Quantitative trait locus analysis of spontaneously hypertensive mice

我们对15个近交系10周龄雄性小鼠的收缩压和舒张压进行了分析，发现各系间血压呈连续分布，C3H/HeJ的平均收缩压和舒张压最低（100.5±3.2和66.8±3.5 mmHg），肥胖和糖尿病的NZO/HILtJ的平均收缩压和舒张压最高（132.4±3.1和86.6±6.9 mmHg）。为了了解血压与胰岛素抵抗和肥胖之间的关系，我们将肥胖、糖尿病和高血压品系NZO与血压最低的品系C3H/HeJ进行正交，得到F_1和F_2后代。10周龄雄性（NZO × C3H）F_1和（C3H × NZO）F_1的平均收缩压相近（114.9±3.8和117.2±5.0 mmHg），与亲本株的平均收缩压相近。F_2男性（n = 223）的收缩压呈正态分布，表明血压是一种多基因性状。F_2子代体重指数（BMI）和血浆胰岛素水平与血浆瘦素水平呈显著正相关，表明肥胖与胰岛素抵抗有关。相比之下，收缩压与BMI、血浆瘦素水平和血浆胰岛素水平无关，这表明在这种交叉中导致高血压的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C3H交叉的后代是鉴定血压基因和了解人类多基因高血压的实用而有力的工具。在对15个近交系小鼠的第一项研究中，我们发现NZO/HILtJ小鼠（代谢综合征）和C3H/HeJ小鼠（普通瘦株）的收缩压分别最高和最低。为了确定代谢综合征中与高血压相关的基因座，我们对NZO/HILtJ和C3H/HeJ小鼠的F_2雄性进行了以交叉方向为协变量的血压数量性状位点（QTL）分析。我们发现了影响收缩压和舒张压（收缩压和舒张压）的三个提示性主要效应qtl。我们分析了收缩压和舒张压产生的第一主成分（PC1）来研究血压。除了在收缩压和舒张压中发现所有提示QTL （Chr 1、3和8）外，主扫描在PC1中发现1个Chr 4的提示QTL。同时搜索发现了PC1的两个显著上位位点对（Chr 1和4，Chr 4和8）。多元回归分析显示，3个血压qtl （Bpq10， Chr 1上100 cM； Bpq11， Chr 4上6 cM； Bpq12， Chr 8上29 cM）占血压变异的29.4%。这些是上位互作qtl，构建了一个以Chr 4为中心的小网络，提示遗传互作对高血压发展的重要性。在多个研究中，使用常见的近交非肥胖小鼠品系反复检测到Chr 1、4和8上的血压QTL，这意味着大量的QTL与肥胖和胰岛素抵抗的发展无关。这些结果增强了我们对代谢性疾病高血压复杂遗传因素的认识。少

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