Sequence variants in IL10, ARPC2 and multiple other
loci contribute to ulcerative colitis susceptibility
Andre Franke1,17, Tobias Balschun1,17, Tom H Karlsen2,17, Jurgita Sventoraityte1, Susanna Nikolaus3,4,
Gabriele Mayr5, Francisco S Domingues5, Mario Albrecht5, Michael Nothnagel6, David Ellinghaus1,
Christian Sina3,4, Clive M Onnie7, Rinse K Weersma8, Pieter C F Stokkers9, Cisca Wijmenga10,
Maria Gazouli11, David Strachan12, Wendy L McArdle13, Se ´verine Vermeire14, Paul Rutgeerts14,
Philip Rosenstiel1, Michael Krawczak6, Morten H Vatn2,15, the IBSEN study group16,
Christopher G Mathew7& Stefan Schreiber1,4
Inflammatory bowel disease (IBD) typically manifests as either
ulcerative colitis (UC) or Crohn’s disease (CD). Systematic
identification of susceptibility genes for IBD has thus far
focused mainly on CD, and little is known about the genetic
architecture of UC. Here we report a genome-wide association
study with 440,794 SNPs genotyped in 1,167 individuals with
UC and 777 healthy controls. Twenty of the most significantly
associated SNPs were tested for replication in three
independent European case-control panels comprising a total
of 1,855 individuals with UC and 3,091 controls. Among the
four consistently replicated markers, SNP rs3024505
immediately flanking the IL10 (interleukin 10) gene on
chromosome 1q32.1 showed the most significant association in
the combined verification samples (P ¼ 1.35 ? 10?12; OR ¼
1.46 (1.31–1.62)). The other markers were located in ARPC2
and in the HLA-BTNL2 region. Association between rs3024505
and CD (1,848 cases, 1,804 controls) was weak (P ¼ 0.013;
OR ¼ 1.17 (1.01–1.34)). IL10 is an immunosuppressive
cytokine that has long been proposed to influence IBD
pathophysiology. Our findings strongly suggest that
defective IL10 function is central to the pathogenesis of
the UC subtype of IBD.
The two main subtypes of inflammatory bowel disease (IBD), ulcera-
tive colitis (UC, MIM191390) and Crohn’s disease (CD, MIM266600),
are chronic relapsing-remitting inflammatory disorders affecting the
intestinal mucosa. Both diseases represent major burdens of morbidity
in Western countries, with prevalence rates in North America and
Europe ranging from 21 to 246 per 100,000 for UC and 8 to 214 per
100,000 for CD1. Although some clinical and pathological features are
shared by these two subphenotypes of IBD, there are important
differences in disease localization, endoscopic appearance, histology
and behavior, which suggest differences in the underlying patho-
physiology. In both diseases, inappropriate control of chronic inflam-
mation has a major role2.
The genetic contribution to disease risk has been documented more
clearly for CD than for UC (relative sibling risks: 15–35 for CD, 6–9
for UC), and the recent identification of several CD susceptibility
genes has yielded valuable insights into the pathogenesis of this IBD
subtype3. In the clinical picture, some overlap is seen and the
systematic analysis of CD risk markers shows that several of them
are also associated with UC, including IL23R, IL12B, NKX2-3, CCNY
and the 3p21.31 (MST1) locus4,5. A genome-wide candidate gene
experiment investigating 10,886 nonsynonymous SNPs in 1,470
British controls and 936 UC cases yielded ECM1 on 1q21.2 as a
new UC-specific susceptibility gene6. However, a systematic, genome-
wide analysis of UC has not been reported so far.
We set out to identify UC susceptibility loci systematically in a large
sample of 1,167 cases and 777 healthy controls (panel A, Table 1) by
testing 440,794 SNPs with the Affymetrix SNP Array 5.0 (Supple-
mentary Methods online). Screening panel A had 80% power to
detect a variant with an odds ratio of 1.5 or higher at the 5%
Received 17 April; accepted 25 July; published online 5 October 2008; doi:10.1038/ng.221
1Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel 24105, Germany.2Medical Department, Rikshospitalet University Hospital, Oslo 0027,
Norway.3popgen Biobank, Christian-Albrechts-University Kiel, Kiel 24105, Germany.4Department of General Internal Medicine, University Hospital Schleswig-
Holstein, Christian-Albrechts-University, Kiel 24105, Germany.5Max-Planck Institute for Informatics, Saarbru ¨cken 66123, Germany.6Institute of Medical Informatics
and Statistics, Christian-Albrechts-University, Kiel 24105, Germany.7Department of Medical and Molecular Genetics, King’s College London School of Medicine,
London SE1 9RT, UK.8Department of Gastroenterology and Hepatology, University Medical Center Groningen and University of Groningen, Groningen 9700 RB, The
Netherlands.9Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.10Department of Genetics,
University Medical Center Groningen and University of Groningen, Groningen 9700 RB, The Netherlands.11Department of Biology, School of Medicine, University of
Athens, Athens 11527, Greece.12St. Georges’s University, Division of Community Health Sciences, London SW17 0RE, UK.13ALSPAC, Department of Social
Medicine, University of Bristol, Bristol BS8 1TQ, UK.14Department of Gastroenterology, University Hospital Gasthuisberg, Leuven 3000, Belgium.15Faculty of
Medicine, Epigen, Akershus University Hospital, 1474 Oslo, Norway.16A full list of members is provided in the Supplementary Note online.17These authors
contributed equally to this work. Correspondence should be addressed to S.S. (firstname.lastname@example.org).
NATURE GENETICS VOLUME 40 [ NUMBER 11 [ NOVEMBER 20081319
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Table 1 Summary of association results of replication
Panel A – GWAS
777 controls/1,167 UC cases
Panel B – Germany
985 controls, 523 UC cases
Panel C – UK
1,091 controls, 304 UC cases
Panel D – Belgium/Netherlands
1,015 controls, 1,028 UC cases
Combined analysis (panels B–D)
3,091 controls, 1,855 UC cases
PCMHOR (95% CI)
Twenty SNPs were genotyped in three independent replication panels of different ancestry. Data are shown for the nine SNPs that were significant in the combined analysis (nominal PCMHo0.05). Results of all 20 SNPs are shown in
Supplementary Table 7 online. SNPs are ranked according to the P value obtained in the GWAS. Nucleotide positions refer to NCBI build 35. A1 denotes the rare allele and A2 is the common allele in controls. The respective allele
frequencies are shown for allele A1 (AFA1). P values obtained in the case-control analysis using an allele-based w2test (one degree of freedom) are listed (PCCA). Significant P values (P o 0.05) are highlighted in bold italic. Odds ratios and 95% confidence
intervals for carriership of the allele A1 are shown. Column PBDlists the asymptotic P values of a Breslow-Day test for heterogeneity. A significant P value indicates a significant heterogeneity between replication panels in terms of the odds ratio of the disease
association. Combined P values (PCMH) and combined ORs of the Cochran-Mantel-Haenszel test statistic (one degree of freedom) are shown. Results for IL10 lead SNP rs3024505 are highlighted by gray shading. Further details including genotype counts are listed in
Supplementary Table 2.
aP value o0.05 after correction for multiple testing (corresponding to a Bonferroni threshold of 0.0025 for the uncorrected P value).bFor the combined analysis of rs3024505, 204 Greek cases and 431 matched controls were included (panel E).
1320VOLUME 40 [ NUMBER 11 [ NOVEMBER 2008 NATURE GENETICS
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significance level, assuming a frequency of the disease-associated allele
of at least 20% in controls (Supplementary Fig. 1 online). Genotyping
was done blind to case-control status, and several HapMap samples
with known genotype were included in each batch for quality control.
After applying stringent quality control criteria (Supplementary
Methods) to the genotype data from panel A, we included all 1,944
samples and a subset of 355,262 SNPs in the final association analysis
(see Supplementary Fig. 2 online). The total genotyping rate across
these samples was 99.8%. We found genetic heterogeneity to be low,
with an estimated genomic inflation factor7of lGC¼ 1.11 (Supple-
mentary Figs. 3 and 4 online). P values with and without correction
for structure were similar and consequently, unadjusted P values are
shown below. We genotyped the 20 most strongly associated SNPs that
passed selection criteria for replication (Supplementary Methods and
Supplementary Fig. 5 online) in three additional panels of UC cases
and healthy controls (panels B, C and D in Table 1, see also
Supplementary Methods). The results of the association analysis are
summarized in Table 1, and full details, including genotype counts,
are given in Supplementary Table 1 online.
New associations that withstood correction for multiple testing
using Bonferroni correction (a ¼ 0.0025 (0.05/20)) across all three
replication panels were obtained for rs3024505 near the 3¢ UTR of the
IL10 gene at 1q32, for rs12612347 near the ARP2C locus at 2q35 and
for rs9268480, rs9268858 and rs9268877 at the class II–class III
junction in the HLA complex at 6p21 (Table 1). The findings at the
latter three SNPs, located near the HLA class II genes on chromosome
6p21, are not surprising given the large body of evidence for an
association between classical HLA loci and UC8. Because of the
complex pattern of linkage disequilibrium (LD) in this region,
comprehensive experiments beyond the scope of the present study
will be required to clarify whether the observed associations are due to
variation in the HLA class II genes themselves, at neighboring loci (for
example, BTNL2), or both. Another notable finding in the present
study is the consistent association between ARPC2 and UC. The exact
function of ARPC2 is not known. The microbial equivalent of human
Arp2/3 associates with the protein encoded by
the WAS gene, which, when mutated in
humans, causes Wiskott-Aldrich syndrome
(WAS). Notably, the WAS protein is involved
in the regulation of regulatory T cells9, and manifestation of UC has
been reported as the first sign of disease in an individual with WAS10.
Genome-wide linkage studies have also provided evidence for UC
susceptibility factors in the respective region at 2q11. That the
previously reported IL23R association4replicated in all sample panels
of the present study (SNP rs11805303: combined P ¼ 1.09 ? 10?5and
OR ¼ 1.23 (1.12–1.35)), albeit at lower levels of significance than IL10,
highlights a role for this locus in UC as well as CD. Population
attributable risk fractions (%) in the combined panel (B–D) were 12.7,
13.3, 42.6, 47.8, 32.1 and 9.8 for SNPs rs3024505, rs12612347,
rs9268480, rs9268858, rs9268877 and rs11805303, respectively (Sup-
In the combined analysis, the most significant association outside
the HLA complex in the replication analysis was obtained for
rs3024505 located 1 kb downstream of the 3 UTR of IL10 (P ¼
1.35 ? 10?12; OR ¼ 1.46 (1.31–1.62)). In a consecutive analysis we
did not find strong evidence for an association between rs3024505 and
the CD phenotype (P ¼ 0.013; OR ¼ 1.17 (1.01–1.34)) in 1,804
healthy controls and 1,848 CD cases. We saturated the IL10 locus using
an additional 22 HapMap tagging SNPs in an attempt to narrow down
the association signal and to support the disease association of the lead
SNP. All fine mapping SNPs were genotyped in the UC replication
panels B to D, revealing associations that included rs3024495 in intron
4 (P ¼ 2.69 ? 10?11in combined analysis) and rs3024493 in intron 3
(P ¼ 6.16 ? 10?12in combined analysis), together with lead SNP
rs3024505 (Fig. 1 and Supplementary Table 2 online). The risk alleles
of these three SNPs were in perfect LD with each other (r2¼ 1.00), but
not with any of the other 20 SNPs used for fine mapping (r2r 0.20).
In a logistic regression analysis of the combined panels B–D, applying
forward selection to the 23 fine-mapping SNPs, we achieved the best
model fit for SNPs rs3024496 (3¢ UTR), rs6658896 (14 kb 3¢ of IL10)
and rs4845140 (25 kb 5¢ of IL10), in addition to lead SNP rs3024505,
suggesting that more than one causal variant might contribute to the
association signal at the IL10 locus. A haplotype analysis of the latter
four SNPs supported this finding (see Supplementary Table 3 online).
Genetic distance from
lead SNP (cM)
Recombination rate (cM/Mb)
203,330203,340203,350 203,360203,370203,380203,390 203,400
–log (P value)
A - GWAS (777 controls/1,167 cases)
B - Germany (985 controls/523 cases)
C - UK (1,091 controls/304 cases)
D - Benelux (1,015 controls/1,028 cases)
E - Greece (431 controls/204 cases)
(P value = 0.05)
Figure 1 Regional plot of the confirmed UC
association at IL10. Plot of the negative decadic
logarithm of the P values obtained in the GWAS
(panel A) and the fine mapping in replication
panels B to E. Twenty-three tagging SNPs,
including lead SNP rs3024505 (highlighted by
filled symbols), were genotyped across the 89-kb
region surrounding the IL10 gene. The three
IL10 promoter SNPs rs1800872 (–C592A),
rs1800871 (–C819T) and rs1800896
(–G1082A) are highlighted. Nominal P values for
each UC case-control panel are shown and are
based on a Pearson w2test with one degree of
freedom. The red dotted line corresponds to a
threshold of 0.05 for the P value. The middle
panel includes plots of the recombination
intensity (cM/Mb) and the cumulative genetic
distance in cM, and the bottom panel shows the
position and intron-exon structure of IL10 and
part of the upstream IL19 gene. Positions are
given as NCBI build 35 coordinates. For details,
see Supplementary Table 2.
NATURE GENETICS VOLUME 40 [ NUMBER 11 [ NOVEMBER 20081321
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These data taken together clearly identified IL10 as a susceptibility
gene for UC, but the causative variant(s) within the gene remained to
be found. We resequenced the entire IL10 gene—that is, the promoter,
introns and exons—in 94 individuals with UC, 94 individuals with
CD and 94 healthy controls (Supplementary Fig. 6 online). In total,
we identified 25 known SNPs and 19 additional SNPs, all of which
were private or rare variants (Supplementary Tables 4 and 5 online).
No indel polymorphism was identified. Two private nonsynonymous
SNPs not previously described (encoding F129Y and R177Q) were
detected alongside a rare synonymous SNP (K135K) and the pre-
viously identified G15R variant, which has failed to show significant
association with CD in previous studies12. Our results corroborate this
finding and extend the association to UC, as only one heterozygote
sample was found among the 282 samples that were resequenced.
Three key observations can be made regarding the possible causality
of the variants identified by the present fine mapping and association
analysis. First, we did not find any evidence of a UC association for
any of the previously investigated SNPs at IL10 promoter positions
–592 (rs1800872), –819 (rs1800871) and –1082 (rs1800896)13–23. Only
two out of as many as ten previous studies have so far yielded evidence
for an association of UC with the SNPs at these positions15,21. That
eight of these previous studies have been unable to generate evidence
for an IL10 association in UC highlights general limitations of study
design and statistical power in a large fraction of historical candidate
gene studies24. The variable evidence for the association detected
between the promoter SNPs and UC is probably due to different
levels of LD between the promoter SNPs and the main SNP respon-
sible for the association signal which, according to our data, is likely to
reside elsewhere at the IL10 locus. Second, the close proximity (79 bp)
of lead SNP rs3024505 to a highly conserved stretch of DNA at the 3¢
end of the gene is of interest. This region has a high regulatory
potential score25and contains a putative AP-1 binding motif. AP-1 is
activated upon stimulation of macrophages by the bacterial cell-wall
component lipopolysaccharide26, and IL10 production could provide
an important anti-inflammatory feedback mechanism. Finally, we
carried out an extensive analysis of the influence of the two newly
identified exonic variants on the interaction sites between IL10 and the
high-affinity IL10 receptor A (IL10RA; see Supplementary Note and
Supplementary Figs. 7 and 8 online). To what extent carriage of either
of these variants can be functionally linked to UC susceptibility in the
individuals in question can, however, only be speculated.
Our findings clearly suggest that IL10 may be a key cytokine in UC
pathogenesis. This hypothesis is strongly supported by the spontaneous
colitis phenotype developed by Il10?/?mice, which seems to result from
a defective anti-inflammatory counter-regulation in response to the
commensal flora. Notably, a reduced IL10 in vitro regulation in inflam-
matory immune cells obtained from the mucosa of individuals of UC has
been described, and therapeutic administration of human recombinant
IL10 to individuals with UC had a positive clinical effect27–29. Subcuta-
neous administration of IL10was not furtherevaluated as a therapeutic in
UC after failing in clinical studies of CD. In light of these results, systemic
or topical delivery of IL10 should be worthy of consideration for clinical
trials in UC. As a delivery mechanism, genetically engineered IL10-
secreting Lactococcus lactis strains have been developed as a potent tool
to influence colonic mucosal immunoregulation30. A role of IL10 has also
been suggested in other forms of chronic inflammation, for example
rheumatoid arthritis, lupus erythematosus and psoriasis, and it should be
worthwhile to investigate the IL10 locus by a haplotype-tagging approach
in these conditions.
IL10 signals through STAT3- and MAPK-mediated pathways to
trigger anti-inflammatory mechanisms dependent on suppressor of
cytokine signaling26. Recently, a targeted assessment of CD suscept-
ibility genes for their role in UC revealed an association between a
SNP in STAT3 and UC5. SNP rs744166, located in intron 2 of STAT3 at
17q21.2, which had been associated with CD in the Wellcome Trust
Case Control Consortium (WTCCC) genome-wide association
study7, proved to be associated with UC in that study (OR ¼ 0.77
(0.66–0.90), P ¼ 5.00 ? 10?4), but not with CD. In this context, it is
of great interest to note retrospectively that SNP rs7212299, located
upstream of STAT3, was also found to be associated with UC in the
present study (panel A). Because of the low level of significance
(P ¼ 0.01, see Supplementary Table 6 online) the SNP was, however,
not included in the replication phase of this study. We anticipate that
further characterization of critical components of the IL10–STAT3
signaling pathway may point to important therapeutic targets and
provide unique insights into the pathogenesis of UC.
Participants. The diagnosis of UC or CD was based on typical clinical,
radiological, histological and endoscopic (type and distribution of lesions)
findings. The full recruitment details for all study panels are given in
Supplementary Methods. All participants gave written informed consent,
and the recruitment protocols were approved by the ethics committees at the
respective recruiting institutions.
Genotyping and sequencing. The genotyping for the GWAS was performed as
a service project by Affymetrix using the Genome-Wide Human SNPArray 5.0
(500K). Genotypes were assigned using the BRLMM-p algorithm. Samples with
more than 5% missing genotypes, who showed excess genetic dissimilarity to
the other subjects (see Supplementary Fig. 2), or who showed evidence for
cryptic relatedness to other study participants (see Supplementary Fig. 2) were
not included. These quality control measures left 1,167 UC samples and 777
control samples for inclusion in screening panel A. SNPs were excluded
(n ¼ 85,532; 19.4% of all SNPs) that had a low genotyping rate (o95% in
cases or controls), were monomorphic or rare (minor allele frequency o2% in
cases or controls), or deviated from Hardy-Weinberg equilibrium (HWE) in
the control sample (PHWEr 0.01).
All downstream genotyping was done with SNPlex and TaqMan technolo-
gies (Applied Biosystems) using an automated laboratory setup and all process
data were written to and administered by a database-driven laboratory
information management system. Sequencing of genomic DNA was done
using BigDye Terminator v3.1 chemistry (Applied Biosystems) and an
ABI3730 capillary sequencer (Applied Biosystems) according to manufacturer’s
protocols. Traces were inspected for SNPs and indels using novoSNP v2.03. See
Supplementary Methods for further details.
Statistical analysis. Genome-wide association analyses were conducted with
PLINK v1.01 in combination with gPLINK v2.049 and GENOMIZER v1.2.0.
Single-marker analyses, permutation tests, estimation of pair-wise linkage
disequilibrium (LD) and SNP selection were done using Haploview v4.0.
Logistic regressions were done within LOGISTIC of the SAS software package
(SAS Institute). For additional details, see Supplementary Methods.
Note: Supplementary information is available on the Nature Genetics website.
We wish to thank all individuals with IBD, families and physicians for their
cooperation. We gratefully acknowledge the cooperation of the German Crohn
and Colitis Foundation (Deutsche Morbus Crohn und Colitis Vereinigung
e.V.), the BMBF competence network ‘‘IBD’’ and of the contributing
gastroenterologists. Finally, we wish to thank T. Wesse, T. Henke, A. Dietsch,
R. Vogler, C.v.d. Lancken and M. Friskovec for expert technical help. We thank
T. Wienker and M. Steffens (IMBIE, University of Bonn) for performing the
quality control of the GWAS datasets. We thank B.A. Lie and the Norwegian
Bone Marrow Donor Registry at Rikshospitalet University Hospital, Oslo, for
contributing the healthy Norwegian control population. This study was supported
by the German Ministry of Education and Research (BMBF) through the
1322 VOLUME 40 [ NUMBER 11 [ NOVEMBER 2008 NATURE GENETICS
© 2008 Nature Publishing Group http://www.nature.com/naturegenetics
National Genome Research Network (NGFN), the popgen biobank and the
SFB617 ‘‘Molecular Mechanisms of Epithelial Defense.’’ The project received
infrastructure support through the DFG excellence cluster ‘‘Inflammation at
Interfaces.’’ We acknowledge use of DNA from the 1958 British Birth Cohort
collection (R. Jones, S. Ring, W. McArdle and M. Pembrey), funded by the UK
MRC (grant G0000934) and The Wellcome Trust (grant 068545/Z/02). C.G.M.
and C.M.O. were supported by The Wellcome Trust and CORE (UK).
A.F., T.B. and J.S. performed the SNP selection, genotyping, data analysis,
resequencing, and prepared the figures and tables; T.H.K. helped with data
analysis. S.N., C.S. and P. Rosenstiel coordinated the recruitment and collected
the phenotype data. M.N. and D.E. helped with data analysis and quality control;
G.M., F.S.D. and M.A. performed in silico protein analysis and contributed to
writing the manuscript. Norwegian, Belgian, Dutch and Greek patient samples
were provided by M.H.V., S.V., P. Rutgeerts, R.K.W., P.C.F.S. and M.G.,
respectively. W.L.M. and D.S. provided the UK and C.W. the Dutch control
samples; M.K. supervised and performed the statistical analysis and edited the
paper. C.M.O. and C.G.M. provided the UK patient sample and edited the
manuscript. A.F., T.H.K. and S.S. designed and supervised the experiment and
wrote the manuscript. All authors approved the final manuscript.
Published online at http://www.nature.com/naturegenetics/
Reprints and permissions information is available online at http://npg.nature.com/
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