An ancestral variant of Secretogranin II confers regulation by PHOX2 transcription factors and association with hypertension

Gen Wen, Jennifer Wessel, Weidong Zhou, Georg B. Ehret, Fangwen Rao, Mats Stridsberg, Sushil K. Mahata, Peter M. Gent, Madhusudan Das, Richard S. Cooper, Aravinda Chakravarti, Huilin Zhou, Nicholas J. Schork, Daniel T. O'Connor, Bruce A. Hamilton

Research output: Contribution to journalArticle

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1752-1764
Number of pages13
JournalHuman molecular genetics
Volume16
Issue number14
DOIs
StatePublished - Jul 15 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Wen, G., Wessel, J., Zhou, W., Ehret, G. B., Rao, F., Stridsberg, M., Mahata, S. K., Gent, P. M., Das, M., Cooper, R. S., Chakravarti, A., Zhou, H., Schork, N. J., O'Connor, D. T., & Hamilton, B. A. (2007). An ancestral variant of Secretogranin II confers regulation by PHOX2 transcription factors and association with hypertension. Human molecular genetics, 16(14), 1752-1764. https://doi.org/10.1093/hmg/ddm123