PMID- 23149563
OWN - NLM
STAT- MEDLINE
DCOM- 20130708
LR  - 20211021
IS  - 1473-5598 (Electronic)
IS  - 0263-6352 (Print)
IS  - 0263-6352 (Linking)
VI  - 31
IP  - 1
DP  - 2013 Jan
TI  - Heredity and cardiometabolic risk: naturally occurring polymorphisms in the human 
      neuropeptide Y(2) receptor promoter disrupt multiple transcriptional response 
      motifs.
PG  - 123-33
LID - 10.1097/HJH.0b013e32835b053d [doi]
AB  - OBJECTIVES: The neuropeptide Y(2) G-protein-coupled receptor (NPY2R) relays 
      signals from PYY or neuropeptide Y toward satiety and control of body mass. 
      Targeted ablation of the NPY2R locus in mice yields obesity, and studies of NPY2R 
      promoter genetic variation in more than 10,000 human participants indicate its 
      involvement in control of obesity and BMI. Here we searched for genetic variation 
      across the human NPY2R locus and probed its functional effects, especially in the 
      proximal promoter. METHODS AND RESULTS: Twin pair studies indicated substantial 
      heritability for multiple cardiometabolic traits, including BMI, SBP, DBP, and 
      PYY, an endogenous agonist at NPY2R. Systematic polymorphism discovery by 
      resequencing across NPY2R uncovered 21 genetic variants, 10 of which were common 
      [minor allele frequency (MAF) >5%], creating one to two linkage disequilibrium 
      blocks in multiple biogeographic ancestries. In vivo, NPY2R haplotypes were 
      associated with both BMI (P = 3.75E-04) and PYY (P = 4.01E-06). Computational 
      approaches revealed that proximal promoter variants G-1606A, C-599T, and A-224G 
      disrupt predicted IRF1 (A>G), FOXI1 (T>C), and SNAI1 (A>G) response elements. In 
      neuroendocrine cells transfected with NPY2R promoter/luciferase reporter 
      plasmids, all three variants and their resulting haplotypes influenced 
      transcription (G-1606A, P < 2.97E-06; C-599T, P < 1.17E-06; A-224G, 
      P < 2.04E-06), and transcription was differentially augmented or impaired by 
      coexpression of either the cognate full-length transcription factors or their 
      specific siRNAs at each site. Endogenous expression of transcripts for NPY2R, 
      IRF1, and SNAI1 was documented in neuroendocrine cells, and the NPY2R mRNA was 
      differentially expressed in two neuroendocrine tissues (adrenal gland, brainstem) 
      of a rodent model of hypertension and the metabolic syndrome, the spontaneously 
      hypertensive rat. CONCLUSION: We conclude that common genetic variation in the 
      proximal NPY2R promoter influences transcription factor binding so as to alter 
      gene expression in neuroendocrine cells, and consequently cardiometabolic traits 
      in humans. These results unveil a novel control point, whereby cis-acting genetic 
      variation contributes to control of complex cardiometabolic traits, and point to 
      new transcriptional strategies for intervention into neuropeptide actions and 
      their cardiometabolic consequences.
FAU - Wei, Zhiyun
AU  - Wei Z
AD  - Department of Medicine, Institute for Genomic Medicine, University of California 
      at San Diego, VA San Diego Healthcare System, La Jolla, California 92093-0838, 
      USA.
FAU - Zhang, Kuixing
AU  - Zhang K
FAU - Wen, Gen
AU  - Wen G
FAU - Balasubramanian, Karthika
AU  - Balasubramanian K
FAU - Shih, Pei-an B
AU  - Shih PA
FAU - Rao, Fangwen
AU  - Rao F
FAU - Friese, Ryan S
AU  - Friese RS
FAU - Miramontes-Gonzalez, Jose P
AU  - Miramontes-Gonzalez JP
FAU - Schmid-Schoenbein, Geert W
AU  - Schmid-Schoenbein GW
FAU - Kim, Hyung-Suk
AU  - Kim HS
FAU - Mahata, Sushil K
AU  - Mahata SK
FAU - O'Connor, Daniel T
AU  - O'Connor DT
LA  - eng
GR  - MD000220/MD/NIMHD NIH HHS/United States
GR  - HL58120/HL/NHLBI NIH HHS/United States
GR  - 1UL1RR031980/RR/NCRR NIH HHS/United States
GR  - P01 HL058120/HL/NHLBI NIH HHS/United States
GR  - P60 MD000220/MD/NIMHD NIH HHS/United States
GR  - R01 DK094894/DK/NIDDK NIH HHS/United States
GR  - K01 DK087813/DK/NIDDK NIH HHS/United States
GR  - UL1 RR031980/RR/NCRR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Netherlands
TA  - J Hypertens
JT  - Journal of hypertension
JID - 8306882
RN  - 0 (FOXI1 protein, human)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Receptors, Neuropeptide Y)
RN  - 0 (neuropeptide Y2 receptor)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Cell Line, Tumor
MH  - Female
MH  - Forkhead Transcription Factors/genetics
MH  - Genetic Predisposition to Disease/*genetics
MH  - Genetic Variation/*genetics
MH  - Humans
MH  - Male
MH  - Metabolic Syndrome/*genetics
MH  - Molecular Sequence Data
MH  - Nucleotide Motifs/genetics
MH  - Obesity/*genetics
MH  - Polymorphism, Genetic
MH  - Promoter Regions, Genetic/*genetics
MH  - Rats
MH  - Rats, Inbred WKY
MH  - Receptors, Neuropeptide Y/*genetics
MH  - Risk Factors
PMC - PMC3615981
MID - NIHMS448088
COIS- Conflicts of interest The authors have no conflicts of interest to declare.
EDAT- 2012/11/15 06:00
MHDA- 2013/07/09 06:00
PMCR- 2014/01/01
CRDT- 2012/11/15 06:00
PHST- 2012/11/15 06:00 [entrez]
PHST- 2012/11/15 06:00 [pubmed]
PHST- 2013/07/09 06:00 [medline]
PHST- 2014/01/01 00:00 [pmc-release]
AID - 10.1097/HJH.0b013e32835b053d [doi]
PST - ppublish
SO  - J Hypertens. 2013 Jan;31(1):123-33. doi: 10.1097/HJH.0b013e32835b053d.