title: A common polymorphism in the promoter region of the TNFSF4 gene is associated with lower allele-specific expression and risk of myocardial infarction.
abstract: BACKGROUND
  The TNFSF4/TNFRSF4 system, along with several other receptor-ligand pairs, is involved in the recruitment and activation of T-cells and is therefore tentatively implicated in atherosclerosis and acute coronary syndromes. We have previously shown that genetic variants in TNFSF4 are associated with myocardial infarction (MI) in women. This prompted functional studies of TNFSF4 expression.
  
  
  RESULTS
  Based on a screening of the TNFSF4 genomic region, a promoter polymorphism (rs45454293) and a haplotype were identified, conceivably involved in gene regulation. The rs45454293T-allele, in agreement with the linked rs3850641G-allele, proved to be associated with increased risk of MI in women. Haplotype-specific chromatin immunoprecipitation of activated polymerase II, as a measure of transcriptional activity in vivo, suggested that the haplotype including the rs45454293 and rs3850641 polymorphisms is functionally important, the rs45454293T- and rs3850641G-alleles being associated with lower transcriptional activity in cells heterozygous for both polymorphisms. The functional role of rs45454293 on transcriptional levels of TNFSF4 was clarified by luciferase reporter assays, where the rs45454293T-allele decreased gene expression when compared with the rs45454293C-allele, while the rs3850641 SNP did not have any effect on TNFSF4 promoter activity. Electromobility shift assay showed that the rs45454293 polymorphism, but not rs3850641, affects the binding of nuclear factors, thus suggesting that the lower transcriptional activity is attributed to binding of one or more transcriptional repressor(s) to the T-allele.
  
  
  CONCLUSIONS
  Our data indicate that the TNFSF4 rs45454293T-allele is associated with lower TNFSF4 expression and increased risk of MI.
authors: Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital Solna, Stockholm, Sweden. massimiliano.ria@well.ox.ac.uk
authors: Massimiliano
authors: M
authors: Ria
authors: Jacob
authors: J
authors: Lagercrantz
authors: Ann
authors: A
authors: Samnegård
authors: Susanna
authors: S
authors: Boquist
authors: Anders
authors: A
authors: Hamsten
authors: Per
authors: P
authors: Eriksson
mesh_terms: D000483:Alleles; D001483:Base Sequence; D016022:Case-Control Studies; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D009203:Myocardial Infarction / Q000235:genetics*; D053278:OX40 Ligand / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D053278:OX40 Ligand; C089251:TNFSF4 protein, human