IL12B encodes the p40 subunit of IL-12, which is also part of IL-23. Recent genome-wide association studies identified IL12B and IL23R as susceptibility genes for inflammatory bowel disease (IBD). However, the phenotypic effects and potential gene-gene interactions of IL12B variants are largely unknow

A Franke

A Marquez

A Zwiers

AB Begovich

B Ciric

B Oppmann

Burkhard Göke

C Abraham

C Filer

C Parham

CA Anderson

CF Flach

Christian Steib

Christoph Fries

CL Langrish

Cornelia Tillack

CW Lees

Darina Czamara

E Tug

EA Festen

F van der Heide

Florian Beigel

G Monteleone

G Morahan

Giovambattista Pani

I Peter

J Dambacher

J Glas

J Muller-Berghaus

J Seiderer

JC Barrett

JD Rioux

Johanna Wagner

Johannes Stallhofer

Julia Diegelmann

Julia Seiderer

Jürgen Glas

K Morgan

K Sugimoto

K Tanaka

K Wang

K Yamazaki

L Torkvist

LA Zenewicz

LR Ferguson

M Cargill

M Chang

M Parkes

Martin Wetzke

Matthias Friedrich

MF Neurath

MS Silverberg

P Danoy

P Delerive

P Parronchi

PR Burton

RH Duerr

RL Smith

RP Nair

S Brand

S Fujino

SH Chan

ST Chelbi

Stephan Brand

T Heinemeyer

T Hirota

Thomas Ochsenkühn

Torsten Olszak

U Huffmeier

V Beynon

W O'Connor Jr

WJ Sandborn

English

PubMed

Crossref

PLoS ONE

Analysis of IL12B Gene Variants in Inflammatory Bowel Disease

Glas, Jürgen

Seiderer, Julia

Wetzke, Martin

Göke, Burkhard

Ochsenkühn, Thomas

Diegelmann, Julia

Czamara, Darina

Brand, Stephan

Wagner, Johanna

Olszak, Torsten

Fries, Christoph

Tillack, Cornelia

Friedrich, Matthias

Beigel, Florian

Stallhofer, Johannes

Steib, Christian

Publikationsserver der RWTH Aachen University

RWTH Publications

<div><h3>Background</h3><p><em>IL12B</em> encodes the p40 subunit of IL-12, which is also part of IL-23. Recent genome-wide association studies identified <em>IL12B</em> and <em>IL23R</em> as susceptibility genes for inflammatory bowel disease (IBD). However, the phenotypic effects and potential gene-gene interactions of <em>IL12B</em> variants are largely unknown.</p> <h3>Methodology/Principal Findings</h3><p>We analyzed <em>IL12B</em> gene variants regarding association with Crohn's disease (CD) and ulcerative colitis (UC). Genomic DNA from 2196 individuals including 913 CD patients, 318 UC patients and 965 healthy, unrelated controls was analyzed for four SNPs in the <em>IL12B</em> gene region (rs3212227, rs17860508, rs10045431, rs6887695). Our analysis revealed an association of the <em>IL12B</em> SNP rs6887695 with susceptibility to IBD (p = 0.035; OR 1.15 [95% CI 1.01–1.31] including a trend for rs6887695 for association with CD (OR 1.41; [0.99–1.31], p = 0.066) and UC (OR 1.18 [0.97–1.43], p = 0.092). CD patients, who were homozygous C/C carriers of this SNP, had significantly more often non-stricturing, non-penetrating disease than carriers of the G allele (p = 6.8×10<sup>−5</sup>; OR = 2.84, 95% CI 1.66–4.84), while C/C homozygous UC patients had less often extensive colitis than G allele carriers (p = 0.029; OR = 0.36, 95% CI 0.14–0.92). <em>In silico</em> analysis predicted stronger binding of the minor C allele of rs6887695 to the transcription factor RORα which is involved in Th17 differentiation. Differences regarding the binding to the major and minor allele sequence of rs6887695 were also predicted for the transcription factors HSF1, HSF2, MZF1 and Oct-1. Epistasis analysis revealed weak epistasis of the <em>IL12B</em> SNP rs6887695 with several SNPs (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694) in the <em>STAT4</em> gene which encodes the major IL-12 downstream transcription factor STAT4 (p<0.05) but there was no epistasis between <em>IL23R</em> and <em>IL12B</em> variants.</p> <h3>Conclusions/Significance</h3><p>The <em>IL12B</em> SNP rs6887695 modulates the susceptibility and the phenotype of IBD, although the effect on IBD susceptibilty is less pronounced than that of <em>IL23R</em> gene variants.</p> </div

Jürgen Glas (107816)

Julia Seiderer (107820)

Johanna Wagner (174709)

Torsten Olszak (107835)

Christoph Fries (174714)

Cornelia Tillack (174718)

Matthias Friedrich (174721)

Florian Beigel (174724)

Johannes Stallhofer (174728)

Christian Steib (174731)

Martin Wetzke (107833)

Burkhard Göke (109829)

Thomas Ochsenkühn (174734)

Julia Diegelmann (107830)

Darina Czamara (107824)

Stephan Brand (107861)

The Francis Crick Institute

Analysis of <em>IL12B</em> Gene Variants in Inflammatory Bowel Disease

Glas, J.

Seiderer, J.

Wagner, J.

Olszak, T.

Fries, C.

Tillack, C.

Friedrich, M.

Beigel, F.

Stallhofer, J.

Steib, C.

Wetzke, M.

Göke, B.

Ochsenkühn, T.

Diegelmann, J.

Czamara, D.

Brand, S.

MPG.PuRe

Open Access LMU ( Ludwig-Maximilians-Univ. München)

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Rostami A (2009) IL-23 drives pathogenic IL-17-producing CD8+ T cells.

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Analysis of IL12B gene variants in inflammatory bowel disease

BACKGROUND: IL12B encodes the p40 subunit of IL-12, which is also part of IL-23. Recent genome-wide association studies identified IL12B and IL23R as susceptibility genes for inflammatory bowel disease (IBD). However, the phenotypic effects and potential gene-gene interactions of IL12B variants are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed IL12B gene variants regarding association with Crohn's disease (CD) and ulcerative colitis (UC). Genomic DNA from 2196 individuals including 913 CD patients, 318 UC patients and 965 healthy, unrelated controls was analyzed for four SNPs in the IL12B gene region (rs3212227, rs17860508, rs10045431, rs6887695). Our analysis revealed an association of the IL12B SNP rs6887695 with susceptibility to IBD (p = 0.035; OR 1.15 [95% CI 1.01-1.31] including a trend for rs6887695 for association with CD (OR 1.41; [0.99-1.31], p = 0.066) and UC (OR 1.18 [0.97-1.43], p = 0.092). CD patients, who were homozygous C/C carriers of this SNP, had significantly more often non-stricturing, non-penetrating disease than carriers of the G allele (p = 6.8×10(-5); OR = 2.84, 95% CI 1.66-4.84), while C/C homozygous UC patients had less often extensive colitis than G allele carriers (p = 0.029; OR = 0.36, 95% CI 0.14-0.92). In silico analysis predicted stronger binding of the minor C allele of rs6887695 to the transcription factor RORα which is involved in Th17 differentiation. Differences regarding the binding to the major and minor allele sequence of rs6887695 were also predicted for the transcription factors HSF1, HSF2, MZF1 and Oct-1. Epistasis analysis revealed weak epistasis of the IL12B SNP rs6887695 with several SNPs (rs11889341, rs7574865, rs7568275, rs8179673, rs10181656, rs7582694) in the STAT4 gene which encodes the major IL-12 downstream transcription factor STAT4 (p<0.05) but there was no epistasis between IL23R and IL12B variants. CONCLUSIONS/SIGNIFICANCE: The IL12B SNP rs6887695 modulates the susceptibility and the phenotype of IBD, although the effect on IBD susceptibilty is less pronounced than that of IL23R gene variants

Analysis of IL12B Gene Variants in Inflammatory Bowel Disease

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