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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Gut. Author manuscript; available in PMC Jun 1, 2010.
Published in final edited form as:
PMCID: PMC2757103
NIHMSID: NIHMS131712

Genetic Variants in the Region Harbouring IL2/IL21 Associated to Ulcerative Colitis

Abstract

Objectives

Genetic susceptibility is known to play a large part in the predisposition to the inflammatory bowel diseases (IBD) known as Crohn’s disease (CD) and ulcerative colitis (UC). The IL2/IL21 locus on 4q27 is known to be a common risk locus for inflammatory disease (shown in celiac disease, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus and psoriasis), while the roles that IL2 and IL21 play in the immune response also make them attractive candidates for inflammatory bowel disease. Our objective was to test for association between the IL2/IL21 locus and the inflammatory bowel diseases.

Methods

The four single nucleotide polymorphisms (SNPs) in the IL2/IL21 locus most associated to celiac disease were genotyped in 1590 IBD cases and 929 controls from the Netherlands, and then replicated in a North American cohort (2387 cases and 1266 controls) and an Italian cohort (805 cases and 421 controls), yielding a total of 4782 cases (3194 UC, 1588 CD) and 2616 controls. Allelic association testing and a pooled analysis using a Cochran-Mantel-Haenszel test were performed.

Results

All four SNPs were strongly associated with UC in all three cohorts and reached genome-wide significance in the pooled analysis (rs13151961 p= 1.35×10−10, rs13119723 p= 8.60×10−8, rs6840978 p= 3.07×10−8, rs6822844 p= 2.77×10−9). We also found a moderate association with CD in the pooled analysis (p value range 0.0016–9.86×10−5).

Conclusions

We found a strong association for the IL2/IL21 locus with UC, which also confirms it as a general susceptibility locus for inflammatory disease.

Keywords: Inflammatory bowel disease, ulcerative colitis, Crohn’s disease, IL2, IL21

Introduction

Inflammatory bowel diseases (IBD) are the most common chronic inflammatory diseases in the Western world after rheumatoid arthritis, with an incidence of about 40 per 100,000 in North America and Western Europe.[1] Ulcerative colitis (UC) and Crohn’s disease (CD) are the two main types of IBD, both characterized by recurring inflammation of the digestive tract. In CD the inflammation can occur throughout the gastrointestinal tract, most commonly affecting the terminal part of the small intestine and causing weight loss and abdominal pain. In UC the disease is confined to the colon and patients usually present with bloody diarrhoea and abdominal cramping.[2]

Genetic susceptibility plays an important role in the pathogenesis of IBD. CD and UC are complex diseases with numerous genetic and environmental factors leading to disease. Epidemiological studies suggest stronger heritability in CD as compared to UC.[1] Many genetic factors contributing to CD pathogenesis have been identified during the last decade. There are currently more than 30 genes or loci associated with CD, the majority having been identified since the introduction of genome-wide association studies.[3] Far fewer have been found for UC. Recently the first genome-wide association study in UC was published identifying several new loci and another genome-wide association study will be published shortly.[4, 5]

Genetic studies have also shown that susceptibility genes are commonly shared between inflammatory diseases. For example, the IL2/IL21locus on chromosome 4q27 has been shown to be associated with celiac disease, type 1 diabetes (T1D), Grave’s disease (GD), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and psoriasis (PS).[611] Interestingly, there appears to be at least two independent association signals in this region, one conferring increased risk to disease, while the other a protective effect.[8, 11]

There are several reasons why the IL2/IL21 locus could also represent an interesting locus for IBD. Firstly, a number of shared autoimmune and inflammatory genes show an association to IBD: IL12B, for example, is associated to psoriasis,[10] systemic lupus erythematosus,[12] asthma[13] and both forms of IBD[14], while IL18RAP was found to be associated with both celiac disease[15] and IBD.[16] IL2/IL21 is another shared inflammatory locus, and both IL2 and IL21 are attractive functional candidate genes for association to IBD. An overexpression of IL21 in inflamed regions of bowel of IBD patients has been reported.[17] This overexpression is most marked in CD, but a significant overexpression compared to that in diverticular disease and healthy controls is also present in UC.[17] Finally, Il2−/−mice develop inflammatory bowel disease most reminiscent of UC.[18]

Given all these observations, and that IBD and celiac disease are chronic inflammatory diseases of the gut, we were specifically interested in testing whether the IL2/IL21 region variants identified in the celiac GWA studies also have a role to play in IBD. This was achieved via a case-control association study with a three-stage design in a large cohort of IBD patients. In addition, we performed genotype-phenotype analysis to identify association with specific subsets of IBD. Our data unequivocally show that the IL2/IL21 locus is strongly associated to UC. We confirmed this finding in multiple IBD populations.

Methods

Subjects

For the first phase, the cases consisted of a cohort of 1590 IBD patients (777 CD and 813 UC) collected from the outpatient clinics of the Departments of Gastroenterology and Hepatology at the Amsterdam Medical Center (n = 732), the Radboud University Medical Centre, Nijmegen (n = 273), and the University Medical Center Groningen, the Netherlands (n = 585).[19] The control cohort consisted of 929 healthy Dutch individuals collected from blood donors.[6]

To replicate the findings from the first phase two independent cohorts were examined. The first replication cohort consists of an IBD case – control cohort (2387 cases of which 654 CD and 1733 UC, and 1266 controls) collected through the North American NIDDK IBD Genetics Consortium (IBDGC) as described previously.[20, 21] Cases and geographically matched controls were ascertained through the University of Montreal, Cedars-Sinai Medical Center, Johns Hopkins University, University of Chicago, University of Pittsburgh, and the University of Toronto Genetics Research Centers (GRCs). This NIDDK-IBDGC IBD cohort contained five related pairs of cases between UC and CD samples. All cases were included in the subphenotype analysis, but in the IBD analysis one member of each pair (five cases) was removed. The second replication cohort consists of an Italian IBD case – control cohort (805 cases of which 157 CD and 648 UC, and 421 controls) collected at the S. Giovanni Rotondo “CSS ” (SGRC) Hospital in Italy. This cohort has previously been used and characterized in several association reports from our group. [22, 23] A f0ourth cohort consisting of 398 cases and 418 controls from the US of Jewish descent was also included; this cohort was also collected by the NIDDKIBDGC and has previously been characterized.[20, 21]

All patients and controls were of European Caucasian descent. The diagnosis of IBD required (a) one or more symptoms of diarrhoea, rectal bleeding, abdominal pain, fever, or complicated perianal disease, (b) occurrence of symptoms on two or more occasions separated by at least 8 weeks or ongoing symptoms of at least 6 weeks duration, and (c) objective evidence of inflammation from radiologic, endoscopic, and histopathologic evaluation. All affected subjects fulfil clinical criteria for IBD. For CD patients, phenotypic details were registered according to the Vienna classification. However, perianal disease was scored as an independent variable and not included in the group with penetrating disease behaviour. For UC patients, phenotypes were described according to age of onset, maximum extent of disease (proctitis, left-sided, or extensive), necessity of colectomy, and the occurrence of malignancy and extraintestinal manifestations. A summary of the phenotype information available for each cohort can be found in supplementary table 1 (CD) and supplementary table 2 (UC).

In all cases, informed consent was obtained using protocols approved by the local institutional review board in all participating institutions. All DNA samples and data in this study were denominalized.

Genotyping

We analyzed the four most strongly associated SNPs in IL2/IL21 found by Van Heel et al.: rs6822844, rs13151961, rs13119723 and rs6840978.[6] Genotyping of the Dutch cohort was performed using TaqMan technology, while SNP genotyping assays for PCR were supplied by Applied Biosystems, as described.[6] The patient and control DNA samples were processed in 384-well plates and each plate also contained 16 genotyping controls (4 duplicates of 4 CEU DNA).

Genotyping of 1577 samples from the North American IBD cohort was performed using primer extension chemistry and mass spectrometric analysis (iPlex assay, Sequenom, San Diego, CA) on the Sequenom MassArray. This was performed at the Laboratory for Genetics and Genomic Medicine of Inflammation (www.inflammgen.org) of the Université de Montréal and at The University of Pittsburgh. Data from an additional set of 2917 North American IBD samples was also obtained from genotyping on Illumina HumanHap300 or HumanHap550 Genotyping BeadChips (Illumina, Inc., San Diego, CA,) as was previously reported in the IBDGC’s CD and UC GWAS studies.[5, 21]

Genotyping for the Italian cohort was also performed at the Laboratory for Genetics and Genomic Medicine of Inflammation, using primer extension chemistry and mass spectrometric analysis on the Sequenom MassArray. The patient and control DNA samples were again processed in 384-well plates and each plate also contained 16 genotyping controls 4 duplicates of 4 CEU DNA). All SNPs were validated and we obtained > 99.9% concordance between our genotype data and the CEU data available from HapMap.

Statistical analysis

Hardy-Weinberg equilibrium was tested by comparing the expected and observed genotypes in a 2 ×3 chi-squared (χ2) table. Controls did not show deviation from HWE (P value (HWE) >0.001). Differences in allele and genotype distribution in the cases and controls of the individual cohorts were tested for significance by the χ2 test. Analysis for association between genotype and subphenotypes were also performed with the χ2 test. A significant threshold for P values was determined at P <0.05. Odds ratios (ORs) were calculated and the confidence intervals (CIs) were approximated using Woolf’s method with Haldane’s correction. Power calculations were performed using the online Genetic Power Calculator by Shaun Purcell (http://pngu.mgh.harvard.edu/~purcell/gpc/).[24] Combined analysis of the different cohorts was performed by Cochran-Mantel-Haenszel meta-analysis.

Results

Initially the rs13151961, rs13119723, rs6840978 and rs6822844 SNPs were tested in 1590 Dutch patients (777 CD patients and 813 UC patients) and 929 healthy controls. The minor alleles of all four SNPs tested were associated with IBD with a P value range between 0.00093 and 0.00039 and an OR between 0.76 and 0.78. This association was even stronger in the UC subgroup of the cohort (P value range 0.00038 – 0.00001 and OR range 0.71 – 0.67). In the CD subgroup, the rs13119723 SNP was borderline significant with a P value of 0.0327, while only a trend towards association was observed for the other SNPs. This indicated that the association of the IL2/IL21 locus with IBD was coming predominantly from the UC subgroup. The results are shown in table 1

Table 1
Summary of the association results in our screening (Dutch) and replication (North American and Italian) cohorts, as well as the combined results following the Cochran-Mantel-Haenszel meta-analysis.

To replicate these findings we studied two independent cohorts. In the North American cohort (2387 IBD cases (654 CD and 1733 UC) and 1266 controls) we observed association with the same alleles of all SNPs in IBD (P value range 0.0011 – 0.0003 and OR range 0.77 – 0.81). As in the original cohort, this effect was strongest in the UC subgroup of the cohort (P value range 0.0046–0.0004 and OR range 0.77 – 0.81). In the CD subgroup of the North American cohort a moderate association with the same alleles was also observed (P value range 0.0123–0.0011). Testing of all four SNPs in the Italian cohort (805 IBD cases 157 CD, 648 UC) and 421 controls) showed the same strong association of the minor alleles in UC as seen in the original cohort, with a P value range between 0.0123 and 0.0002 and an OR range between 0.75 and 0.62. The CD subgroup of the Italian cohort showed only a trend towards association with the same alleles, which was not significant with a P value range between 0.3495 and 0.0873. The results are shown in table 1

A Cochran-Mantel-Haenszel meta-analysis of the results from all three cohorts showed a very convincing association of all IL2/IL21 SNPs in IBD (P value range 7.45×10−6 – 1.41×10−9). In UC this effect also reached genome-wide significance with a P value of 3.07×10−8 for rs6840978 and a P value of 1.35×10−10 for rs13151961. The meta-analysis showed a moderate association with CD for all four SNPs to the same alleles (P value range 0.0016–9.86×10−5).

The fourth cohort consisting of patients with a Jewish background was analyzed separately, these results are depicted in table 2. We did not find a significant association between any of the SNPs and CD in this cohort. We were reluctant to add this cohort to the meta analysis for all CD patients because of the large discrepancy in minor allele frequency (MAF) between Jewish controls and controls from the other cohorts: the MAF for SNP rs13119723 in Jewish controls was 0.06, while the MAF in the other cohorts was between 0.16 and 0.17. We performed a meta analysis of all CD cohorts including the Jewish cohort (data not shown), which yielded a P value of 1.4 ×10−3 for SNP rs13151961, a P value of 1.0 × 10−4 for SNP rs13119723, a P value of 4.1 × 10−4 for SNP rs6822844 and a P value of 1.4× 10−3 for SNP rs6840978.

Table 2
Association of the IL2/IL21 SNPs in a Jewish cohort.

Because the association of the IL2/IL21 locus to CD is much more moderate than that to UC it might be that the association is mainly to colonic disease. If this were the case, then we would predict that the association signal from CD comes exclusively from disease localised in the colon. To test this hypothesis we performed a within-cases analysis for the association in colonic and non-colonic CD. However this did not yield any significant results. Further genotype-phenotype analysis for disease localization or extent, disease behaviour, necessity for operation, the occurence of malignancy and extraintestinal manifestations did not yield any phenotype-specific associations (data not shown). Although phenotype data was available for a large proportion of cases (80% for both CD and UC) this might still be due to a lack of power in each specific subgroup to detect true genotype-phenotype associations.

Another possible explanation for the comparatively modest association to CD is the relatively low total number of CD patients: 1588 CD patients compared to 3194 UC patients. This, however, does not appear likely as the power calculations showed that with the 1588 CD patients we have in our study there is 95% power to detect an effect with an OR of 0.85 which is similar to that observed in UC.

Discussion

In the current study we have identified and replicated a novel association between genetic variants in the IL2/IL21 locus and IBD (OR 0.66; P value 1.4×10−9), with the strongest evidence of association in UC (OR 0.62; p-value 1.35×10−10). This association is consistent with the recent findings of a common protective allele in celiac disease, rheumatoid arthritis, psoriasis and type 1 diabetes and thus confirms this locus as a general risk locus for inflammatory disease.[6, 810]

This locus on chromosome 4q27 comprises a region of 480 kb of extensive linkage disequilibrium (LD) that harbours the testis nuclear RNA-binding protein (TENR) gene, a gene encoding a protein of unknown function (KIAA1109), and genes encoding the interleukin-2 (IL2) and interleukin-21 (IL21) cytokines. TENR is expressed primarily in testis and KIAA1109 transcripts are ubiquitous, hence their roles in inflammatory diseases are not particularly compelling, which leaves IL2 and IL21 as the most likely candidates for disease association in the region.[6] As previously reported in other immune diseases, the four SNPs tested and found to be associated to IBD in this study are correlated to each (with r2 correlation coefficients ranging from 0.5 to 0.97) and are all located in non-coding regions within this 480 kb LD block. Two SNPs, rs13151961 and rs13119723, are situated in intronic regions of the KIAA1109 gene. SNP rs6822844 is located in the intergenic region between IL2 and IL21 and SNP rs6840987 is located downstream of IL21. These SNPs are not known to have an effect on expression of the genes in the IL2-IL21 region.[25]

Interleukin 2 is secreted in an autocrine fashion by antigen-stimulated T cells and stimulates T cell activation and proliferation. In these T cells, IL2 stimulates the production of the pro-inflammatory cytokines interferon-gamma and interleukin 4. Furthermore, IL2 has an important role in regulating the adaptive immune response by stimulating T regulatory (CD4+ CD25+) cells and by its ability to stimulate activation-induced cell death in antigen-activated T cells.[26] Interleukin 21 is also a T cell derived cytokine; it stimulates class switching to IgG in B cells and regulates natural killer cell proliferation and differentiation. IL21 augments proliferation in cells of the monocyte-macrophage lineages and induces an immuno-suppressive phenotype by stimulating the formation of immature monocytes that inhibit antigen-specific T cell proliferation. During inflammatory processes, the receptor for interleukin 21, IL-21 R, can be found on non-immune cells, such as colon epithelial cells or fibroblasts. When stimulated by IL-21, these cells secrete proteins that mobilize T cells to areas of immune challenge.[27]

The overexpression of IL21 in IBD patients compared to healthy controls and diverticulitis patients shows the importance of this interleukin in the inflammatory process of both CD and UC.[17] Interestingly, Monteleone et al. observed the increase in IL21 expression level predominantly in the CD subgroup of IBD patients, whereas we here observed a stronger association of the IL2/IL21 locus to UC rather than CD. Although speculative this prioritizes the IL2 gene as the more likely involved gene. IL2 is an attractive functional candidate gene for UC pathogenesis, as the Il2−/− mouse develops a disease similar to UC, supporting an association between IL2 and UC.[18] The fact that calcineurin inhibitors, which mainly suppress the expression of IL2, are effective in therapy-resistant UC, but not in CD, might also point to a key role of this interleukin in UC.[28] Further support of the importance of IL2 in UC comes from the fact that a pilot trial with antibodies against the IL2 receptor in therapy-resistant UC was successful.[29] The fact that both a lack of IL2 and an excess of IL2 predispose to colitis is however puzzling. Further functional studies on these genetic variants are needed to define the specific role of the IL2/IL21 locus in the pathogenesis of inflammatory bowel diseases.

An equivalent protective association signal of the IL2/IL21 locus to celiac disease, rheumatoid arthritis, type 1 diabetes and psoriasis has previously been reported. This shows that this locus plays an important role in inflammatory diseases. Previously MAGI2, PARD3, MYOIXB and IL18RAPwere reported to be associated to both celiac disease and UC.[15 16 3032] The IL2–IL21 locus is now the fifth locus to be associated with both diseases, further supporting a model where a common set of biological pathways lead to celiac disease and UC. Interestingly, multiple SNPs in this same region, that are independent of the SNPs studied herein, have recently been reported to confer risk to T1D and potentially to celiac disease.[11] Although these SNPs conferring risk were not tested in the current study a published study in CD (rs17388568, pvalue = 1.7 ×10−4; rs716501, pvalue=3.8 × 10−4 potentially supports the presence of alleles conferring increased risk to disease.[3] Further examination of these risk-conferring alleles are warranted in CD and UC.

Extensive sequencing in celiac cases and matched controls, as well as functional studies will be needed to find the true causal variant in the IL2/IL21 locus and determine the molecular mechanisms by which this locus influences an individual’s risk to multiple immune mediated diseases.

Supplementary Material

Supplementary table 1

Supplementary table 2

Footnotes

The work was performed at address, Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, the Netherlands and Laboratory in Genetics and Genomic Medicine of Inflammation, Montreal Heart Institute Université de Montréal, Montreal, Canada.

Authors’ disclosure: No authors have a conflict of interest to declare.

The Corresponding Author has the right to grant on behalf of all authors, and does grant on behalf of all authors, an exclusive licence (or non-exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if accepted) to be published in Gut and any other BMJPGL products to exploit 75 all subsidiary rights, as set out in our licence (http://gut.bmj.com/ifora/licence.pdf).

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