Molecular characterization of the NLRC4 expression in relation to interleukin-18 levels
| Autor: | Wolfgang Koenig, E J Benjamin, Christian Herder, Philipp S. Wild, Barbara Thorand, Christian P. Müller, Tina Haase, Thomas Münzel, Carole Proust, Jens Baumert, Jasmin Krause, Carola Marzi, Melanie Waldenberger, Karl J. Lackner, Renate B. Schnabel, Tanja Zeller, Denise Lau, Annette Peters, Medea S. Eleftheriadis, Ole Pless, Josée Dupuis, Sonja Zeilinger, Konstantin Strauch, Simon Zeller, Stefan Blankenberg, Laurence Tiret, Andreas Ziegler, Holger Prokisch, Helene Riess |
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| Přispěvatelé: | Publica |
| Jazyk: | němčina |
| Rok vydání: | 2015 |
| Předmět: |
Gene isoform
Inflammasomes Gene Expression Single-nucleotide polymorphism Biology Polymorphism Single Nucleotide Article Cohort Studies NLRC4 Gene expression Genetics medicine Humans Protein Isoforms Computer Simulation Alleles Genetics (clinical) Reporter gene Calcium-Binding Proteins Interleukin-18 Inflammasome Molecular biology CARD Signaling Adaptor Proteins HEK293 Cells Diabetes Mellitus Type 2 Interleukin 18 Cardiology and Cardiovascular Medicine Nlrc4 Pu.1 Gene Regulation Genetic Variation Transcription Factors TCF7L2 Genome-Wide Association Study medicine.drug |
| Zdroj: | Circ. Cardiovasc. Genet. 8, 717-726 (2015) |
| Popis: | Background— Interleukin-18 (IL-18) is a pleiotropic cytokine centrally involved in the cytokine cascade with complex immunomodulatory functions in innate and acquired immunity. Circulating IL-18 concentrations are associated with type 2 diabetes mellitus, cardiovascular events, and diverse inflammatory and autoimmune disorders. Methods and Results— To identify causal variants affecting circulating IL-18 concentrations, we applied various omics and molecular biology approaches. By genome-wide association study, we confirmed association of IL-18 levels with a single nucleotide polymorphism in the untranslated exon 2 of the inflammasome component NLRC4 (NLR family, caspase recruitment domain–containing 4) gene on chromosome 2 (rs385076; P =2.4×10 −45 ). Subsequent molecular analyses by gene expression analysis and reporter gene assays indicated an effect of rs385076 on NLRC4 expression and differential isoform usage by modulating binding of the transcription factor PU.1. Conclusions— Our study provides evidence for the functional causality of single nucleotide polymorphism rs385076 within the NLRC4 gene in relation to IL-18 activation. |
| Databáze: | OpenAIRE |
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