Functional profiling of uncommon VCAM1 promoter polymorphisms prevalent in African American populations

Multiple variants of the vascular adhesion molecule‐1 (VCAM1) promoter show increased nucleotide heterozygosity in the African American population. Using a novel transfection‐based transcriptional pathway profiling method, we show that select uncommon variants are functionally hyperactive. Eight can...

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Bibliographic Details
Published in:Human mutation 2007-08, Vol.28 (8), p.824-829
Main Authors: Idelman, Gila, Taylor, James G., Tongbai, Ron, Chen, Renee A., Haggerty, Cynthia M., Bilke, Sven, Chanock, Stephen J., Gardner, Kevin
Format: Article
Language:English
Subjects:
African American populations
African Americans
African Americans - genetics
Base Sequence
Binding sites
bioinformatics
Cancer
Cloning
Disease
Gene expression
Genomes
Haplotypes
Humans
Jurkat Cells
Mitogens - pharmacology
Molecular Sequence Data
Mutation
Polymorphism, Single Nucleotide - genetics
promoter
Promoter Regions, Genetic - genetics
regulatory SNPs
SNP
Transcription, Genetic - drug effects
Vascular Cell Adhesion Molecule-1 - genetics
VCAM1
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Summary:Multiple variants of the vascular adhesion molecule‐1 (VCAM1) promoter show increased nucleotide heterozygosity in the African American population. Using a novel transfection‐based transcriptional pathway profiling method, we show that select uncommon variants are functionally hyperactive. Eight candidate VCAM1 promoter haplotypes comprising 13 previously identified SNPs were assessed for response to known mitogens. Activity was correlated with bioinformatic analysis of hyper‐ and hyporesponsive variants to identify the gain or loss of haplotype‐specific transcription factor binding site (TFBS). Using this approach, a low frequency regulatory allele (c.–540A>G; dbSNP rs3783605:A>G), found in a hyperactive VCAM1 promoter haplotype, was shown to create a candidate binding site for ETS2 that was confirmed in vivo by chromatin immunoprecipitation. This report provides the first functional evaluation of VCAM1 promoter polymorphisms and establishes a hypothetical foundation for investigation of their role in the pathogenesis of VCAM1‐associated diseases that disproportionately afflict African Americans, including thromboembolic diseases, asthma, and multiple myeloma. Hum Mutat 28(8), 824–829, 2007. Published 2007, Wiley‐Liss, Inc.
ISSN:1059-7794
1098-1004
DOI:10.1002/humu.20523