Modularized Genes in an Adrenal Pathway Reveal a Novel Mechanism in Hypertension Pathogenesis

Human epidemiological studies have statistically localized a multitude of quantitative trait loci (QTLs) for blood pressure (BP). However, their potential pathogenic mechanisms causing hypertension remain mysterious. To fill this void, we utilized congenic knock-in genetics to physiologically analyze the BP effects of individual and combinational QTLs. The effect magnitude from a single QTL in vivo ranged from 33.8 to 59.8%. 'Double' and multiple combinations of QTLs exhibited the same BP impact as a single QTL alone. Consequently, the products of these QTLs seemed to belong to the same pathway involved in physiological BP regulations. From this, we identified a novel pathway of hypertension pathogenesis in vivo controlled by the CUE domain containing 1 protein (Cuedc1). This pathway physiologically modulates blood pressure, aldosterone production, and renal and cardiac functions. CUEDC1 originated from common mammalian ancestors, partly explaining similar blood pressures between humans and rodents on this shared mechanistic basis. A translation of CUEDC1 into diagnostic and treatment applications to humans seems individualized and mechanistic because humans and rats may utilize the same BP-regulating mechanisms involving CUEDC1. The future sustainability of post-GWAS will depend on a balanced and robust 'ecosystem' provided by model studies that are founded on the physiologies and mechanisms of BP regulations in vivo.