Quantitative trait locus analysis of spontaneously hypertensive mice

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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