Kainulainen K, Perola M, Terwilliger J, Kaprio J, Koskenvuo M, Syvänen A C, Vartiainen E, Peltonen L, Kontula K
Department of Medicine, University of Helsinki, Finland.
Hypertension. 1999 Mar;33(3):844-9. doi: 10.1161/01.hyp.33.3.844.
Components of the renin-angiotensin system play an important role in the normal regulation of blood pressure. We carried out a comprehensive genetic linkage study of the genes involved in the renin-angiotensin cascade in Finnish hypertensive twins and their affected siblings. We found no evidence for linkage between essential hypertension and the genes coding for renin, angiotensinogen, angiotensin-converting enzyme, or kallikrein 1 in the 329 hypertensive individuals of 142 families studied. In contrast, two intragenic markers for the type 1 angiotensin II receptor (AT1) showed some evidence for linkage in the total sample. A closer examination of this gene locus was carried out using subgroups of nonobese sibpairs with early onset of hypertension and uniform geographical origin. These stratifications yielded suggestive evidence for linkage of hypertension to the genetic area containing the AT1 gene, with a maximal multipoint logarithm of the odds (LOD) score of 2.9. A genetic association study carried out in an independent series of 50 hypertensive cases and 122 normotensive controls showed an increase in the frequency of the A1166-->C allele of the AT1 gene in the hypertensive individuals. In a novel variant of model-free multipoint linkage analysis allowing linkage disequilibrium in the calculations, an LOD score of 5.13 was obtained. Sequence analyses of the entire coding region and 848 bp of promoter region in the DNA sample on 8 index samples did not reveal previously unpublished sequence variations. The data provide evidence that a common genetic variant of the AT1 gene locus influences the risk of essential hypertension in the Finnish population.
肾素-血管紧张素系统的组成部分在血压的正常调节中起着重要作用。我们对芬兰高血压双胞胎及其患病同胞中参与肾素-血管紧张素级联反应的基因进行了全面的基因连锁研究。在研究的142个家庭的329名高血压个体中，我们没有发现原发性高血压与肾素、血管紧张素原、血管紧张素转换酶或激肽释放酶1编码基因之间存在连锁的证据。相比之下，1型血管紧张素II受体（AT1）的两个基因内标记在总样本中显示出一些连锁的证据。我们使用高血压发病早且地理来源一致的非肥胖同胞对亚组对该基因座进行了更深入的研究。这些分层产生了高血压与包含AT1基因的遗传区域连锁的提示性证据，最大多点对数优势（LOD）评分为2.9。在一个由50例高血压病例和122例血压正常对照组成的独立系列中进行的基因关联研究表明，高血压个体中AT1基因A1166→C等位基因的频率增加。在一种允许在计算中存在连锁不平衡的无模型多点连锁分析新变体中，获得了5.13的LOD评分。对8个索引样本的DNA样本中整个编码区和848 bp启动子区的序列分析未发现以前未发表的序列变异。这些数据提供了证据，表明AT1基因座的一个常见遗传变体影响芬兰人群原发性高血压的风险。
