An ancestral variant of Secretogranin II confers regulation by PHOX2 transcription factors and association with hypertension.
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.
Wen
Gen
G
Department of Medicine, Moores UCSD Cancer Center, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Wessel
Jennifer
J
Zhou
Weidong
W
Ehret
Georg B
GB
Rao
Fangwen
F
Stridsberg
Mats
M
Mahata
Sushil K
SK
Gent
Peter M
PM
Das
Madhusudan
M
Cooper
Richard S
RS
Chakravarti
Aravinda
A
Zhou
Huilin
H
Schork
Nicholas J
NJ
O'connor
Daniel T
DT
Hamilton
Bruce A
BA
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*
D018398:Homeodomain Proteins; C491061:PHOX2A protein, human; D053381:Secretogranin II