Neuropeptide Y1Receptor NPY1R : Discovery of Naturally Occurring Human Genetic Variants Governing Gene Expression In Cella as Well as Pleiotropic Effects on Autonomic Activity and Blood Pressure In Vivo

ObjectivesWe asked whether naturally occurring genetic variation at the human NPY1Rlocus alters autonomic traits that might predispose individuals to cardiovascular disease.BackgroundNeuropeptide Y (NPY) interacts with the Y1receptor, NPY1R, to control adrenergic activity and blood pressure (BP).MethodsWe searched for polymorphism at NPY1Rby systematic resequencing in ethnically diverse people. There were 376 twins/siblings who were evaluated for heritable autonomic traits: baroreflex function and pressor response to environmental stress.ResultsThe common NPY1Rvariant A+1050G in the 3′-untranslated region (3′-UTR) predicted baroreceptor slope (p = 0.014–0.047) and BP change to cold stress (p = 0.0091–0.016), with minor allele homozygotes displaying blunted slope and exaggerated pressor response. In 936 individuals with the most extreme BPs in the population, not only 3′-UTR A+1050G (p = 1.2 × 10−4) but also promoter A-585T (p = 0.001) affected both systolic BP and diastolic BP, in interactive fashion (p = 0.007), with combined homozygotes showing the highest diastolic BP (>20 mm Hg). The 3′-UTR variant +1050G decreased expression of a transfected luciferase reporter/NPY1R3′-UTR plasmid; promoter variant A-585 also decreased expression of an NPY1Rpromoter/luciferase reporter. Thus, alleles that increased BP in vivo (3′-UTR +1050G, promoter A-585) also decreased NPY1R expression in cella. Computational alignment showed that A+1050G disrupted a microRNA motif.ConclusionsOur results indicate that naturally occurring genetic variation at the NPY1Rlocus has implications for heritable autonomic control of the circulation, and ultimately, for systemic hypertension. The findings suggest novel pathophysiological links between the NPY1Rlocus, autonomic activity, and blood pressure, and suggest new strategies to approach the mechanism, diagnosis, and treatment of systemic hypertension.