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Genetic variation at the human LTA locus, encoding lymphotoxin-alpha, is associated with susceptibility to myocardial infarction, asthma and other diseases. By detailed haplotypic analysis of the locus, we identified a single-nucleotide polymorphism (SNP) at LTA+80 as a main predictor of LTA protein production by human B cells. We found that activated B-cell factor-1 (ABF-1) binds to this site in vitro and suppresses reporter gene expression, but only in the presence of the LTA+80A allele. Using haplotype-specific chromatin immunoprecipitation, we confirmed that ABF-1 is preferentially recruited to the low-producer allele in vivo. These findings provide a molecular model of how LTA expression may be genetically regulated by allele-specific recruitment of the transcriptional repressor ABF-1.

Original publication

DOI

10.1038/ng1331

Type

Journal article

Journal

Nature genetics

Publication Date

04/2004

Volume

36

Pages

394 - 399

Addresses

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. julian@well.ox.ac.uk

Keywords

Cell Line, Transformed, Humans, Precipitin Tests, Electrophoretic Mobility Shift Assay, Gene Expression Regulation, Haplotypes, Alleles, Plasmids, Lymphotoxin-alpha