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

原发性高血压降压激素编码基因异常的研究。

• 批准号: 10671044
• 负责人: SOMA Masayoshi
• 金额: $ 0.38万
• 依托单位: NIHON UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671044/
• 关键词: hypertension; gene; polymorphism; receptor; nitric oxide; natriuretic peptide; adenosine; dopamine; ナトリウム利尿ホルモン; レセプター; プロスタサイクリン; 一酸化窒素合成酵素

(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

(1)内皮型一氧化氮合酶(EcNOS)基因可能参与了EH的发病过程。我们研究了ecNOS基因内含子4的可变数目串联重复序列(VNTR)多态与EH之间的可能关联。等位基因频率的总体分布在两组之间有显著差异，EH组中四重复等位基因的频率高于正常血压组(p=0.00027，优势比=4.0.)。因此，ecNOS基因的4个重复等位基因与EH相关，可能是日本人EH的遗传标志。(2)钠尿肽家族参与血压和液体量的调节。我们测定了人A型利尿肽受体(HNPRA)基因的外显子/内含子组织。该基因全长16kb，由22个外显子组成，我们分离了该基因的5‘侧翼区，并在该区域…中发现了一个插入/缺失突变我们的结果表明，hNPRA基因的这种缺失降低了受体的活性，可能增加了发生EH或LVH的易感性。(3)我们确定了人钠尿肽受体B型(NPRB)基因的组织结构。该基因全长约16.5kb，由22个外显子组成，内含子-外显子连接遵循GT-AG规则。用热不对称交错聚合酶链式反应(Tail-PCR)方法对其5‘侧翼区的750个碱基进行了测序。该区域含有10个潜在的Sp1结合位点，缺少TATA盒。快速扩增cDNAEnds(RACE)显示转录起始点位于-14个碱基。用杂交法鉴定CA/GT微卫星重复序列，并将其转化为序列标签位点(STS)。使用一种新的与EH相关的GT重复多态的关联性研究被证实。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)基因被认为与高血压有关，因为腺苷通过这种受体引起血管扩张和降低动脉血压，而且A2aAR基因的破坏会增加小鼠的血压。因此，利用A2aAR基因的限制性片段长度多态性(RFLP)，我们在EH患者中进行了一项相关性研究。我们的结果提示，A2aAR基因这个RFLP多态性检测到的等位基因与EH无关。(5)已有EH患者肾脏多巴胺受体功能缺陷的报道。利用多巴胺D1重复序列(DRD1)基因的RFLP，我们在EH患者中进行了一项相关性研究。DRD1基因的这种RFLP多态性检测到的等位基因与EH相关，它们似乎影响日本EH患者的舒张压。较少

项目成果

Takahashi Y, Nakayama T, Soma M, Izumi Y, Kanmatsuse: "Organization of the human natriuretic peptide receptor A gene."Biochem Biophys Res Commun. 246. 736-739 (1998)

Takahashi Y、Nakayama T、Soma M、Izumi Y、Kanmatsuse：“人类利钠肽受体 A 基因的组织。”Biochem Biophys Res Commun。

Masayoshi Soma: "NOS gene polymerphism and its influence on cardiovascular disease." Current Opinion in Nephrology and Hypertension. 8(1). 83-87 (1999)

Masayoshi Soma：“NOS 基因聚合及其对心血管疾病的影响。”

Soma M, Nakayama T, Satoh M, Uwabo J, Duolikun R, Takahashi Y, Fukuda N, Watanabe Y, Izumi Y and Kanmatsuse K: "A T1083C polymorphism in the human adenosine A2a receptor gene is not associated with essential hypertension."Am J Hypertens. 11. 1492-1494 (19

Soma M、Nakayama T、Satoh M、Uwabo J、Duolikun R、Takahashi Y、Fukuda N、Watanabe Y、Izumi Y 和 Kanmatsuse K：“人腺苷 A2a 受体基因中的 T1083C 多态性与原发性高血压无关。”Am

Soma M, Nakayama T, Kanmatsuse K: "NOS gene polymorphism and its influence on cardiovascular disease."Cur Opinion in Nephrol Hypertens. 8. 83-87 (1999)

Soma M、Nakayama T、Kanmatsuse K：“NOS 基因多态性及其对心血管疾病的影响。”肾性高血压的当前观点。

Nakayama T, Soma M, Kanmatsuse K: "Oraganization of the human prostacyclin synthase gene and association analysis of a novel CA repeat in essential hypertension."Recent Advances in Prostaglandin, Thromboxane, and Leukotriene Research. 127-130 (1998)

Nakayama T、Soma M、Kanmatsuse K：“人类前列环素合酶基因的组织和原发性高血压中新型 CA 重复的关联分析。”前列腺素、血栓素和白三烯研究的最新进展。