Study for the gene abnormality encoding depressor hormones in essential hypertension.

(1)内皮构成型NO合成酶（ecNOS）基因可能参与了原发性高血压（EH）的发病机制。我们研究了ecNOS基因4内含子可变数目串联重复序列（VNTR）多态性与EH之间的可能关联。等位基因频率的总体分布在两组之间存在显著差异，EH组的4重复等位基因频率高于正常血压组（p=0.00027，优势比=4.0）。因此，ecNOS基因的四重复等位基因与EH相关，可能是日本受试者中该病的遗传标记。(2)利钠肽（NP）家族参与血压和体液量的调节。我们测定了人天然肽受体A型（hNPRA）基因的外显子/内含子组织。该基因跨越超过16000个碱基，由22个外显子组成，我们分离了该基因的5'-侧翼区域，并在该区域发现了插入/缺失突变。我们的研究结果表明，hNPRA基因的缺失降低了受体活性，可能增加了发生EH或LVH的易感性。(3)确定了人钠肽受体B型（NPRB）基因的组织。该基因全长约16.5千碱基（kbp），由22个外显子组成，内含子-外显子连接遵循GT-AG规则。采用热不对称交错pcr （TAIL-PCR）方法对750个5'侧区碱基对进行测序。该区域含有10个潜在的sp1结合位点，缺乏TATA盒。cDNA末端快速扩增（RACE）显示转录起始位点为- 14bp。用杂交方法鉴定了CA/GT微卫星重复序列，并将其转化为序列标记位点（STS）。利用一种新的与EH相关的GT重复多态性进行关联研究。这些结果表明，EH的一个原因是该基因或密切相关的基因或区域的突变。(4)腺苷A2a受体（A2aAR）基因被认为与原发性高血压有关，因为腺苷通过该受体引起血管舒张并降低动脉血压，并且因为A2aAR基因的破坏会增加小鼠的血压。因此，我们利用A2aAR基因的限制性片段长度多态性（RFLP）对EH患者进行了相关性研究。我们的研究结果表明，A2aAR基因中RFLP多态性检测到的等位基因与EH无关。(5) EH中有肾多巴胺受体功能缺陷的报道。利用多巴胺D1再释放因子（DRD1）基因的RFLP，我们对EH患者进行了相关性研究。DRD1基因中RFLP多态性检测到的等位基因与EH相关，并且它们似乎影响日本EH患者的舒张压。少

(1) Endothelial constitutive NO synthase (ecNOS) gene may be involved in the pathogenesis of essential hypertension (EH). We investigated the possible association between a variable number of tandem repeats (VNTR) polymorphism in intron 4 of the ecNOS gene and EH. The overall distributions of allele frequencies differed significantly between the two groups, with the four-repeat allele more frequent in the EH group than in the normotensive group (p=0.00027, odds ratio=4.0). The four-repeat allele of the ecNOS gene was thus associated with EH and may be a genetic marker of this disease in Japanese subjects.(2) The natriuretic peptide (NP) family is involved in regulation of blood pressure and fluid volume. We determined the exon/intron organization of human natiuretic peptide receptor the type A (hNPRA) gene. The gene, which spans more than 16 kilobases, is composed of 22 exons, and we isolated the 5'-flanking region of the gene and identified an insertion/deletion mutation in this regio … More n. Our results suggest that this deletion in the hNPRA gene reduces receptor activity and may confer increased susceptibility to developing EH or LVH.(3) We determined the organization of human natriuretic peptide receptor the type B (NPRB) gene. This gene, which spans approximately 16.5 kilobase (kbp), is composed of 22 exons, and the intron-exon junctions follow the GT-AG rule. Seven hundred fifty basepaires of the 5' flanking region were sequenced using a thermal asymmetric interlaced-PCR (TAIL-PCR) method. This region contains 10 potential Sp1-binding sites and lacks a TATA box. Rapid amplification of cDNA ends (RACE) revealed the transcriptional start site at -14 bp. A CA/GT microsatellite repeat was identified with a hybridization-based method and was converted to sequence tagged site (STS). Association study using a novel GT repeat polymorphism, which associated with EH, was identified. These results suggest that one cause of EH is a mutation in this gene or a closely related gene or region.(4) The adenosine A2a receptor (A2aAR) gene is thought to be involved in essential hypertension because adenosine elicits vasodilation and decreases arterial blood pressure via this receptor, and because disruption of the A2aAR gene increases blood pressure in mice. Therefore, using a restriction fragment length polymorphism (RFLP) of the A2aAR gene, we performed an association study in patients with EH. Our resullts suggest that the alleles detected by this RFLP polymorphism in the A2aAR gene is not associated with EH.(5) Defective renal dopamine receptor function have been reported in EH. Using a RFLP of the dopamine D1 redeptor (DRD1) gene, we performed an association study in patients with EH. The alleles detected by this RFLP polymorphism in the DRD1 gene are associated with EH, and they appear to influence diastolic blood pressure of Japanese EH patients. Less