Quantitative trait locus analysis of spontaneously hypertensive mice

自发性高血压小鼠数量性状位点分析

• 批准号: 16300135
• 负责人: SUGIYAMA Fumihiro
• 金额: $ 9.41万
• 依托单位: University of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16300135/
• 关键词: mice; blood pressure; QTL; obesity; insulin resistance; 高血圧; NZO; 遺伝子座; 近交系; 糖尿病

We characterized the systolic and diastolic blood pressures of 10-week old males from 15 inbred mouse strains and found that blood pressures among strains were continuously distributed and that strain C3H/HeJ had the lowest mean systolic and diastolic pressures (100.5 ±3.2 and 66.8 ±3.5 mmHg), and a strain with obesity and diabetes, NZO/HILtJ, had the highest (132.4 ±3.1 and 86.6 ± 6.9 mmHg). To understand the relationship of blood pressure with insulin resistance and obesity, we produced F_1 and F_2 progeny from reciprocal crosses of NZO, the strain with obesity, diabetes, and high blood pressure, and the strain with the lowest blood pressures, C3H/HeJ. Mean systolic pressures of 10-week old (NZO x C3H)F_1 and (C3H x NZO)F_1 males were similar to each other (114.9 ± 3.8 and 117.2 ±5.0 mmHg) and were intermediate to those of the parental strains. Systolic pressure of F_2 males (n = 223) were distributed normally about the mean, suggesting that blood pressure is a polygenic trait. The b … More ody mass index (BMI) and plasma insulin levels of F_2 progeny correlated significantly and positively with plasma leptin levels, suggesting that obesity is associated with insulin resistance. In contrast, systolic pressure did not correlate with BMI, plasma leptin levels, and plasma insulin levels, suggesting that genes underlying the development of hypertension in this intercross are not associated with the development of obesity and insulin resistance. Our results demonstrate that the progeny of NZO and C3H intercrosses are a practical and powerful tool for identifying blood pressure genes and for understanding human polygenic hypertension.In the first study in 15 inbred mouse strains, we found highest and lowest systolic blood pressures in NZO/HILtJ mice (metabolic syndrome) and C3H/HeJ mice (common lean strain), respectively. To identify the loci involved in hypertension in metabolic syndrome, we performed quantitative trait locus (QTL) analysis for blood pressure with direction of cross as a covariate in segregating F_2 males derived from NZO/HILtJ and C3H/HeJ mice. We detected three suggestive main effect QTLs affecting systolic and diastolic blood pressure (SBP and DBP). We analyzed the first principle component (PC1) generated from SBP and DBP to investigate blood pressure. In addition to all the suggestive QTLs (Chr 1, 3, and 8) in SBP and DBP, one suggestive QTL on Chr 4 was found in PC1 in the main scan. Simultaneous search identified two significant epistatic locus pairs (Chr 1 and 4, Chr 4 and 8) for PC1. Multiple regression analysis revealed three blood pressure QTLs (Bpq10, 100 cM on Chr 1 ; Bpq11, 6 cM on Chr 4 ; Bpq12, 29 cM on Chr 8) accounting for 29.4% of blood pressure variance. These were epistatic interaction QTLs constructing a small network centered on Chr 4, suggesting the importance of genetic interaction for development of hypertension. The blood pressure QTLs on Chr 1, 4, and 8 were detected repeatedly in multiple studies using common inbred non-obese mouse strains, implying substantial QTL independent of development of obesity and insulin resistance. These results enhance our understanding of complicated genetic factors of hypertension in metabolic diseases. Less

我们对来自15个近交系小鼠品系的10周龄雄性小鼠的收缩压和舒张压进行了表征，发现品系间的血压是连续分布的，并且品系C3 H/HeJ具有最低的平均收缩压和舒张压肥胖和糖尿病的NZO/HILtJ最高（132.4 ±3.1和86.6 ± 6.9mmHg）。为了了解血压与胰岛素抵抗和肥胖的关系，我们用肥胖、糖尿病和高血压的品系NZO和血压最低的品系C3 H/HeJ正反交产生F_1和F_2后代。10周龄（NZO × C3 H）F_1和（C3 H × NZO）F_1雄性的平均收缩压相似（114.9 ± 3.8和117.2 ±5.0 mmHg），均介于亲本品系之间。F_2雄性（n = 223）的血压在平均值附近呈正态分布，表明血压是一个多基因性状。B ...更多信息 F_2代体重指数（BMI）、血浆胰岛素水平与血浆瘦素水平呈显著正相关，提示肥胖与胰岛素抵抗有关。相反，收缩压与BMI、血浆瘦素水平和血浆胰岛素水平不相关，这表明在这种交叉中高血压发展的潜在基因与肥胖和胰岛素抵抗的发展无关。我们的研究结果表明，NZO和C3 H杂交的后代是一个实用的和强大的工具，为确定血压基因和了解人类多基因hypertension.In第一次在15个近交系小鼠strain. In研究中，我们发现最高和最低的收缩压NZO/HILtJ小鼠（代谢综合征）和C3 H/HeJ小鼠（普通瘦株），分别。为了确定代谢综合征高血压的相关基因位点，我们对NZO/HILtJ和C3 H/HeJ小鼠分离的F_2雄性进行了以杂交方向为协变量的血压数量性状基因座（QTL）分析。我们检测到三个提示性的影响收缩压和舒张压（SBP和DBP）的主效应QTL。我们分析了由SBP和DBP产生的第一主成分（PC 1）来研究血压。除了SBP和DBP的所有提示性QTL（Chr 1，3和8）外，在主扫描中还在PC 1中发现了Chr 4上的一个提示性QTL。同时搜索发现两个显着的上位性位点对（Chr 1和4，Chr 4和8）的PC 1。多元回归分析显示，血压QTL有3个（Bpq 10，Chr 1为100 cM，Bpq 11，Chr 4为6 cM，Bpq 12，Chr 8为29 cM），可解释血压变异的29.4%。这些上位性互作QTL以Chr 4为中心构建了一个小网络，提示遗传互作在高血压发病中的重要性。在使用常见近交非肥胖小鼠品系的多项研究中重复检测了Chr 1、4和8上的血压QTL，这意味着大量的QTL独立于肥胖和胰岛素抵抗的发展。这些结果加深了我们对代谢性疾病中高血压复杂遗传因素的理解。少

项目成果

Takimoto-Ohnishi E, Saito T, Ishida J, Ohnishi J, Sugiyama F, Yagami K, Fukamizu A.

泷本大西 E、斋藤 T、石田 J、大西 J、杉山 F、八神 K、深水 A.

• 发表时间: 2005
• 期刊: Mol Endocrinol. 19(5)
• 作者: Song M;Kojima N;Hanamura K;Sekino Y;Inoue KH;Mikuni M;Shirao T;Kato H et al.;Takimoto-ohnishi et al.
• 通讯作者: Takimoto-ohnishi et al.

Enhanced erythropoiesis mediated by activation of the renin-angiotensin system via angiotensin II type la receptor.

通过血管紧张素II 1a型受体激活肾素-血管紧张素系统介导红细胞生成增强。

• 发表时间: 2005
• 期刊: FASEB J. 19
• 作者: Kato;H.;Fukamizu;A.
• 通讯作者: A.