Haplotypes of angiotensinogen in essential hypertension
Haplotypes of angiotensinogen in essential hypertension
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DOI：
10.1086/515452
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发表时间：
1997-06-01
影响因子：
9.8
通讯作者：
Lalouel, JM
中科院分区：
文献类型：
--
作者：
Jeunemaitre, X;Inoue, I;Lalouel, JM
血管紧张素原基因（AGT）M235 T多态性与原发性高血压和妊娠高血压相关。单倍型的产生可以帮助解决T235等位基因本身是否易患高血压或作为一个未知的致病分子变异的标记。我们确定了10个双等位基因多态性在AGT位点和基因分型的一系列477先证者的高血压家族和364个控制，所有法国白人，以及一系列的92高血压和122控制来自日本。尽管在基因频率上存在很大的种族差异，但在高加索人（.46 vs. .38，P = .004）和日本人（.91 vs. .76，P = .002）中观察到T235与高血压的显著相关性。在两组中，位于初始转录位点上游-6位的G-->A取代以相同的频率发生，并且与T235等位基因完全连锁不平衡。没有发现其他多态性与高血压相关。产生了细分T235等位基因的五种信息性单倍型。其中两个与高加索人的高血压相关，而这两个单倍型（H3和H4）在日本人中均未达到统计学显著性。对AGT-GT重复序列的分析显示，每个双等位基因多态性和一些（GT）（16）等位基因之间存在明显的连锁不平衡，两个群体中的模式相似。M235和GT之间的强不平衡解释了法国对照组与高血压患者相比该特定等位基因的频率增加（0.42 vs.36，P <0.01）。结合M235 T和G-GA多态性的单倍型似乎是人类AGT基因的祖先等位基因，并且与高血压相关。
The M235T polymorphism of the angiotensinogen gene (AGT) has been associated with essential and pregnancy-induced hypertension. Generation of haplotypes can help to resolve whether the T235 allele itself predisposes to the development of hypertension or acts as a marker of an unknown causal molecular variant. We identified 10 diallelic polymorphisms at the AGT locus and genotyped both a series of 477 probands of hypertensive families and 364 controls, all French Caucasians, as well as a series of 92 hypertensives and 122 controls from Japan. Despite a large ethnic difference in gene frequency, a significant association of T235 with hypertension was observed both in Caucasians (.46 vs. .38, P = .004) and in Japanese (.91 vs. .76, P = .002). In both groups, the G-->A substitution located at position -6 upstream of the initial transcription site occurred at the same frequency and in complete linkage disequilibrium with the T235 allele. No other polymorphism was found to be consistently associated with hypertension. Five informative haplotypes subdividing the T235 allele were generated. Whereas two of them were associated with hypertension in Caucasians, none of these two haplotypes (H3 and H4) reached statistical significance in Japanese. The analysis of the AGT-GT repeat revealed marked linkage disequilibriums between each of the diallelic polymorphisms and some (GT)(16) alleles, with similar patterns in the two populations. The strong disequilibrium between M235 and (GT)(16) explained the increased frequency of that particular allele in French controls compared with hypertensives (.42 vs. .36, P < .01). The haplotype combining the M235T and G-GA polymorphisms appears as the ancestral allele of the human AGT gene and as the one associated with hypertension.