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IL23R polymorphisms influence phenotype and response to therapy in patients with ulcerative colitis

Cravo, Marília L.; Ferreira, Paula A.; Sousa, Patricia; Moura-Santos, Paula; Velho, Sónia; Tavares, Lurdes; de Deus, João R.; Ministro, Paula; Peixe, Paula; Correia, Luis A.; Velosa, José F.; Maio, Rui F.; Brito, Miguel

European Journal of Gastroenterology & Hepatology: January 2014 - Volume 26 - Issue 1 - p 26–32
doi: 10.1097/MEG.0000000000000004
Original Articles: Inflammatory Bowel Disease

Objective We aimed to identify the clinical and genetic [IL23 receptor (IL23R) single nucleotide polymorphisms (SNPs)] predictors of response to therapy in patients with ulcerative colitis.

Patients and methods A total of 174 patients with ulcerative colitis, 99 women and 75 men, were included. The mean age of the patients was 47±15 years and the mean disease duration was 11±9 years. The number of patients classified as responders (R) or nonresponders (NR) to several therapies was as follows: 110 R and 53 NR to mesalazine (5-ASA), 28 R and 20 NR to azathioprine (AZT), 18 R and 7 NR to infliximab. Clinical and demographic variables were recorded. A total of four SNPs were studied: IL23R G1142A, C2370A, G43045A, and G9T. Genotyping was performed by real-time PCR using Taqman probes.

Results Older patients were more prone to respond to 5-ASA (P=0.004), whereas those with pancolitis were less likely to respond to such therapies (P=0.002). Patients with extraintestinal manifestations (EIMs) were less likely to respond to 5-ASA (P=0.001), AZT (P=0.03), and corticosteroids (P=0.06). Carriers of the mutant allele for IL23R SNPs had a significantly higher probability of developing EIMs (P<0.05), a higher probability of being refractory to 5-ASA (P<0.03), but a higher likelihood of responding to AZT (P=0.05). A significant synergism was observed between IL23R C2370A and EIMs with respect to nonresponse to 5-ASA (P=0.03).

Conclusion Besides extent of disease and age at disease onset, the presence of EIMs may be a marker of refractoriness to 5-ASA, corticosteroids, and AZT. IL23R SNPs are associated both with EIMs and with nonresponse to 5-ASA and corticosteroids.

aGastroenterology Service

bDietetics Service, Beatriz Angelo Hospital, Loures

cFaculty of Medicine, Lisbon University

dDepartment of Natural Sciences, School of Health Technologies

eGastroenterology Service, Santa Maria Hospital

fGastroenterology Service, Egas Moniz Hospital, Lisbon

gGastroenterology Service, Fernando da Fonseca Hospital, Amadora

hGastroenterology Service, S. Teotónio Hospital, Viseu, Portuga

Correspondence to Marília L. Cravo, MD, PhD, Gastroenterology Service, Beatriz Angelo Hospital, Avenue Carlos Teixeira #3, Loures 2774-514, Portugal Tel: +351 919439192; fax: +351219847209; e-mail: marilia.cravo@sapo.pt

Received July 24, 2013

Accepted September 12, 2013

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Introduction

The majority of patients with ulcerative colitis (UC) respond to therapy with mesalamine either orally and/or topically. For nonresponders, either immunosuppressants (IS) and/or anti-TNF agents are recommended, although the responses to these agents are less well documented than in patients with Crohn’s disease (CD) 1. Previous studies have been carried out aiming at identifying patients with a poor prognosis in whom aggressive therapies could be started earlier. Most of these studies focused on clinical, endoscopic, or histologic parameters. Extensive colitis, severe disease activity, younger age, and female sex have been associated with poor outcome in most population-based studies 2–5. The presence of basal plasmacytosis and a Geboes score of at least 3.1 were associated recently with a greater chance of disease relapse 6.

A different issue from predicting patients with a poor prognosis is to predict response to therapy. Although patients with poor clinical prognostic indicators are usually those proposed to start more aggressive therapies, to prevent complications, this does not necessarily relate with response to therapy.

Most studies have focused on predictors of response to infliximab 7–9. As most patients are initially treated with mesalazine (5-ASA) compounds and respond to such therapies, we believe that it would be clinically more useful to have early indicators of nonresponse to these compounds. In these patients, a more aggressive therapeutic strategy could be started early on. This is even more relevant as recent papers propose that UC should also be considered as a progressive disease, where structural damage of the intestinal wall may ensue, thereby stressing the need for early effective therapy to prevent it 10–13.

Besides clinical factors, serological and genetic predictors have also been studied in UC, although far less than in CD 13,14. The IL23 receptor (IL23R) gene has been identified as a susceptibility gene both for CD and for UC 14–16. The IL23R gene is mapped to chromosome 1p32.1-p31.2, and the protein encoded by this gene is a subunit of the receptor for IL23A/IL23. IL23 is produced by bacteria-stimulated antigen-presenting cells in response to microbial stimulation and has been shown to promote expansion of CD4+ T helper 17 cells 15,16 and to induce the production of Th17-type cytokines by non-T cells/innate cells. Th17 cytokines are now considered crucial factors for enhancing the effector phase of T-cell responses that cause tissue inflammation and damage in the gut. In several models of colitis, it has been shown that IL23 is the major driver of intestinal inflammation 17,18. Furthermore, genome-wide association studies of large cohorts of patients with inflammatory bowel disease (IBD) and healthy controls subsequently identified several single nucleotide polymorphisms (SNPs) in the IL23R gene locus associated with either susceptibility or resistance to IBD 15,19. So far, few studies have explored an association between IL23R SNPs and phenotype and/or response to therapy in patients with UC. Previous authors 7,9 reported that ANCA seronegativity and the IL23R genotype were predictors of early response to infliximab. Jurgens et al. 7 found that carriers of IBD risk-increasing IL23R variants were more likely to respond to infliximab as compared with those homozygous for IBD risk-decreasing IL-23R variants. Besides predicting response to infliximab, the value of these SNPs in predicting response to 5-ASA compounds and/or azathioprine has not been studied so far.

The aim of the present study was to identify clinical and specific IL23R SNPs as predictors of response to therapy in patients with UC.

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Patients and methods

This was a multicenter study with participating hospitals from central Portugal. Informed consent was obtained from all patients entering the study, which was approved by the scientific and ethical committees of the several participating hospitals.

Phenotypic characteristics retrospectively collected from charts included demographic data, age at disease onset, disease extent, time of follow-up, smoking habits, presence of extraintestinal manifestations (EIMs), and previous therapies. All phenotypic data were collected in a blinded manner to the results of the genotypic data. Patients were selected to enter the study if a definitive classification in terms of response to a specific drug could be obtained clearly after reviewing the chart and interviewing the patient at the time of entering the study. Patients were considered responders if they presented a long-term sustained remission, defined as a stool frequency of 3 or less with no bleeding and no urgency, lasting at least 1 year after a specific therapy was started, not needing steroids, surgery, or escalation of therapy. Patients requiring the addition or switching to other therapies, corticosteroids, or surgery before 1 year were considered nonresponders. If a clear distinction between these two scenarios was not possible for a specific drug, the patient was not considered, at least for this drug.

The decision to switch therapy was made by the treating physician. Remission was recorded after a new therapy was started, until the drug was discontinued, or until the end of follow-up. Biologic parameters such as CRP levels or endoscopic response were not used to classify patients as responders or nonresponders. For mesalamine, patients received for induction therapy 4.8 g/day or equivalent together with topic therapy (enemas and/or suppositories) as needed to control rectal bleeding. Once remission was achieved, the maintenance dosage was decreased to 2.4 g/day according to ECCO recommendations 1. If they relapsed, patients were treated in the same way. Therapy optimization was not considered nonresponse. Steroids were started if remission was not obtained after 4–6 weeks of therapy with mesalamine or if disease activity was considered severe. Only short-term response (1 month) was considered. Steroid dependence was defined as recurrent flare-up on withdrawal of glucocorticoids or the need for glucocorticoid treatment twice within 6 months. Patients were considered refractory to steroids when no remission was obtained with a dose of 1 mg/kg during a period of at least 4 weeks. Steroid dependency or nonresponse to mesalamine was considered an indication to escalate therapy to 6-mercaptopurine (1 mg/kg/day) or azathioprine (2.0–2.5 mg/kg/day). Nonresponse to purine analogues after 10–12 weeks was considered an indication to infliximab. None of the patients included in the present study received adalimumab.

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DNA extraction and genotyping

Blood samples were taken from all the study participants and genomic DNA was isolated from peripheral blood using the DNA blood mini kit from Qiagen (Hilden, Germany) according to the manufacturer’s guidelines. A total of four SNPs were studied: IL23R G1142A (rs11209026), C2370A (rs10889677), G43045A (rs 1004819), and G9T (rs1884444). These SNPs were chosen because previous studies had found either an association with increased or decreased susceptibility and/or response to infliximab 7,18. All genotypes were determined using real-time PCR methods with TaqMan Pre-Designed SNP Genotyping Assays (Applied Biosystems, Grand Island, New York, USA). For the genotype analysis, the target fragments were amplified in a 20 µl reaction mixture containing 10 µl TaqMan Universal PCR Master Mix, 1 µl primers, 5 µl MilliQ water, and 4 µl DNA. Real-time PCR using an iCycler IQ Multicolor Real-Time PCR Detection System (Bio-Rad, Hercules, California, USA), was carried out as follows: 10 min of the initial step at 95°C, 50 cycles of 15 s, and 1 min at 92°C and 60°C, respectively.

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Statistical analysis

Statistical analysis was carried out using SPSS (version 14.0; SPSS Inc, Chicago, Illinois, USA) and SNPassoc 1.6 package in R software (Center for Genomic Regulation, Unit of Biostatistics and Bioinformatics Epidemiology Service, Bellvitge Biomedical Research Institute, Catalan Institute of Oncology, Barcelona, Spain). Data were expressed as mean±SD, number of participants and percentage, or as odds ratio (OR) and 95% confidence interval (CI). Primary analyses were carried out using the χ 2-test and univariate analysis. The association between outcome and SNPs was analyzed using the SNPassoc library (Center for Genomic Regulation, Unit of Biostatistics and Bioinformatics Epidemiology Service, Bellvitge Biomedical Research Institute, Catalan Institute of Oncology). Different inheritance models (dominant, recessive, log-add, and overdominant) were considered and were presented as eligible. Haplotype analysis was carried out for the four IL23R SNPs. Statistical significance was established for P less than 0.05. Differences in genotypic and allelic frequencies and Hardy–Weinberg tests were performed using GENEPOP Web version 4.0.10 program (Michel Raymond and Francois Rousset at Laboratiore de Genetique et Environment, Montpellier, France). To obtain the exact P value of Hardy–Weinberg equilibrium, the Markov chain method 20 with a dememorization number of 1000, 100 batches, and 1000 iterations per batch was used. The P value returned by this method is calculated as the sum of the probabilities of all tables and its SE. Genotypic frequencies are under Hardy–Weinberg equilibrium when the P value is more than 0.001.

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Results

A total of 174 patients entered the study; the median follow-up was 3.9 years. The clinical characteristics and percentages of responders to several therapies are shown in Table 1. Allelic and genotypic frequencies for all the studied SNPs are shown in Table 2. The genotypic frequencies of all SNPs did not deviate significantly from those expected under Hardy–Weinberg equilibrium (P>0.001).

Table 1

Table 1

Table 2

Table 2

The association between clinical variables and response to several drugs was analyzed; only a significant or near-significant associations are shown in Table 3.

Table 3

Table 3

We observed that older patients and those diagnosed after the age of 40 responded better to 5-ASA compounds. In contrast, duration of disease for more than 5 years was a negative predictor of response both for 5-ASA and for azathioprine, although the latter did not reach statistical significance (P=0.008 and 0.07, respectively). Disease extent negatively influenced response to 5-ASA and azathioprine, with patients with pancolitis showing poorer responses (Table 3). With respect to EIMs, we observed that it was a negative predictor of response to 5-ASA, corticosteroids, and azathioprine (P=0.001, 0.06, and 0.02, respectively) but it seemed to positively influence response to biologics, although not significantly (OR 8.0, 95% CI 0.72–88.22; P=0.09).

Interestingly, previous therapies also seemed to influence response to several drugs. Thus, previous users of corticosteroids, azathioprine, and/or biologics responded better to 5-ASA. The same was observed for corticosteroids and azathioprine, suggesting that the use of IS or biologics may allow recapture of patients to respond to therapies to which they were previously nonresponsive.

Table 4 shows the associations between IL23R SNPs and clinical characteristics including response to therapy. We observed that carriers of IL23R C2370A and IL23R_G4305A alleles were at an increased risk of showing EIMs (Table 4). No significant association was observed with disease extension or other phenotypic characteristics. With respect to response to therapy, we observed that IL23R_C2370A negatively influenced response to 5-ASA and corticosteroids, whereas homozygous carriers for IL23R_G9T were more likely to respond to azathioprine.

Table 4

Table 4

We also examined whether there was any interaction between clinical and genetic predictors of response. We observed that IL23R_C2370A CA carriers with EIMs had a significantly lower chance of responding to 5-ASA compounds (OR 0.12, 95% CI 0.018–0.86; P=0.03).

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Discussion

Compared with CD, the individual natural history of patients with UC is harder to predict than in CD 21,22 and the relevance of clinical predictors has not been validated in independent cohorts 13. Recent papers strongly suggest that UC, as CD, should be considered as progressive diseases resulting in cumulative bowel damage, thereby affecting bowel function and the patient’s quality of life 10–12.

As most patients with UC respond to 5-ASA-based therapies, clinicians should focus on early identification of nonresponders to these therapies as these should be started on more aggressive and effective therapies as early as possible. Most series published so far identified young age, female sex, and extensive colitis as poor prognostic markers, theoretically but not necessarily, with less probability of responding to therapy with 5-ASA only 2–4. Serologic and genetic predictors have been far less explored in UC than in CD and only a few clinical settings have been investigated 13. In a recent study carried out in 94 children with IBD, the authors identified pANCA positivity and a diagnosis of UC as predictors for a primary nonresponse to infliximab 7. Genetic markers are more attractive as they are already present at the onset of the disease and remain stable over time, which is not the case for clinical and serologic parameters. In the present study, we focused on IL23R SNPs because there is accumulating evidence that IL23 cytokine is essential to drive the chronic intestinal inflammation observed in IBD, namely UC. IL23 is produced by activated dendritic cells and macrophages present in the gut mucosa in response to microbial stimulation 17. Although initially found to support the expansion and maintenance of CD4+ T helper 17 cells, IL23 is now recognized as having multiple effects on the immune response, including restraining Foxp3+ regulatory T-cell activity and inducing the expression of Th17-type cytokines from non-T-cell sources 17. Certainly related to this diversity and multiplicity of upstream and downstream effects, certain of these SNPs confer a protective effect against developing IBD 19, whereas others increase the susceptibility to develop IBD 7,15. Furthermore, there are significant ethnic differences, with some variants increasing the risk of developing IBD in Whites but not in Asian individuals 18. These apparent discrepancies may be explained by the fact that IL23R contributes to colitis pathogenesis through various pathways that may be tackled in a number of different ways, thereby resulting in various types of responses. The exact mechanism by which the studied polymorphisms exert their effect on disease pathogenesis and on metabolism and mechanism of action of drugs is still not known. When we consider SNPs affecting coding regions, such as the IL23R G1142A or G9T polymorphisms, we can hypothesize changes in protein structure, namely an effect on the helical structure of the protein product 23 and consequently modifications in receptor affinity. In what concerns the SNP IL23R C2370A, located in the 3′ untranslated region, the latter may be associated with RNA stability or even translation efficiency, which in turn lead to changes in protein expression. Finally, the IL23R G43045A with intronic localization could be associated with RNA splicing or control of transcription, and indirectly affect RNA stability or gene expression. However, we cannot exclude that these polymorphisms could be in linkage with other variants in genes located nearby, responsible for UC pathogenesis and/or disease phenotype. Finally, the reason why certain of these variants are associated with different responses to therapy is probably through the modulation of the phenotype that they produce as opposed to a direct interference with drug metabolism.

In the present study, besides clinical and genetic predictors of response to infliximab, we also focused on predictors of nonresponse to other therapies including 5-ASA and azathioprine, which is certainly useful in clinical practice, as only a minority of patients will need escalation to biologics. We also decided to use long-term, more than 1-year, response, because we believe that this concept is clinically more relevant. Thus, a patient who responded to 5-ASA, but before 1 year relapsed with the need for corticosteroids or escalation of therapy, was considered a nonresponder to 5-ASA. Early institution of IS and/or biologic therapy in these patients could be a way of maintaining the patient in remission and avoiding the complications of undertreated disease.

In the present study, we examined whether clinical and/or IL23R SNPs, alone or in combination, could be used as predictors of response to several drugs used in the treatment of UC. Similar to previous series, over 60% of patients responded to 5-ASA compounds. We had estimated that at least 40% of patients would be refractory to 5-ASA and would require azathioprine and/or biologics. As a step-up approach was followed in all instances of patients not responding to 5-ASA, most of these patients were started on azathioprine, 58% of whom responded to this therapy. Thus, only 25 of 174 patients ultimately required biologics, which may preclude some statistical significance.

Consistent with previous studies 2–5,24,25, we observed that older patients responded better to 5-ASA, whereas no influence was observed in terms of probability of response to azathioprine or biologics. Duration of disease for more than 5 years was associated with a lower probability of response both for 5-ASA and for azathioprine. In agreement with previous studies, disease extent 2–5,24,25 was also a negative predictive factor for responding to 5-ASA and azathioprine but not to steroids or biologics. EIMs were strongly associated with poor response to 5-ASA, steroids, and azathioprine, whereas a nonsignificant but positive association was observed in terms of biologics. To our knowledge, this has not been clearly reported before. EIMs are among the clinical risk factors that may be associated with disease extent and severity 26, and a recent review on this topic 27 suggests that early aggressive therapy may be required for treating several EIMs to prevent chronic damage. According to our results, together with young age of disease onset and greater disease extent, the presence of EIMs may predict nonresponse to 5-ASA and need for aggressive therapy.

A very interesting association was also observed with previous therapies. Thus, previous users of steroids, azathioprine, or biologics were more likely to respond to 5-ASA. This recapture phenomenon is frequently observed in clinical practice. Similarly, previous users of azathioprine and biologics had a greater chance of responding to corticosteroids and that of biologics with a greater likelihood of responding to azathioprine. These observations suggest that patients who did not respond to 5-ASA and required escalation of therapy, after remission was achieved, may be maintained on 5-ASA.

With respect to IL23R SNPs, these have been described as susceptibility genes but to our knowledge there are no previous reports on whether these SNPs influence phenotypic manifestations in UC patients. A recent study by a German group suggests that homozygous carriers of IL23R variants that increase the risk of developing IBD are more likely to respond to infliximab 7. In the present study, we found that IL23R SNPs were associated with a significantly increased risk of developing EIMs, with a lower chance of responding to 5-ASA and corticosteroids but with a higher chance of responding to azathioprine. No association was found between these SNPs and response to infliximab, which may be related to the low number of patients treated with this drug. We also found a significant interaction between the IL23R_C2370A allele and the presence of EIM in predicting nonresponse to 5-ASA. This is consistent with these two factors, alone or in combination, being early indicators of need for azathioprine and/or infliximab therapy in agreement with a previous study published by Jurgens et al. 7. According to our data, older patients, with limited disease, not showing EIMs and not carrying IL23R variants are more prone to respond to 5-ASA compounds. The effect of IL23R variant alleles may be independent or because of the fact that they are more often associated with EIM, which is also a negative predictor for responding to 5-ASA compounds.

This study had some limitations that need to be addressed. A major drawback is the fact that response to drugs was evaluated retrospectively from data recorded in the charts. The decision to change a drug was made according to the treating physician, which might not be uniform across the several centers involved in the study. Nonetheless, the numbers obtained for response to several drugs are close to the ones reported in the literature, thereby suggesting similar policies of treatment. In our opinion, evaluating the response to a specific drug after the long-term evolution and whether the patient required therapy escalation after a transitory response that lasted less than 1 year is clinically more relevant than evaluating short-term responses. Another drawback of this study was that disease activity was not recorded on admission and it is plausible that this influenced therapeutic decisions. However, our main purpose was to identify early predictors of response and not prognosis and a conventional step-up approach was followed in the large majority of patients. Finally, it would be interesting to have a better characterization of the type of EIMs to determine whether they all had the same prognostic value.

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Conclusion

In the present study, we could identify a number of clinical variables that could predict nonresponse to 5-ASA compounds, namely, the existence of EIMs. The latter were significantly more frequent in IL23R SNPs carriers, which was also associated with poor response to 5-ASA but to a higher probability of responding to azathioprine. These findings might be valuable in clinical practice, although further confirmation is still needed.

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Acknowledgements

This work was funded by a grant from GEDII 2009-2012.

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Conflicts of interest

There are no conflicts of interest.

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Keywords:

extraintestinal manifestations; IL23R single nucleotide polymorphisms; predictors of response to therapy; ulcerative colitis

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