BIOCHEMISTRY AND GENETICS OF HYPERTENSION

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The overall objective is to identify-the loci which cause genetic differences in blood pressure in the rat. Because hypertension in animals and humans is a complex polygenic disease it can best be understood genetically in animals where controlled breeding is possible. We have focused our genetic studies on candidate genes in the inbred Dahl salt-hypertension sensitive (S) and inbred Dahl salt-hypertension resistant (R) rats. Genetic polymorphisms are sought at the DNA level in or near genetic loci thought (on the basis of their known biochemical/ physiological actions) to be relevant to blood pressure regulation. It is determined if a component of blood pressure and genotypes at the candidate locus cosegregate in populations derived from crosses of S and R, or S and other contrasting "control" strains. If so, this establishes the candidate locus (or an unknown closely linked locus) as a cause for genetic differences in blood pressure. DNA sequence analysis of the candidate alleles involved is then required to find a structural difference that is likely to have functional consequences with regard to blood pressure. If cosegregation is negative the candidate locus can be rejected as causing blood pressure differences provided the experiments have adequate statistical power and several different populations are studied. For candidate loci which cosegregate with blood pressure, the result will be con-firmed by the production of congenic strains. The low blood pressure allele from a control strain is transferred to the S genetic background by the standard genetic technique of repeated backcrossing to S with counter selection for the low blood pressure allele. The congenic S strain should have lower blood pressure than the parental S strain if in fact the allele transferred lowers blood pressure. "Double congenic" strains will be produced by crossing two single congenics each of which carries genes for low blood pressure at different loci on the S genetic background. Comparisons of blood pressure among double and single congenics with the parental S strain will allow definition of interactions between the loci involved. Initial studies show that such interactions are required for really high levels of genetically regulated blood pressure to be achieved. It is likely that understanding such complexity requires animal breeding techniques, and cannot be initially unraveled in work with humans.