Functional Genomics of Blood Pressure Determination: Dissecting and Assembling a Polygenic Trait by Experimental Genetics

Major accomplishments in sequencing mammalian genomes have ushered in the era of post-genomics. With it, the mechanics of positional cloning could soon be transformed into simply querying databases, an emerging strategy of gene identifications from a sequence to implicating a gene function. An encyclopedic collection of sequences and everevolving innovations in genome technologies have raised expectations for experimental models to reveal mechanisms underlying polygenic hypertension. In synchrony with the build-up of genomic infrastructures and analytical tools, the development of genetic models has also become refined, sophisticated and even more indispensable, as they provide substrates in vivo for functional genomics. In addition to gene discovery, the mechanisms establishing relationships among quantitative trait loci (QTLs) for blood pressure (BP) can be established and validated in the context of an integrated physiological system. Genetic analyses by congenic strains have illustrated a highly complex and hierarchical organization among BP QTLs. These genes do no function in isolation, but act in concert via epistatic and additive interactions with one another. The understanding of complex QTL interactions will facilitate rationally targeted pharmacological designs and clinical treatment of hypertension. Identifications of these QTLs will provide new therapeutic targets and genetically oriented diagnostic tools.