Abstract 1786: Dynamic Effect of Posture on Linkage of Candidate Genes for Blood Pressure Homeostasis and Hypertension
Hypertension results from interactions between genetic factors regulating blood pressure (BP) and environment. Bipedalism, a landmark of human evolution, is associated with an increase in BP. Yet, it is unclear whether orthostatism influences the genetic architecture of BP. Here, we investigated the influence of posture on polygenic heritability, genetic covariance, and linkage signals of BP phenotypes.
Methods and Results: Hypertensive and normotensive sibpairs from a relatively isolated cohort of 120 French-Canadian families ascertained by early-onset hypertension and dyslipidemia were phenotyped for several hemodynamic and neuroendocrine factors related to BP during recumbency and standing upright, and model free linkage of 1018 SNPs located inside or in the vicinity of 196 candidate genes was performed. Simulations were designed to calculate empirical estimates of significance and a permutation test was implemented to test for differences in linkage between positions. A genetic profile of BP specific to each posture was constructed. Polygenic bivariate analyses showed that both the polygenic contribution to trait’s variation and the genetic covariance of BP phenotypes were influenced by orthostatism. 27 genes were selectively linked during supine, whereas 13 genes were specific to standing. Moreover, the use of delta change and principal component analysis revealed additional loci and clusters of QTLs with pleiotropic effects. Thus, important part of BP genetic component will be missed by performing genetic studies for BP exclusively in a single position. In effect, linkage of genes located under previously published BP QTLs on chromosomes 1 (e.g. KCNH1) and 3 (e.g. SLC2A2) were only observed during supine or standing, and highly significant novel findings such as linkage of EDNRA with standing BP (P=10−8), KCNH8 and Delta change of cyclic GMP (P=10−16), PRKCA and a hemodynamic component of standing (P=10−9) were only evident through this dynamic approach.
Conclusions: We show for the first time that supine and standing BP have distinct genetic signatures, and that the use of standardized maneuvers influences the results of genetic studies for BP. We suggest “dynamic linkage” as a novel approach to uncover genetic variants of hypertension.