title: Molecular Characterization of the NLRC4 Expression in Relation to Interleukin-18 Levels.
abstract: 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.
  
  
  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.
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authors.lastname: Zeller
authors.forename: Tina
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authors.lastname: Haase
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authors.lastname: Müller
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authors.lastname: Riess
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authors.lastname: Zeller
authors.forename: Jasmin
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authors.lastname: Krause
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authors.lastname: Baumert
authors.forename: Ole
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authors.forename: Josée
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authors.initials: PS
authors.lastname: Wild
authors.forename: Medea
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authors.lastname: Eleftheriadis
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
authors.forename: Sonja
authors.initials: S
authors.lastname: Zeilinger
authors.forename: Andreas
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authors.lastname: Ziegler
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.forename: Laurence
authors.initials: L
authors.lastname: Tiret
authors.forename: Carole
authors.initials: C
authors.lastname: Proust
authors.forename: Carola
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authors.lastname: Marzi
authors.forename: Thomas
authors.initials: T
authors.lastname: Munzel
authors.forename: Konstantin
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authors.lastname: Strauch
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Lackner
authors.forename: Christian
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authors.lastname: Herder
authors.forename: Barbara
authors.initials: B
authors.lastname: Thorand
authors.forename: Emilia J
authors.initials: EJ
authors.lastname: Benjamin
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Koenig
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authors.lastname: Schnabel
mesh_terms: D000483:Alleles; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D015331:Cohort Studies; D003198:Computer Simulation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics
chemical_list: D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; D058847:Inflammasomes; D020382:Interleukin-18; C435692:NLRC4 protein, human; D020033:Protein Isoforms
keywords: gene expression; genetic variation; inflammasomes; interleukin-18; transcription factors