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1 Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA; Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, USA
2 Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
3 Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA; Bioinformatics Research Center, Medical College of Wisconsin, Milwaukee, WI, USA
4 Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA; Center for Biotechnology and Biomedical Engineering, Medical College of Wisconsin, Milwaukee, WI, USA
5 Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA; Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, USA; Bioinformatics Research Center, Medical College of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: cowley{at}mcw.edu.
Genetic linkage analyses in human populations have traditionally combined the male and female progeny for determination of quantitative trait loci (QTL). In contrast, most rodent studies have focused primarily on males. The present study represents an extensive female specific linkage analysis in which 236 neuroendocrine, renal and cardiovascular traits related to arterial pressure (BP) were determined in 99 female F2 rats derived from a cross of Dahl salt sensitive SS/JrHsdMcwi (SS) and Brown Norway normotensive BN/SsNHsdMcwi (BN) rats. 126 quantitative trait loci (QTL) for 96 traits were identified on 19 of the 20 autosomal chromosomes of the female progeny. Four chromosomes (3, 6, 7 and 11) were identified as especially important in regulation of arterial pressure and renal function since aggregates of 8-11 QTL mapped together on these chromosomes. Blood pressure QTL in this female population differed considerably from those previously found in male, other female, or mixed gender population linkage analysis studies using SS rats. Kidney weight divided by body weight was identified as an intermediate phenotype that mapped to the same region of the genome as the resting diastolic blood pressure, and was correlated with that same blood pressure phenotype. Seven other phenotypes were considered as "potential intermediate phenotypes", which mapped to the same region of the genome as a blood pressure QTL but were not correlated with blood pressure. These included renal vascular responses to angiotensin II (AngII) and acetylcholine (ACh), and indices of baroreceptor responsiveness. Secondary traits were also identified that were likely to be consequences of hypertension (correlated with blood pressure but not mapped to a BP QTL). Seven such traits were found, notably heart rate, plasma cholesterol, and renal glomerular injury. The development of a female rat Systems Biology Map of Cardiovascular Function represents the first attempt to prioritize those regions of the genome important for the development of hypertension and end organ damage in female rats.
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