title: An ancestral variant of Secretogranin II confers regulation by PHOX2 transcription factors and association with hypertension.
abstract: Granins regulate secretory vesicle formation in neuroendocrine cells and granin-derived peptides are co-released with neurotransmitters as modulatory signals at sympathetic sites. We report evidence for association between a regulatory polymorphism in Secretogranin II (SCG2) and hypertension in African-American subjects. The minor allele is ancestral in the human lineage and is associated with disease risk in two case-control studies and with elevated blood pressure in a separate familial study. Mechanistically, the ancestral allele acts as a transcriptional enhancer in cells that express endogenous Scg2, whereas the derived allele does not. ARIX (PHOX2A) and PHOX2B are identified as potential transactivating factors by oligonucleotide affinity chromatography and mass spectrometry and confirmed by chromatin immunoprecipitation. Each of these transcription factors preferentially binds the risk allele, both in vitro and in vivo. Population genetic considerations suggest positive selection of the protective allele within the human lineage. These results identify a common regulatory variation in SCG2 and implicate granin gene expression in the control of human blood pressure and susceptibility to hypertension.
authors.affiliation: Department of Medicine, Moores UCSD Cancer Center, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Gen
authors.initials: G
authors.lastname: Wen
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wessel
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhou
authors.forename: Georg B
authors.initials: GB
authors.lastname: Ehret
authors.forename: Fangwen
authors.initials: F
authors.lastname: Rao
authors.forename: Mats
authors.initials: M
authors.lastname: Stridsberg
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
authors.forename: Peter M
authors.initials: PM
authors.lastname: Gent
authors.forename: Madhusudan
authors.initials: M
authors.lastname: Das
authors.forename: Richard S
authors.initials: RS
authors.lastname: Cooper
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.forename: Huilin
authors.initials: H
authors.lastname: Zhou
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Schork
authors.forename: Daniel T
authors.initials: DT
authors.lastname: O'connor
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Hamilton
mesh_terms: D000328:Adult; D001483:Base Sequence; D016022:Case-Control Studies; D015331:Cohort Studies; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D005260:Female; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D053381:Secretogranin II / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C491061:PHOX2A protein, human; D053381:Secretogranin II