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An ancestral variant of secretogranin ii confers regulation by phox2 transcription factors and association with hypertension

Academic Article
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Overview

authors

  • 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, Nicholas
  • O'Connor, D. T.
  • Hamilton, B. A.

publication date

  • July 2007

journal

  • Human Molecular Genetics  Journal

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.

subject areas

  • Adult
  • Base Sequence
  • Case-Control Studies
  • Cohort Studies
  • Enhancer Elements, Genetic
  • Evolution, Molecular
  • Female
  • Gene Expression Regulation
  • Homeodomain Proteins
  • Humans
  • Hypertension
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Polymorphism, Single Nucleotide
  • Secretogranin II
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Identity

PubMed Central ID

  • PMC2695823

International Standard Serial Number (ISSN)

  • 0964-6906

Digital Object Identifier (DOI)

  • 10.1093/hmg/ddm123

PubMed ID

  • 17584765
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Additional Document Info

start page

  • 1752

end page

  • 1764

volume

  • 16

issue

  • 14

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