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Hypertension and Associated End Organ Damage

H.J. Jacob1, U. Broeckel1, N.J. Schork2, A. Greene1, R.J. Roman1, B. Theil2, M. Stoll1, P. Dumas1, P.J. Tonellato1, A.P. Provoost3, A.W. Cowley, Jr.1

1. Medical College of Wisconsin, Milwaukee, WI 2. Case Western Reserve University, Cleveland Ohio 3. Erasmus University

With the draft sequence of the human genome available there is a need to define gene function, particularly with respect to end organ damage. In the case of hypertension, end organ damage is the major cause of morbidity and mortality. To date functional genomics--e.g. microarrays, single nucleotide polymorphisms, and the systematic knock-out of genes--has applied limited physiology. We have studied more than 200 cardiovascular phenotypes, ranging from biochemical assays; and acute responses to various pharmacological agents and changes in dietary salt; to end organ damage in each of 113 male and 88 female animals derived from an F2 intercross (SS/MCW x BN/MCW). We identified 65 quantitative trait loci (QTLs) that have been linked to 56 determinants of organ function after performing a total genome scan in the F2 progeny. These results have been compared to our results in the fawn-hooded hypertensive rat. We have also developed physiological profiling, which combines the analytical strategies analogous to expression profiling and genomic mapping that incorporate mechanistically detailed phenotypes. This strategy revealed how the cardiovascular system responds to various stimuli. When physiological profiling was combined with genome mapping we were able to assess the effect of allelic substitutions on the overall cardiovascular system. These data provide the first opportunity to study the relationships between a large number of cardiovascular phenotypes measured within each animal in a genomic context by the assignment of cardiovascular physiology onto the genome.

We also combined the results from several rat genetic studies for blood pressure regulation to predict regions of the human genome that are very likely to harbor hypertension genes. These predictions were then compared to quantitative trait loci (QTLs), which contain a gene(s) contributing to human hypertension. Fifty-seven QTLs for 33 blood pressure traits were identified in the progenies of seven F2 rat intercrosses for genetic hypertension, and translated into 26 homologous regions in the human genome using a comparative mapping strategy. Importantly, 5 out of 6 known QTLs for human hypertension were correctly predicted. Therefore, the remaining 21 predicted human regions are ideal targets for developing single nucleotide polymorphisms (SNPs) and for linkage disequilibrium testing in clinical populations. We have tested the ability to "transfer" genomic data from rats to humans by testing a region responsible for hypertension-associated end stage renal disease using the SNP case/control strategy. This strategy revealed a homologous region in rats and humans that appears to contribute to susceptibility hypertension associated end stage renal disease in both species.

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