyte balance and systemic blood pressure. Because of its key function in the renin-angiotensin system, many association studies have been performed with DCP1. Nearly all studies have associated the presence (insertion, I) or absence (deletion, D) of a 287-bp Alu repeat element in intron 16 with the levels of circulating enzyme or cardiovascular pathophysiologies(1-3). Many epidemiological studies suggest that the DCP1*D allele confers increased susceptibility to cardiovascular disease; however, other reports have found no such association or even a beneficial effect (refs 4-7), We present here the complete genomic sequence of DCP1 from 11 individuals, representing the longest contiguous scan (24 kb) for sequence variation in human DNA, We identified 78 varying sites in 22 chromosomes that resolved into 13 distinct haplotypes. Of the variant sites, 17 were in absolute linkage disequilibrium with the commonly typed Alu insertion/deletion polymorphism, producing two distinct and distantly related clades. We also identified a major subdivision in the Alu deletion clade that enables further analysis of the traits associated with this gene. The diversity uncovered in DCP1 is comparable to that described for other regions in the human genomes-(8-11), The highly correlated structure in DCP1 raises important issues for the determination of functional DNA variants within genes and genetic studies in humans based on marker association.