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Functional profiling of uncommon VCAM1 promoter polymorphisms prevalent in African American populations
Author(s) -
Idelman Gila,
Taylor James G.,
Tongbai Ron,
Chen Renee A.,
Haggerty Cynthia M.,
Bilke Sven,
Chanock Stephen J.,
Gardner Kevin
Publication year - 2007
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20523
Subject(s) - biology , haplotype , chromatin immunoprecipitation , single nucleotide polymorphism , genetics , promoter , allele , linkage disequilibrium , transcription factor , gene , microbiology and biotechnology , genotype , gene expression
Abstract 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.