Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
23021333
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
2012 Oct 23
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 NOTE
Cites Regul Pept. 1987 Dec;19(5-6):313-24 3438489
Cites Am J Hum Genet. 1988 Oct;43(4):520-6 3177389
Cites Ann N Y Acad Sci. 1990;611:99-110 2248487
Cites Am J Physiol. 1991 Feb;260(2 Pt 2):R328-34 1996720
Cites Curr Opin Nephrol Hypertens. 1993 Jan;2(1):106-13 7922157
Cites J Auton Pharmacol. 1994 Jun;14(3):187-200 7929473
Cites Hypertension. 1995 Jan;25(1):71-6 7843757
Cites Ann N Y Acad Sci. 1995 Dec 29;771:219-33 8597401
Cites Stat Med. 2000 May 15;19(9):1217-35 10797518
Cites Am J Hum Genet. 2000 Nov;67(5):1208-18 11032785
Cites Hypertension. 2000 Dec;36(6):1040-4 11116122
Cites Am J Hum Genet. 2002 Jun;70(6):1480-9 11992254
Cites Endocrinology. 2002 Jun;143(6):2333-40 12021198
Cites Nat Rev Genet. 2002 Nov;3(11):872-82 12415317
Cites Am J Med. 2002 Oct 15;113(6):472-9 12427496
Cites Can J Physiol Pharmacol. 2003 Feb;81(2):177-85 12710532
Cites Hypertension. 2004 Feb;43(2):169-75 14610101
Cites Neuropeptides. 2004 Aug;38(4):189-200 15337371
Cites Nature. 1983 Dec 8-14;306(5943):584-6 6358901
Cites Regul Pept. 1984 Apr;8(3):225-35 6379758
Cites Am J Physiol. 1996 Feb;270(2 Pt 2):H796-800 8779858
Cites Hypertension. 1997 Jan;29(1 Pt 1):137-43 9039093
Cites Eur J Pharmacol. 1998 May 15;349(1):1-14 9669490
Cites Regul Pept. 1998 Sep 25;75-76:175-80 9802406
Cites Eur J Endocrinol. 1999 Oct;141(4):431-5 10526260
Cites Bioinformatics. 2005 Jan 15;21(2):263-5 15297300
Cites J Exp Med. 2005 Dec 5;202(11):1527-38 16330815
Cites Biol Psychiatry. 2006 Apr 1;59(7):660-3 16325152
Cites Gen Comp Endocrinol. 2006 Apr;146(2):126-35 16338231
Cites J Hypertens. 2006 Jul;24(7):1375-81 16794487
Cites Peptides. 2007 Feb;28(2):310-4 17207896
Cites Circulation. 2007 Aug 28;116(9):993-1006 17698732
Cites J Psychosom Res. 2007 Oct;63(4):413-9 17905050
Cites Hypertension. 2007 Nov;50(5):862-8 17909120
Cites Nature. 2008 Apr 24;452(7190):997-1001 18385673
Cites PLoS Genet. 2009 Jan;5(1):e1000318 19119412
Cites Neuroendocrinology. 2009;89(3):351-60 19122447
Cites J Neurochem. 2009 May;109(3):911-22 19309436
Cites Hum Mutat. 2010 Aug;31(8):E1594-608 20648632
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