MOLECULAR GENETIC ANALYSIS OF BLOOD PRESSURE

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My long-term goal is to identify and describe the genes which cause differences in blood pressure among various strains of hypertensive and normotensive rats. This work is basic to understanding the mechanism of genetic hypertension in man. The main focus here is the renin gene. I have established important effects on blood pressure for the renin alleles from Dahl salt-hypertension sensitive (S) rats and Dahl salt-hypertension resistant (R) rats. Renin alleles carried by these strains, designated s and r respectively, cosegregated with blood pressure in genetic experiments. The effect on blood pressure of two additional renin alleles that I have recently found will be evaluated by comparing each new allele to the s allele. This is done by determining if a component of blood pressure cosegregates with a given new renin allele in an F2 population derived from Dahl salt-sensitive (S) rats and a strain carrying the new allele. Structural information on the known renin alleles will be extended and a search made for additional alleles in more strains of rats. Transgenic experiments will be performed to determine if the s and r renin alleles are actually causing differences in blood pressure. The alternate possibility is that these s and r renin alleles cosegregate with blood pressure because they are linked to an unknown locus that, in fact, causes the blood pressure differences. s and r renin alleles will be inserted in the salt-sensitive (S) rat strain using transgenic techniques. This will allow evaluation of the blood pressure altering effects of these alleles independent of linked loci. Components of the s and r renin alleles can be exchanged in DNA constructs that are inserted transgenically in order to localize 'the' DNA polymorphism within these alleles that is important in creating blood pressure changes. Lastly, other components of the renin-angiotensin system (angiotensinogen, converting enzyme, the angiotensin receptor coded by the mas oncogene) will be evaluated for DNA polymorphisms among rat strains, and such polymorphisms will be tested for cosegregation with blood pressure.