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）基因可能参与了原发性高血压（EH）的发病过程。我们调查了可变数目的串联重复序列（VNTR）多态性在内含子4的ecNOS基因和EH之间的可能关联。两组间等位基因频率的总体分布差异显著，EH组中四重复等位基因的频率高于血压正常组（p=0.00027，比值比=4.0）。因此，ecNOS基因的四个重复等位基因与EH相关，可能是日本受试者这种疾病的遗传标记。(2)利钠肽（NP）家族参与血压和液体容量的调节。我们测定了人A型利钠肽受体（hNPRA）基因的外显子/内含子结构。该基因由22个外显子组成，跨越16个以上的内切酶，我们分离了该基因的5 '侧翼区，并在该区域鉴定了一个插入/缺失突变。 ...更多信息 n.我们的研究结果表明，这种缺失在hNPRA基因降低受体活性，并可能赋予发展EH或LVH的易感性增加。(3)我们确定了人钠尿肽受体B型（NPR B）基因的组织结构。该基因由22个外显子组成，长度约为16.5 kbp，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5'侧翼区的750个碱基对进行测序。该区域含有10个潜在的Sp1结合位点，并且缺少TATA盒。cDNA末端快速扩增（RACE）显示转录起始位点在-14 bp处。用杂交法鉴定了一个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GT重复序列多态性进行关联研究，该多态性与EH相关。这些结果表明，EH的原因之一是该基因或密切相关的基因或区域的突变。(4)腺苷A2 a受体（A2 aAR）基因被认为与原发性高血压有关，因为腺苷通过该受体增强血管舒张并降低动脉血压，并且因为A2 aAR基因的破坏会增加小鼠的血压。因此，使用限制性片段长度多态性（RFLP）的A2 aAR基因，我们进行了关联性研究，高血压患者。提示A2 aAR基因的RFLP多态性与EH无关。(5)高血压患者肾多巴胺受体功能缺陷已有报道。使用多巴胺D1受体（DRD 1）基因的限制性片段长度多态性，我们进行了一项关联研究，在EH患者。DRD 1基因的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。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。