|
|
| PMID |
|
|
| TITLE |
|
| Neuropeptide Y (NPY): genetic variation in the human promoter alters glucocorticoid signaling, yielding increased NPY secretion and stress responses. |
|
| ABSTRACT |
|
| OBJECTIVES |
NlmCategory: OBJECTIVE |
| This study sought to understand whether genetic variation at the Neuropeptide Y (NPY) locus governs secretion and stress responses in vivo as well as NPY gene expression in sympathochromaffin cells. |
| BACKGROUND |
NlmCategory: BACKGROUND |
| The NPY is a potent pressor peptide co-released with catecholamines during stress by sympathetic axons. Genome-wide linkage on NPY secretion identified a LOD (logarithm of the odds ratio) peak spanning the NPY locus on chromosome 7p15. |
| METHODS |
NlmCategory: METHODS |
| Our approach began with genomics (linkage and polymorphism determination), extended into NPY genetic control of heritable stress traits in twin pairs, established transcriptional mechanisms in transfected chromaffin cells, and concluded with observations on blood pressure (BP) in the population. |
| RESULTS |
NlmCategory: RESULTS |
| Systematic polymorphism tabulation at NPY (by re-sequencing across the locus: promoter, 4 exons, exon/intron borders, and untranslated regions; on 2n = 160 chromosomes of diverse biogeographic ancestries) identified 16 variants, of which 5 were common. We then studied healthy twin/sibling pairs (n = 399 individuals), typing 6 polymorphisms spanning the locus. Haplotype and single nucleotide polymorphism analyses indicated that proximal promoter variant ∇-880Δ (2-bp TG/-, Ins/Del, rs3037354) minor/Δ allele was associated with several heritable (h(2)) stress traits: higher NPY secretion (h(2) = 73 ± 4%) as well as greater BP response to environmental (cold) stress, and higher basal systemic vascular resistance. Association of ∇-880Δ and plasma NPY was replicated in an independent sample of 361 healthy young men, with consistent allelic effects; genetic variation at NPY also associated with plasma NPY in another independent series of 2,212 individuals derived from Australia twin pairs. Effects of allele -880Δ to increase NPY expression were directionally coordinate in vivo (on human traits) and in cells (transfected NPY promoter/luciferase reporter activity). Promoter -880Δ interrupts a novel glucocorticoid response element motif, an effect confirmed in chromaffin cells by site-directed mutagenesis on the transfected promoter, with differential glucocorticoid stimulation of the motif as well as alterations in electrophoretic mobility shifts. The same -880Δ allele also conferred risk for hypertension and accounted for approximately 4.5/approximately 2.1 mm Hg systolic BP/diastolic BP in a population sample from BP extremes. |
| CONCLUSIONS |
NlmCategory: CONCLUSIONS |
| We conclude that common genetic variation at the NPY locus, especially in proximal promoter ∇-880Δ, disrupts glucocorticoid signaling to influence NPY transcription and secretion, raising systemic vascular resistance and early heritable responses to environmental stress, eventuating in elevated resting BP in the population. The results point to new molecular strategies for probing autonomic control of the human circulation and ultimately susceptibility to and pathogenesis of cardiovascular and neuropsychiatric disease states. |
| Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved. |
|
| DATE PUBLISHED |
|
|
| HISTORY |
|
| PUBSTATUS |
PUBSTATUSDATE |
| received |
2012/05/09 |
| revised |
2012/06/15 |
| accepted |
2012/06/15 |
| aheadofprint |
2012/09/26 |
| entrez |
2012/10/02 06:00 |
| pubmed |
2012/10/02 06:00 |
| medline |
2013/01/09 06:00 |
|
| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Zhang K |
|
Zhang |
Kuixing |
K |
|
Department of Medicine and Institute for Genomic Medicine, University of California at San Diego, San Diego, California, USA. |
| Rao F |
|
Rao |
Fangwen |
F |
|
|
| Miramontes-Gonzalez JP |
|
Miramontes-Gonzalez |
Jose Pablo |
JP |
|
|
| Hightower CM |
|
Hightower |
C Makena |
CM |
|
|
| Vaught B |
|
Vaught |
Brian |
B |
|
|
| Chen Y |
|
Chen |
Yuhong |
Y |
|
|
| Greenwood TA |
|
Greenwood |
Tiffany A |
TA |
|
|
| Schork AJ |
|
Schork |
Andrew J |
AJ |
|
|
| Wang L |
|
Wang |
Lei |
L |
|
|
| Mahata M |
|
Mahata |
Manjula |
M |
|
|
| Stridsberg M |
|
Stridsberg |
Mats |
M |
|
|
| Khandrika S |
|
Khandrika |
Srikrishna |
S |
|
|
| Biswas N |
|
Biswas |
Nilima |
N |
|
|
| Fung MM |
|
Fung |
Maple M |
MM |
|
|
| Waalen J |
|
Waalen |
Jill |
J |
|
|
| Middelberg RP |
|
Middelberg |
Rita P |
RP |
|
|
| Heath AC |
|
Heath |
Andrew C |
AC |
|
|
| Montgomery GW |
|
Montgomery |
Grant W |
GW |
|
|
| Martin NG |
|
Martin |
Nicholas G |
NG |
|
|
| Whitfield JB |
|
Whitfield |
John B |
JB |
|
|
| Baker DG |
|
Baker |
Dewleen G |
DG |
|
|
| Schork NJ |
|
Schork |
Nicholas J |
NJ |
|
|
| Nievergelt CM |
|
Nievergelt |
Caroline M |
CM |
|
|
| O'Connor DT |
|
O'Connor |
Daniel T |
DT |
|
|
|
| INVESTIGATORS |
|
|
| JOURNAL |
|
| VOLUME: 60 |
| ISSUE: 17 |
| TITLE: Journal of the American College of Cardiology |
| ISOABBREVIATION: J. Am. Coll. Cardiol. |
| YEAR: 2012 |
| MONTH: Oct |
| DAY: 23 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1558-3597 |
| ISSNTYPE: Electronic |
|
| MEDLINE JOURNAL |
|
| MEDLINETA: J Am Coll Cardiol |
| COUNTRY: United States |
| ISSNLINKING: 0735-1097 |
| NLMUNIQUEID: 8301365 |
|
| PUBLICATION TYPE |
|
| PUBLICATIONTYPE TEXT |
| Comparative Study |
| Journal Article |
| Research Support, N.I.H., Extramural |
| Research Support, Non-U.S. Gov't |
| Research Support, U.S. Gov't, Non-P.H.S. |
|
| COMMENTS AND CORRECTIONS |
|
| REFTYPE |
REFSOURCE |
REFPMID |
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| ErratumIn |
J Am Coll Cardiol. 2012 Nov 20;60(21):2261 |
20648632 |
|
|
| GRANTS |
|
| GRANTID |
AGENCY |
COUNTRY |
| K05 AA017688 |
NIAAA NIH HHS |
United States |
| KL2 TR000099 |
NCATS NIH HHS |
United States |
| P01 HL058120 |
NHLBI NIH HHS |
United States |
| P60 MD000220 |
NIMHD NIH HHS |
United States |
| R01 DK094894 |
NIDDK NIH HHS |
United States |
| R01 MH093500 |
NIMH NIH HHS |
United States |
|
| GENERAL NOTE |
|
|
| KEYWORDS |
|
|
| MESH HEADINGS |
|
| DESCRIPTORNAME |
QUALIFIERNAME |
| Adolescent |
|
| Adult |
|
| Aged |
|
| Aged, 80 and over |
|
| Alleles |
|
| DNA |
genetics |
| Electrophoretic Mobility Shift Assay |
genetics |
| Female |
genetics |
| Gene Expression Regulation |
genetics |
| Genetic Predisposition to Disease |
genetics |
| Genetic Variation |
genetics |
| Genotype |
genetics |
| Humans |
genetics |
| Hypertension |
genetics |
| Male |
genetics |
| Middle Aged |
genetics |
| Neuropeptide Y |
genetics |
| Promoter Regions, Genetic |
genetics |
| Receptors, Glucocorticoid |
blood |
| Signal Transduction |
blood |
| Stress, Psychological |
genetics |
|
| SUPPLEMENTARY MESH |
|
|
| GENE SYMBOLS |
|
|
| CHEMICALS |
|
| REGISTRYNUMBER |
NAMEOFSUBSTANCE |
| 0 |
Neuropeptide Y |
| 0 |
Receptors, Glucocorticoid |
| 9007-49-2 |
DNA |
|
| OTHER ID's |
|
| OTHERID |
SOURCE |
| NIHMS455834 |
NLM |
| PMC3687554 |
NLM |
|
|
