title: Neuropeptide Y(1) Receptor 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.
abstract: OBJECTIVE
  We asked whether naturally occurring genetic variation at the human NPY1R locus alters autonomic traits that might predispose individuals to cardiovascular disease.
  
  
  BACKGROUND
  Neuropeptide Y (NPY) interacts with the Y(1) receptor, NPY1R, to control adrenergic activity and blood pressure (BP).
  
  
  METHODS
  We searched for polymorphism at NPY1R by 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.
  
  
  RESULTS
  The common NPY1R variant 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 x 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/NPY1R 3'-UTR plasmid; promoter variant A-585 also decreased expression of an NPY1R promoter/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.
  
  
  CONCLUSIONS
  Our results indicate that naturally occurring genetic variation at the NPY1R locus has implications for heritable autonomic control of the circulation, and ultimately, for systemic hypertension. The findings suggest novel pathophysiological links between the NPY1R locus, autonomic activity, and blood pressure, and suggest new strategies to approach the mechanism, diagnosis, and treatment of systemic hypertension.
authors.affiliation: Department of Medicine, University of California at San Diego, California, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Fangwen
authors.initials: F
authors.lastname: Rao
authors.forename: Kuixing
authors.initials: K
authors.lastname: Zhang
authors.forename: Manjula
authors.initials: M
authors.lastname: Mahata
authors.forename: Juan L
authors.initials: JL
authors.lastname: Rodriguez-Flores
authors.forename: Maple M
authors.initials: MM
authors.lastname: Fung
authors.forename: Jill
authors.initials: J
authors.lastname: Waalen
authors.forename: Myles G
authors.initials: MG
authors.lastname: Cockburn
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Hamilton
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001341:Autonomic Nervous System / Q000502:physiology*; D017704:Baroreflex / Q000502:physiology; D001794:Blood Pressure / Q000235:genetics* / Q000502:physiology; D003080:Cold Temperature; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology; D015810:Linkage Disequilibrium; D008156:Luciferases / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D009478:Neuropeptide Y / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D017476:Receptors, Neuropeptide Y / Q000235:genetics* / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology; D014162:Transfection; D055815:Young Adult; D001616:beta-Galactosidase / Q000096:biosynthesis
chemical_list: D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; D008156:Luciferases; D001616:beta-Galactosidase