title: Heredity and cardiometabolic risk: naturally occurring polymorphisms in the human neuropeptide Y(2) receptor promoter disrupt multiple transcriptional response motifs.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Institute for Genomic Medicine, University of California at San Diego, VA San Diego Healthcare System, La Jolla, California 92093-0838, USA.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Wei
authors.forename: Kuixing
authors.initials: K
authors.lastname: Zhang
authors.forename: Gen
authors.initials: G
authors.lastname: Wen
authors.forename: Karthika
authors.initials: K
authors.lastname: Balasubramanian
authors.forename: Pei-an B
authors.initials: PA
authors.lastname: Shih
authors.forename: Fangwen
authors.initials: F
authors.lastname: Rao
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Friese
authors.forename: Jose P
authors.initials: JP
authors.lastname: Miramontes-Gonzalez
authors.forename: Geert W
authors.initials: GW
authors.lastname: Schmid-Schoenbein
authors.forename: Hyung-Suk
authors.initials: HS
authors.lastname: Kim
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'Connor
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics*; D008969:Molecular Sequence Data; D059372:Nucleotide Motifs / Q000235:genetics; D009765:Obesity / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D051381:Rats; D011921:Rats, Inbred WKY; D017476:Receptors, Neuropeptide Y / Q000235:genetics*; D012307:Risk Factors
chemical_list: C477894:FOXI1 protein, human; D051858:Forkhead Transcription Factors; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor