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Human Molecular Genetics Advance Access published online on April 6, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl071
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received February 3, 2006
Accepted March 15, 2006

Article

Context-specific functional effects of IFNGR1 promoter polymorphism

Oliver Koch 1, Dominic P. Kwiatkowski 1, and Irina A. Udalova 1 *

1 Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom

* To whom correspondence should be addressed.
Irina A. Udalova, E-mail: i.udalova{at}imperial.ac.uk


  Abstract

We report evidence of a polymorphism in the promoter region of IFNGR1 (encoding interferon-{gamma} receptor 1) that has opposite functional effects in different cellular contexts. It is a deletion/insertion polymorphism that is found in Africans but not Europeans or Asians, and has been associated with resistance to severe malaria. We find that the IFNGR1-470del allele acts to suppress binding of nuclear proteins to the IFNGR1 promoter region in manner that is specific for cell type. In B-lymphocytes, the IFNGR1-470del allele suppresses the binding of a ~35 kDa nuclear protein and acts to increase reporter gene expression. In epithelial cells, the same allele acts to decrease gene expression and suppresses the binding of ~90 kDa STAT-1 and STAT-2 proteins. In T-lymphocytes, this allele causes only subtle differences in nuclear protein binding and has no significant effect on gene expression. These findings suggest a mechanism by which a single genetic variant may cause a broad range of phenotypic consequences.


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