Modularisation épistatique des loci à trait quantitatif associés à la pression artérielle et identification de gènes candidats pour l’hypertension

Introduction: Essential hypertension, a major risk factor in the development of cardiovascular diseases, is a complex multigenic trait whose knowledge about genetic determinism require further study. Many quantitative trait loci (QTLs); genes responsible for varying blood pressure (BP), have been identified in humans and animal models. However, the mystery still lingers on how these genes work together to regulate the BP. Hypothesis and aim: Rather than an addition of QTLs, each with an infinitesimal effect on the BP, an epistatic interaction between genes would be responsible for the hypertensive phenotype. Thus, the study of this epistasis among genes involved directly or indirectly in the homeostasis of the BP allow us to explore new molecular regulatory pathways involved in this disease. Methods: Via the embodiment of rats congenic strains, where a chromosomal segment from a recipient hypertensive strain (Dahl Salt Sensitive, SS/Jr) is replaced by its homologue from a donor normotensive strain (Lewis, LEW); QTLs may be identified. In this context, the combination of QTLs by creating double or multiple congenics constitutes the first functional demonstration of intergenic interactions. Results: Twenty-seven combinations in total have led us to the assessment of a modularization of QTLs. These have been categorized according to two main epistatic modules (EMs) where QTLs belonging to the same EM are epistatic with each other and participate in the same regulatory pathway. The EMs / pathway then act in parallel to control the BP. Thanks to the existence of QTLs with opposite effects on BP, we were able to establish hierarchical order between three pairs of QTLs. However, when this regulatory sequence cannot be determined, other approaches are needed. Our work led us to the identification of a QTL on rat chromosome 16 (C16QTL) belonging to the EM1 revealing a new way of BP homeostasis. The retinoblastoma-associated protein gene 140 (Rap140) / family with sequence similarity 208 member A (Fam208a) having a nonsynonymous mutation between SS/Jr and LEW is the most plausible candidate gene to represent C16QTL. It encodes a transcription factor and appear to influence the expression of Solute carrier family 7 (cationic amino acid transport,   y + system) member 12 (Slc7a12) specifically and significantly under expressed in the kidneys of the congenic strain carrying C16QTL compared to the strain SS/Jr. Rap140 / Fam208a acts as an inhibitor of Slc7a12 transcription leading to a BP decrease in the congenic strain. Conclusions: The complex architecture of the regulation of BP unveils featuring new players, mostly unknown to their involvement in the BP. The study of the new signaling pathway Rap140 / Fam208a - Slc7a12 will deepen our knowledge about the homeostasis of blood pressure and hypertension in SS/Jr. In the long term, new antihypertensive treatments, targeting more than one regulatory cascade at a time may emerge.

Keyphrases: Hypertension, Slc7a12, QTLs, Congenic strains, Epistasis, Hierarchy, Fam208a