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 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.
Idelman
Gila
G
Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Bethesda, Maryland 20892-5065, USA.
Taylor
James G
JG
Tongbai
Ron
R
Chen
Renee A
RA
Haggerty
Cynthia M
CM
Bilke
Sven
S
Chanock
Stephen J
SJ
Gardner
Kevin
K
D001741:Black or African American / Q000235:genetics*; D001483:Base Sequence; D006239:Haplotypes; D006801:Humans; D019169:Jurkat Cells; D008934:Mitogens / Q000494:pharmacology; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics*
D008934:Mitogens; D019010:Vascular Cell Adhesion Molecule-1