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Human Molecular Genetics Advance Access originally published online on June 21, 2007
Human Molecular Genetics 2007 16(14):1752-1764; doi:10.1093/hmg/ddm123
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Gen Wen1, Jennifer Wessel2,8,13, Weidong Zhou3,4, Georg B. Ehret11, Fangwen Rao1, Mats Stridsberg9, Sushil K. Mahata1,10, Peter M. Gent5, Madhusudan Das1, Richard S. Cooper12, Aravinda Chakravarti11, Huilin Zhou3,4,5,7, Nicholas J. Schork2,5,6,13, Daniel T. O'Connor1,5,6,7 and Bruce A. Hamilton1,4,5,7,*

1 Department of Medicine, 2 Department of Psychiatry, 3 Ludwig Institute for Cancer Research, 4 Department of Cellular and Molecular Medicine, 5 Biomedical Sciences Graduate Program, 6 Center for Human Genetics and Genomics, 7 Moores UCSD Cancer Center, University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA, 8 Department of Family and Preventive Medicine, UCSD and Graduate School of Public Health, San Diego State University Joint Doctoral Program in Public Health Epidemiology, USA, 9 Department of Medical Sciences, University Hospital, Uppsala, Sweden, 10 VA San Diego Healthcare System, USA, 11 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA, 12 Department of Preventive Medicine and Epidemiology, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60153, USA and 13 Scripps Genomic Medicine and The Scripps Research Institute, La Jolla, CA, USA

* To whom correspondence should be addressed. Tel: +1 8588221055; Email: bah{at}ucsd.edu

Received March 16, 2007; Accepted April 30, 2007

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.


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