The molecular genetics of hypertension has been an exciting and fruitful field of scientific discovery over recent years. This Genetics Symposium was held in Glasgow earlier this year (June 21) as a satellite of the International Society of Hypertension. It brought together scientists and clinicians dedicated to developing a clearer insight into the genetic determinants of hypertension, both in experimental models and in human essential hypertension. The first of these articles follow, and the remainder will appear in next month's journal.
In the first session of the symposium, concepts and strategies were discussed by Drs Klaus Lindpaintner, Nicholas Schork, Florent Soubrier, and Howard Jacob. It has become clear that new approaches for dissection of complex polygenic disorders such as hypertension require the development of a new statistical genetic strategy. Dr Schork discussed extensions to the standard quantitative trait loci (QTL mapping approach), which included accommodation of heterogeneity, modeling of multiple-loci effects, the use of multiple phenotypes, design of pharmacogenetic studies, assignment of significance levels to the results of a genome-wide search for influential loci, and assessment of the genetic basis of quantitative traits that exhibit developmental trends. With a somewhat similar approach, Dr Jacob and colleagues proposed a new mutiphased, targeted genotyping strategy that has reduced genotyping requirements while maintaining the overall power of the study. In the second session, the genetics of experimental hypertension was discussed. The current genetic linkage map of the rat allows for statistical estimates of QTL localization in only the 15 to 20 centimorgan range. The best strategy to confirm such putative QTLs is the construction of congenic strains, as discussed by Drs John Rapp, Ted Kurtz, and Michael Pravenec. These experiments have now been taken further by development of congenic substrains with small overlapping substituted chromosomal regions to achieve fine genetic mapping of the QTLs of interest. The importance of recombinant inbred strains for studying blood pressure and other phenotypes such as cardiac hypertrophy in longitudinal fashion was stressed by Drs Pavel Hamet, Pravenec, and Kurtz.
Extensive consideration was also given to the genetics of human essential hypertension. Dr Richard Lifton discussed mendelian forms of human blood pressure variation. These include glucocorticoid-remediable aldosteronism and Liddle's syndrome, in which single-gene mutations cause marked elevation in blood pressure, as well as three autosomal recessive forms of hypotension (pseudohypoaldosteronism type I, Gitelman's syndrome, and Bartter's syndrome). He pointed out that the final common pathway is the alteration of net renal sodium reabsorption, an abnormality that may also be important in essential hypertension. In line with these findings, Dr Gordon Williams described sodium-mediated modulation of the adrenal response to angiotensin II, which may be a useful intermediate phenotype to identify genes involved in essential hypertension. This intermediate phenotype is associated with angiotensinogen gene polymorphism, which is the strongest candidate for the genetic basis of high blood pressure. Other candidate genes within the renin-angiotensin system remain controversial. Dr Soubrier, on behalf of his colleagues from Paris and Oxford, discussed the principles of candidate genes and genome screen strategies and concluded that a complementary approach should be used. He emphasized the need for international collaborations between groups to achieve this goal. In the last session, gene targeting strategies were discussed in the context of hypertension and cardiovascular disease. Targeted deletions of angiotensinogen gene, AT1A, and AT2 receptor genes in mice were discussed by Dr Tadashi Inagami. These experiments suggest that angiotensin II affects blood pressure by a balance between hypertensive AT1 and hypotensive AT2 receptors. Drs Victor Dzau and John Mullins discussed transgenic technologies and homologous recombination strategies. Dr Dzau focused on new in vivo gene transfer strategies, which produce local overexpression of a target gene (gain-of-function approach) or an inhibition of a specific gene by antisense oligonucleotide (loss-of-function approach).
It appears that experimental strategies for the future will include congenic approaches and substitution mapping to narrow the size of the QTLs of interest. It is also clear that high-fidelity phenotyping, such as radiotelemetry, will be increasingly used. Moreover, alternative phenotypes to blood pressure, such as cardiac mass, insulin resistance, lipid levels, and other complex quantitative traits, must be examined in these studies. The genetics of human hypertension will combine a total genome scan and candidate gene approaches. These are increasingly seen as complementary strategies. Both sib-pair and association studies will be performed in large homogeneous populations, and national and international collaborations will allow us to combine the data sets to dissect the genes responsible for blood pressure regulation and vascular complications of hypertension.