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.
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.
Wang
Lei
L
Department of Medicine, University of California at San Diego, California, USA.
Rao
Fangwen
F
Zhang
Kuixing
K
Mahata
Manjula
M
Rodriguez-Flores
Juan L
JL
Fung
Maple M
MM
Waalen
Jill
J
Cockburn
Myles G
MG
Hamilton
Bruce A
BA
Mahata
Sushil K
SK
O'Connor
Daniel T
DT
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
D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; D008156:Luciferases; D001616:beta-Galactosidase