ATG16L1 and IL23 receptor (IL23R) genes are associated with disease susceptibility in Hungarian CD patients.

Abstract

North American and European genome-wide association scans have identified ATG16L1 and IL23R as novel inflammatory bowel disease (IBD) susceptibility genes and subsequent reports confirmed these findings in large independent populations. The aims of this study were to investigate the association and examine genotype-phenotype relationships in a Hungarian IBD cohort.
415 unrelated IBD patients (CD: 266, age: 35.2+/-12.1 years, duration: 8.7+/-7.5 years and UC: 149, age: 44.4+/-15.4 years, duration: 10.7+/-8.9 years) and 149 healthy subjects were investigated. IL23R Arg381Gln (R381Q, rs11209026) and ATG16L1 Thr300Ala (T300A, rs2241880) polymorphisms were tested using LightCycler allele discrimination method. Detailed clinical phenotypes were determined by reviewing the medical charts.
The association between IL23R rs11209026, ATG16L1 rs2241880 and CD was confirmed (OR(IL23R381Q): 0.38, 95% CI: 0.16-0.87; OR(ATG16L1300AA): 1.86, 95% CI: 1.04-3.40). No difference was found between patients with UC and either controls or CD. In CD, IL23R 381Gln heterozygosity was associated with inflammatory disease (70% vs. 34%, p=0.037), while disease restricted to the colon was more prevalent in patients with the ATG16L1 300Ala/Ala homozygosity (33.3% vs. 21.1%, p=0.036). In addition, carriage of the variant alleles did not predict response to steroids, infliximab or need for surgery.
We confirmed that ATG16L1 and IL23R are susceptibility loci for CD in Hungarian CD patients. Further studies are needed to confirm the reported phenotype-genotype associations found in this study.

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Available online at www.sciencedirect.com
Digestive and Liver Disease 40 (2008) 867–873
Alimentary Tract
ATG16L1 and IL23 receptor (IL23R) genes are associated with disease
susceptibility in Hungarian CD patients
P.L. Lakatosa,∗,1, T. Szamosia,1, A. Szilvasib, E. Molnarb, L. Lakatosc, A. Kovacsd,
T. Molnare, I. Altorjayf, M. Pappf, Z. Tulassayg, P. Mihellerg, J. Pappa, A. Tordaib,
H. Andrikovicsb,
The Hungarian IBD Study Group2
a1st Department of Medicine, Semmelweis University, Koranyi St. 2/A, H-1083 Budapest, Hungary
bDepartment of Molecular Diagnostics, Hungarian National Blood Transfusion Service, Budapest, Hungary
c1st Department of Medicine, Csolnoky F. County Hospital, Veszprem, Hungary
d1st Department of Medicine, Erzsebet Hospital, Budapest, Hungary
e1st Department of Medicine, University of Szeged, Szeged, Hungary
f2nd Department of Medicine, University of Debrecen, Debrecen, Hungary
g2nd Department of Medicine, Semmelweis University, Budapest, Hungary
Received 23 February 2008; accepted 31 March 2008
Available online 22 May 2008
Abstract
Background. North American and European genome-wide association scans have identified ATG16L1 and IL23R as novel inflammatory
bowel disease (IBD) susceptibility genes and subsequent reports confirmed these findings in large independent populations. The aims of this
study were to investigate the association and examine genotype–phenotype relationships in a Hungarian IBD cohort.
Methods. 415 unrelated IBD patients (CD: 266, age: 35.2±12.1 years, duration: 8.7±7.5 years and UC: 149, age: 44.4±15.4 years,
duration: 10.7±8.9 years) and 149 healthy subjects were investigated. IL23R Arg381Gln (R381Q, rs11209026) and ATG16L1 Thr300Ala
(T300A,rs2241880)polymorphismsweretestedusingLightCyclerallelediscriminationmethod.Detailedclinicalphenotypesweredetermined
by reviewing the medical charts.
Results. The association between IL23R rs11209026, ATG16L1 rs2241880 and CD was confirmed (ORIL23R381Q: 0.38, 95% CI: 0.16–0.87;
ORATG16L1300AA: 1.86, 95% CI: 1.04–3.40). No difference was found between patients with UC and either controls or CD. In CD, IL23R
381Gln heterozygosity was associated with inflammatory disease (70% vs. 34%, p=0.037), while disease restricted to the colon was more
prevalent in patients with the ATG16L1 300Ala/Ala homozygosity (33.3% vs. 21.1%, p=0.036). In addition, carriage of the variant alleles
did not predict response to steroids, infliximab or need for surgery.
Conclusions. We confirmed that ATG16L1 and IL23R are susceptibility loci for CD in Hungarian CD patients. Further studies are needed
to confirm the reported phenotype–genotype associations found in this study.
© 2008 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
Keywords: CD; UC; IL23R; ATG16L1; Genetics; Phenotype; Pharmacogenetics
∗Corresponding author. Tel.: +36 1 210 0278/1500, 1520; fax: +36 1 313 0250.
E-mail address: kislakpet@bel1.sote.hu (P.L. Lakatos).
1These authors contributed equally to this work.
2Further Hungarian IBD Study Group members are: Simon Fischer, Henrik Csaba Horvath, Zsuzsanna Elekes, Orsolya Kontar, Peter Vargha (Semmelweis
University, 1st Department of Medicine, Budapest, Hungary); Zsuzsanna Erdelyi, Gabor Mester, Csaba Molnar, Tunde Pandur (Csolnoky F. County Hospital,
1st Department of Medicine, Veszpr´ em, Hungary); Laszlo Bene (Erzsebet Hospital, 1st Department of Medicine, Budapest, Hungary); Ferenc Nagy, Janos
Lonovics (University of Szeged, 1st Department of Medicine, Szeged, Hungary); Karoly Palatka (University of Debrecen, 2nd Department of Medicine,
Debrecen); Pal Demeter, Levente Balint, Ferenc Huoranszky, Istvan Dobo (Department of Gastroenterology and Surgery, St. Margit Hospital, Budapest,
Hungary); Laszlo Herszenyi, Pal Miheller, Annamaria Nemeth (Semmelweis University, 2nd Department of Medicine, Semmelweis University, Budapest,
Hungary).
1590-8658/$30 © 2008 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.dld.2008.03.022

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1. Introduction
Inflammatory bowel diseases (IBDs) are multifactorial
with both environmental and genetic components, the latter
displaying heterogeneity in terms of disease presentation as
well as response to treatment [1,2]. As the incidence of IBD
israpidlyincreasinginsomepartsofEasternEurope [1],itis
therefore of great importance to study social, environmental
as well as host genetic factors that may underlie this trend.
Crohn’s disease (CD) has a strong genetic component,
and to date, at least nine susceptibility loci have been iden-
tified [3]; the first, and most consistently replicated critical
mutations, were found in the NOD2/CARD15 gene on chro-
mosome 16 (IBD1), alongside several other gene loci coding
for cytokines (interleukin [IL]1, IL6, IL23 receptor (IL23R),
andTNF-?),humanleukocyteantigen(HLA),toll-likerecep-
tors (TLRs), and genes related to the autophagy pathway
[4–7].
In December 2006, Duerr et al. [5] reported on an asso-
ciation between CD and variants in the IL23R gene at
1q31 discovered in a genome-wide association analysis. A
rare coding variant, Arg381Gln (rs11209026, c.1142G>A,
R381Q) was reported to exert the most significant protective
effect in both Jewish (OR: 0.45) and non-Jewish (OR: 0.26)
populations. The glutamine allele was much less common
with an allele frequency of 1.9% in CD vs. 7.0% in match-
ingcontrols.Inaddition,distortionofalleletransmissionwas
observed in CD families.
Subsequentstudiesreplicatedtheaboveassociationindif-
ferent Western European and New Zealand CD populations
(OR: 0.19–0.65), and to a lesser extent, it was also found
to be associated with UC (OR: 0.33–0.78) [8–12]. In con-
trast, in the only study to also include patients from Eastern
Europe, the researchers did not find a significant association
betweentheIL23R381GlnvariantandCDorUCintheEast-
ern European cohort [10]. In a German study [13], beside
R381Q, the intronic IL23R variant rs1004819 showed the
strongest association, without any epistatic interaction with
eitherNOD2/CARD15orSLC22A4/A5.Thisvariantwasalso
associated with ileal involvement (OR: 4.24).
The association between the autophagy 16-like 1
(ATG16L1) rs2241880 on 2q37 and CD, was identified
through a genome-wide association study of 19,779 nonsyn-
onymous SNPs [6]. ATG16L1 encodes a small coiled-coil
protein which interacts with ATG5 and ATG12 to form a
350kDa multimeric complex that plays a crucial role in the
bulk degradation, or autophagy, of cytoplasmic proteins and
organelles. ATG16L1 is expressed in the colon, small bowel,
intestinal epithelial cells, leukocytes, and spleen. Multiple
splice variants have been reported; however, no significant
difference in expression was observed in CD vs. control
tissues. Expression of ATG16L1 was independent of the
rs2241880 genotype [6].
Disease susceptibility appears to be confined to CD
patients carrying the 300Ala allele of rs2241880 SNP
[14–16], but not to UC. The reported risk for the variant
allelecarriagewas1.35–1.45,whileforhomozygouscarriers
itwas1.71–1.77.Resultsareconflictiveabouttheriskallele’s
associationwithCARD15/NOD2.Thecarriageofthe300Ala
variantwasalsoassociatedwiththeriskforCDintheNether-
lands(OR:1.36)[12]andinCaucasianCDpatientsfromNew
Zealand[11].Inaddition,Prescottetal.[16]reportedthatthe
homozygous carriage of the variant allele increased the risk
for ileal disease by 2.2-fold. In the same study, the variant
allele was also associated with a modest but significant risk
for UC (p=0.026). In contrast, no data are available from
Eastern Europe.
In light of the limited data available on the prevalence of
IL23R Arg381Gln and ATG16L1 Thr300Ala variants in East
European countries, our aim was to investigate the presence
of variant alleles of these genes in a large cohort of Hun-
garian IBD patients. We also studied a possible association
between genotype and clinical phenotype, need for surgery,
and response to medical therapy.
2. Patients and methods
2.1. Study population
Four-hundred fifteen unrelated IBD patients (CD: 266,
age: 35.2±12.1 years old, m/f: 130/136, duration: 8.7±7.6
years; UC: 149, age: 44.5±15.4 years old, m/f: 73/76,
duration: 10.7±8.9 years) and 149 healthy subjects (blood
donors) were investigated. The clinical data of the CD and
UC patients are presented in Table 1.
The diagnosis was based on the Lennard-Jones Cri-
teria [17]. Age, age at onset, presence of extraintestinal
manifestations (EIM; arthritis: peripheral and axial; ocu-
lar manifestations: conjunctivitis, uveitis, iridocyclitis;
skin lesions: erythema nodosum, pyoderma gangrenosum;
and hepatic manifestations: primary sclerosing cholangitis
[PSC]), frequency of flare-ups (frequent flare-up: >1 clinical
relapse/year), therapeutic effectiveness (e.g., steroid and/or
immunosuppressiveuse,steroidresistance),needforsurgery
(resections), the presence of familial IBD, and smoking
habits, and in CD, perianal involvement, were investigated
by reviewing the medical charts by the physician and com-
pleting a questionnaire. The disease phenotype (age at onset,
duration, location and behaviour) was determined according
to the Montreal Classification [18]. Response and resistance
to steroids was classified according to the accepted crite-
ria recently published by the European Crohn’s and Colitis
Organisation [19]. Response to infliximab induction therapy
(dose5mg/kgbwatweeks0,2,and6)wasmeasuredatweek
8.WeclassifiedpartialresponseasaCDAIdecreasedby≥70
points and/or ≥50% decrease in the number of draining fis-
tulas, while remission was a CDAI score <150 or closure of
all fistulas.
The control group for mutation analysis consisted of 149
age-andgender-matchedhealthyblooddonors(male/female:
72/77, age: 37.9±10.9 years old). The control subjects

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869
Table 1
Clinical characteristics of patients with inflammatory bowel diseases
CD (n=266)UC (n=149)
Male/female
Age (years)
Age at presentation (years)
Duration (years)
Familial IBDa
130/136
35.2±12.1
26.6±10.4
8.7±7.5
31 (11.7%)
73/76
44.4±15.5
34.1±14.6
10.7±8.9
11 (7.3%)
Location (n) in CD
L1
L2
L3
All L4
L4 only
60
67
133
13
6
-
Maximum extent (n)
In UC proctitis
In UC left-sided
In UC extensive
–8
85
56
Behaviour (n) in CD
B1
B2
B3
Perianal diseasea
Frequent relapse in CD/chronic continuous in UCa
Arthritisa
Steroid use/refractorya
Azathioprine usea
Surgery in CD/colectomy in UCa
94
73
99
97 (36.5%)
118 (44.3%)
108 (40.6%)
192 (72.2%)/36 (18.7%)
184 (69.2%)
115 (43.2%)
–
–
29 (19.5%)
40 (26.8%)
82 (55.0%)/12 (14.6%)
30 (20.1%)
5 (3.3%)
Smoking habits (n)
No
Yes
Previous
156
88
22
114
17
18
an (%).
did not have any gastrointestinal and/or liver diseases and
were selected from consecutive blood donors in Szeged and
Budapest. The study protocol was approved by the Ethi-
cal and Science Committee of the Ministry of Health and
the Semmelweis University Regional and Institutional Com-
mittee of Science and Research Ethics. Each patient was
informed of the nature of the study and signed the informed
consent form.
2.2. Genotyping
2.2.1. DNA isolation
Genomic DNA was isolated from whole blood accord-
ing to the manufacturers’ description with High Pure PCR
Template preparation Kit (Roche, Budaors, Hungary)
2.2.2. Detection of IL23R (rs11209026, R381Q,
c.1227G>A) and ATG16L1 (rs2241880, T300A,
c.1338A>G) polymorphisms
Genotyping was performed using the LightCycler (Roche
Diagnostics) allelic discrimination system. Amplification
primers and hybridisation probes were designed by the
LightCycler Probe Design software (Roche Diagnostics)
or Primer3 primer design software [20]. All oligonu-
cleotides were synthesised by Integrated DNA Technologies
(Coralville, USA).
The following amplification primers and hybridisation
probeswereused:IL23R-R381Q-F:5?-CCCCACCCTTTC
TCCTTTGA-3?,IL23R-R381Q-R:5?-TTTGTAGAGAGT
TTG GCAT GGG TA-3?, IL23R-R381Q-ANC: 5?-/5Bo650-
XN/-CAAAGAAAGAATTGACAACATAACAGCAAA
GAC GA-/3Phos/3?, IL23R-R381Q-SENS: 5?-CCA GTT
CGG AAT GAT CTG TTA AAT ATC CCA-/36-FAM/-3?;
ATG-T300A-F:5?-GCAAGGTCGTCTTGGAGTCCT-3?,
ATG-T300A-R: 5?-TGC CAG GCT CTG TCA CCA TA-3?,
ATG-T300A-ANC:5?-TGTCTCTTCCTTCCCAGTCCC
C/6-FAM/-3?, ATG-T300A-SENS: 5?-/5CY55/-GGA CAA
TGT GGA TAC TCA TCC-/3Phos/-3?.
PCR was performed by rapid cycling in glass capil-
laries in a reaction volume of 10?l with 50ng genomic
DNA, 5?l 2× PCR Master Mix (Promega), supplemented
by 0.7U Taq DNA polymerase (Finnzyme, Espoo, Fin-
land),1.5mMMgCl2,and2.5pmoloftherespectivelabelled
oligonucleotide (sensor and anchor). Asymmetric PCR was
applied in the composition of the unlabelled amplification
oligonucleotides (1.5:5pmol forward:reverse amplification
oligonucleotideratioincaseofATG16L1and5:1.5pmolF:R
ratio in case of IL23R) [21]. Cycling conditions were the fol-

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P.L. Lakatos et al. / Digestive and Liver Disease 40 (2008) 867–873
lowing:initialdenaturationat94◦Cfor2min,followedby70
cyclesofdenaturationat94◦C,annealingat55◦Cfor10sfor
the ATG16L1 and 50◦C for 10s for the IL23R variants, and
extension at 72◦C for 15s, with a ramping rate of 20◦C/s.
After amplification, a melting curve analysis was performed
bycoolingthesamplesto45◦C,followedbygradualheating
to 85◦C with a ramp rate of 0.1◦C/s. The decline of fluo-
rescence was continuously monitored. Melting curves were
converted to melting peaks with wild type and variant alleles
showing distinct melting points. Results were evaluated by
two independent investigators.
3. Statistical methods
Variables were tested for normality using Shapiro Wilk’s
W test. Hardy–Weinberg equilibrium test was performed by
using Pearson’s χ2-test, with one degree of freedom. T-test
with separate variance estimates, χ2-test and χ2-test with
Yates correction were used to evaluate differences between
IBDpatientsandcontrols,aswellaswithinsubgroupsofIBD
patients. Logistic regression was used to compare genetic
and clinical data and results are expressed as odds ratios
(OR) with 95% confidence intervals (95% CI). A p value of
<0.05 was considered as significant. For the statistical anal-
ysis, SPSS13.0 (SPSS Inc., Chicago, IL) was used with the
assistance of a statistician (Dr. Peter Vargha).
4. Results
4.1. Association between IL23R Arg381Gln, ATG16L1
Thr300Ala and disease susceptibility
AllinvestigatedpolymorphismswereinHardy–Weinberg
equilibrium (HWE p=0.38–0.95). The genotype and allele
frequencies of IL23R Arg381Gln and ATG16L1 Thr300Ala
are presented in Table 2. The genotype frequencies of
both IL23R Arg381Gln (p=0.018) ATG16L1 Thr300Ala
Table 3
Association between IL23R Arg381Gln genotypes and disease behaviour in
CD
Behaviour in CD
InflammatoryPenetrating/stenosing
Wild typea
Heterozygousa
85(34%)
7(70%)
169 (66%)
3 (30%)
p=0.037, ORhet: 0.22, 95% CI: 0.06–0.87.
an (%).
(p=0.027) were significantly different between CD patients
and controls. The carriage of the ATG16L1 300Ala/Ala
(p=0.037) genotype or the Ala allele (58.1% vs. controls:
50.0%, OR: 1.39, 95% CI: 1.05–1.85) was associated signif-
icantly with the risk for CD. In addition, the heterozygous
carriage of the IL23R variant (p=0.018) was inversely asso-
ciated with the risk for CD compared to the controls. No
homozygous IL23R carriers were identified.
In contrast, although the tendency was similar, no signifi-
cant associations were found in UC compared to controls or
CD (p=NS). Furthermore, there was no interaction between
ATG16L1 Thr300Ala and IL23R Arg381Gln variant SNPs in
Hungarian patients.
4.2. The role of IL23R Arg381Gln or ATG16L1
Thr300Ala variants in predicting gender, familial
disease, age at onset, disease location, phenotype or
extraintestinal manifestations
Significant results for phenotype–genotype associations
in CD patients are shown in Tables 3 and 4. The carriage of
the variant IL23R 381Gln allele was associated with inflam-
matory disease phenotype in CD (p=0.037, ORhet: 0.22,
95%CI:0.06–0.87).Inaddition,thehomozygouscarriageof
the ATG16L1 300Ala was associated with disease restricted
to the colon (p=0.036, ORAla/AlaAcolonic: 1.83, 95% CI:
1.04–3.25). No other significant associations were found in
either CD or UC patients (data not shown).
Table 2
ATG16L1 Thr300Ala and IL23R Arg381Gln genotypes and allele frequencies in CD, UC, and controls
CD (n=266)UC (n=149)Controls (n=149)
IL23R Arg381Gln
381Gln/Arg
OR381Glncarriervs. controls (95% CI)
MAF
OR vs. controls
10 (3.8%)
0.38 (0.16–0.87)
10 (1.87%)
0.39, 95% CI: 0.17–0.89
8 (5.4%)
0.55 (0.22–1.34)
8 (2.68%)
0.56, 95% CI: 0.23–1.35
14 (9.4%)
14 (4.69%)
ATG16L1 Thr300Ala
300Thr/Thr
300Thr/Ala
300Ala/Ala
ORAla/Alavs.Thr/Thr
ORAla/Ala+Ala/Thrvs.Thr/Thr
MAF
OR vs. controls
49 (18.4%)
125 (47.0%)
92 (34.6%)
1.86, 95% CI: 1.04–3.40
1.26, 95% CI: 0.77–2.10
309 (58.1%)
1.39, 95% CI: 1.05–1.85
32 (21.5%)
72 (48.3%)
45 (30.2%)
1.41, 95% CI: 0.73–2.73
1.04, 95% CI: 0.60–1.81
166 (52.7%)
1.26, 95% CI: 0.91–1.74
33 (22.1%)
83 (55.8%)
33 (22.1%)
149 (50.0%)
MAF=minor allele frequency (IL23 381 Gln or ATG16L1 300 Ala).

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871
Table 4
Association between ATG16L1 Thr300Ala genotypes and disease location
in CD
Location in CD
Ileal-involvementColon-only disease
300Ala/Ala homozygousa
300Thr carriera
60(66.7%)
132(78.9%)
30(33.3%)
36(21.1%)
p=0.036, ORAla/Alacolonic: 1.83, 95% CI: 1.04–3.25.
an (%)
4.3. Association between IL23R Arg381Gln, ATG16L1
Thr300Ala and response to medical therapy or need for
surgery
We also investigated the association between the IL23R
Arg381GlnorATG16L1Thr300Alavariantsandtheresponse
to steroids, infliximab or need for surgery in patients with
CD. Forty-seven unrelated CD patients (m/f: 24/23, age:
33.2±11.6 years old, duration: 7.6±4.7 years) received
infliximab therapy: disease location was ileal in two, colonic
in 19, and ileocolonic in 25 patients. In addition, three
patients had upper GI involvement. Disease behaviour was
inflammatory in 17 and penetrating in 30 patients. Perianal
complicationswereobservedin27(57.4%)patients.Steroids
(93.6%) and azathioprine (93.6%) were prescribed to almost
all patients. Overall, there was a tendency for ATG16L1 to be
associated with short-term response to infliximab induction
therapy (see Table 5), but not to steroid resistance or need
for surgery (data not shown). In addition, no association was
found for IL23R Arg381Gln. The re-operation rate was also
not different (data not shown).
In UC, no association was found between either of the
variants and steroid use/resistance, azathioprine use or need
for surgery (data not shown).
5. Discussion
This is the first report on the prevalence of the ATG16L1
Thr300AlaandIL23RArg381Glnpolymorphismsinpatients
with IBD from an East European country. The variant
ATG16L1 allele did appear to confer risk, in contrast to the
IL23R protection, in Hungarian CD patients. In addition, the
IL23Rvariantwasassociatedwithdiseasephenotypeandthe
ATG16L1 with disease location in CD. In contrast, no signif-
icant associations were reported in UC. However, the study
was underpowered to detect such an association.
The genotype and allele frequencies for IL23R 381Gln
in CD, UC, and controls reported in the present study
were in line with most previous reports in Caucasian pop-
ulations [5,8–11]. The rare 381Gln allele was present in
approximately 3% of the IBD patients, in contrast to 6.0%
of the controls in these studies. However, in the present
study, we could not replicate the protective effect of the
variant allele observed for UC. Although there was a ten-
dency for UC patients to carry a lower frequency of variant
IL23R alleles, the difference did not reach significance.
Genotype–phenotype associations were extensively investi-
gated by a German study [13]. The rs1004819 variant was
associated with ileal involvement (OR: 4.24, p=0.004) and
stenosingdisease(OR:1.99,p=0.045)inthe452CDpatients
for whom a detailed disease phenotype was available. In
contrast, similarly to the present study, the R381Q variant
was not associated with age at onset, disease location, pres-
ence of EIMs, perianal disease or immunosuppressive use
as well as no epistatic interaction was found with either
NOD2/CARD15 or SLC22A4/A5. Interestingly, the presence
of the variant allele was associated with a trend towards a
lower need for surgical interventions (OR: 0.39, p=0.067),
although the type of surgical intervention or the cause for
surgery could not be identified. In the present study, car-
riage of the variant allele was associated with inflammatory
disease phenotype, despite similar disease duration (mean
disease duration in wild type: 8.7 years vs. 8.4 years for vari-
ant allele carriers). Nonetheless, the association could not
be corrected for further possible confounding variables due
to the low number of patients with the variant genotype. In
contrast, in the study by Tremelling et al. [8], though the
authors were able to replicate the protective effect of the
rare IL23R variant in CD (OR: 0.38) and UC (OR: 0.73),
no genotype–phenotype association was found in the 1902
CD patients based on age at onset, gender, disease loca-
tion,behaviour,surgery,perianaldisease,andsmokingstatus.
The presence of EIMs was not studied. Similarly, the IL23R
381Q variant was not associated with disease extent in UC
(n=975).
The R381, is the fifth amino acid, located in the cytoplas-
mic domain, internal to the transmembrane domain, and is
highly conserved between species. In previous animal stud-
ies, IL23 was shown to be important in the development
Table 5
Association between ATG16L1 T300A and response to infliximab induction therapy at week 8
All (n=266)ATG16L1 300AA (n=92)ATG16L1 300TT/TA (n=174)
Response to infliximab
No effect
Partial
Remission
61*
5*
24
17
12 12
143
n (%).
*p=0.06 between ATG16L1 300AA vs. other genotypes.