Circulation: Cardiovascular Genetics

HCG

Molecular Characterization of the NLRC4 Expression in Relation to Interleukin-18 Levels

Characterization of NLRC4 Expression

CIRCCVG/2015/001079

10.1161/CIRCGENETICS.115.001079 8

10/20/15

Sine Kristina

617-542-5100

617-542-6539

Semsarian, Christopher University of Sydney

Prof.

Tanja

Zeller

t.zeller@uke.de

Prof.

University Heart Center Hamburg

Martinistrasse 52

Hamburg

20246

GERMANY

0049-40-741056575

0049-40-40741056574

80750

Tanja

Zeller

University Heart Center Hamburg

t.zeller@uke.de

80750

Tina

Haase

Clinic for General and Interventional Cardiology, University Heart Center Hamburg

t.haase@uke.de

268263

Christian

Müller

University Heart Center Hamburg

christian_m@gmx.net

96692

Helene

Riess

Helmholtz Zentrum München

lenariess@gmx.at

268282

Denise

Lau

University Heart Center Hamburg

d.lau@uke.de

105176

Simon

Zeller

Clinic for General and Interventional Cardiology, University Heart Center Hamburg

s.zeller@uke.de

268264

Jasmin

Krause

Clinic for General and Interventional Cardiology, University Heart Center Hamburg

Krause.jn@googlemail.com

268265

Jens

Baumert

Helmholtz Zentrum München, German Research Center for Environmental Health

baumert@helmholtz-muenchen.de

119042

Ole

Pless

Fraunhofer Institute for Molecular Biology and Applied Ecology

Ole.Pless@ime.fraunhofer.de

270322

Josée

Dupuis

Boston University School of Public Health

dupuis@bu.edu

3982

Philipp

Wild

University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany

philipp.wild@unimedizin-mainz.de

65576

Medea

Eleftheriadis

University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany

medea_sophia@hotmail.com

268266

Melanie

Waldenberger

Helmholtz Zentrum München

waldenberger@helmholtz-muenchen.de

140384

Sonja

Zeilinger

Helmholtz Center München, German Research Center for Environmental Health

sonja.zeilinger@helmholtz-muenchen.de

239250

Andreas

Ziegler

Universität zu Lübeck

Andreas.ziegler@imbs.uni-luebeck.de

146539

Annette

Peters

GSF-National Research Center for Environment and Heal

peters@helmholtz-muenchen.de

11672

Laurence

Tiret

INSERM

laurence.tiret@upmc.fr

53602

Carole

Proust

Inserm U1166

carole.proust@upmc.fr

251343

Carola

Marzi

Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health

carola.marzi@helmholtz-muenchen.de

268269

Thomas

Münzel

Johannes Gutenberg-Universität Mainz

tmuenzel@uni-mainz.de

2018

Konstantin

Strauch

Ludwig-Maximilians University Munich

strauch@helmholtz-muenchen.de

37311

Holger

Prokisch

Technical University Munich

prokisch@helmholtz-muenchen.de

197356

Karl

Lackner

University Medical Center Mainz

karl.lackner@unimedizin-mainz.de

39207

Christian

Herder

German Diabetes Center

christian.herder@ddz.uni-duesseldorf.de

39648

Barbara

Thorand

Helmholtz Zentrum München German Research Center for Envirnomental Health

thorand@helmholtz-muenchen.de

5341

Emelia

Benjamin

Boston University School of Medicine

emelia@bu.edu

5392

Stefan

Blankenberg

University Heart Center Hamburg

s.blankenberg@uke.de

58750

Wolfgang

Koenig

Ulm, University of

wolfgang.koenig@uniklinik-ulm.de

2919

Renate

Schnabel

University Heart Center

r.schnabel@uke.de

4443

03/10/2015

08/19/2015

08/24/2015

09/16/2015

10/20/2015

Original Article

Inflammasome Interleukin 18 NLRC4 PU.1

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, 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 GWAS, we confirmed association of IL-18 levels with a SNP in the untranslated exon 2 of the inflammasome component NLRC4 (NLR family, CARD 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 SNP rs385076 within the NLRC4 gene in relation to IL-18 activation.

yes

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Bill authors $70 per pg.; no excess pgs. Article has supplemental material (1 PDF & 1 Excel) and a clinical perspective. Drs. Zeller & Riess, Ms. Haase, and Mr. Müller contributed equally to this work. Guest Editor for this article was Christopher Semsarian, MBBS, PhD, MPH. Rec'd 3/10/15 NOTE: Please be sure to post the Excel (xlsx) version of the supplemental table 4 along w/ the PDF. The authors have referenced the separate table w/in the main supplemental file. Journal Subject Terms have been updated. Subject Codes: [10081] Gene Expression and Regulation [10084] Genetics [10085] Functional Genomics ksine