Cardioprotective Actions of Cyclic GMP
Lessons From Genetic Animal Models
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Most common diseases and/or their consequences, including hypertension and susceptibility to end-organ damage, have genetic components. Contrary to hereditary mendelian diseases (where the existence of a rare mutation within a single gene usually dictates whether signs of the disease are present), the manifestations of common diseases correspond with what is defined in genetics as “quantitative complex traits.” Such traits within populations show continuous variation from low to high values and are shaped by the interactions of a great number of genes (each typically having small effects on their own) with environmental factors. Consequently, identification of genetic variants contributing to complex traits must rely on methods that are different than those used for the identification of mendelian genetic mutations (which can be performed by following within pedigrees the hereditary transmission of markers linked to the mutated gene). Among several available tools, genetic animal models have proven particularly useful to identify the effects of naturally occurring genetic variants and their effects within mammalian organisms. Indeed, inbred strains are organisms that carry identical copies of each gene. Accordingly, it is possible by performing crosses between them to reduce the complexity of the problem, because the progeny of crosses will carry only 2 possible variants of any gene, and experimental and environmental conditions can be controlled.
Complex Traits and Genetic Animal Models
The pioneering work of Lewis K. Dahl constitutes an early and illustrative example of the use of such models. Dahl had hypothesized from epidemiological studies in human populations that elevated blood pressure may arise from the combination of high dietary salt with individual genetic susceptibility factors. To test that hypothesis experimentally, Dahl began a breeding program where he fed outbred rats with highly salted food. Because some rats developed high blood pressure in response to a high-salt diet but others did not, he selected breeders on the basis …