Identification et regroupement de QTL influençant la pression artérielle en modules épistatiques et analyse de deux gènes candidats chez la souche Dahl Salt-Sensitive
Essential hypertension is a major risk factor for cardiovascular diseases. Understanding the etiology of this pathology is of the outmost importance. Thus, unraveling novel genetic components and mechanisms regulating blood pressure (BP) via QTL identification and QTL-QTL interaction analysis is a promising strategy. Congenic strains establishment is a common and fruitful means for achieving such goal.  A quantitative trait, such as BP, has long been thought to result from the accumulation of infinitesimal effects exerted by multiple QTL. Nevertheless, BP is controlled by an epistasis-based architecture. Pair-wise comparisons of individual QTL based on the existence or lack-of epistatic interaction between them allowed us to establish a modularized organization of BP QTL in the Dahl Salt-sensitive model. Hence, two epistatic modules, namely EM1 and EM2 were constituted. In this fashion, any member of the EM1 is epistatic to all the other members of the same module and is additive to those of EM2. Regulatory hierarchies among BP with paradoxical effects can be revealed within each EM.  The molecular identification of EM1 members, C18QTL4/Hdhd2 and C18QTL3/Tcof1, as well as the revelation of the molecular basis for their epistatic interaction enabled us to suggest a sequential regulation within this EM. Hdhd2 could act upstream of Tcof1 and regulate it by post-transcriptional modification. This interaction is the first experimental evidence derived from the predictive model of QTL modularization.  The elucidation of the molecular mechanisms underlying the genetic architecture of BP, as well as the identification of the causal genes for QTL will lay the grounds for expanding therapeutic targets and for developing more efficient antihypertensive treatments.
Hypertension QTL Hdhd2 Tcof1 Alpk2 epistasis modularization epistatic genetics epistatic module congenics