The effect of IL-10 genetic variation and interleukin 10 serum levels on Crohn's disease susceptibility in a New Zealand population

doi:10.1016/j.humimm.2011.02.014

Human Immunology

Volume 72, Issue 5, May 2011, Pages 431-435

https://doi.org/10.1016/j.humimm.2011.02.014 Get rights and content

Abstract

Interleukin (IL)-10 has important effects in immunoregulation and inflammation, and previous studies have provided evidence for the involvement of IL-10 in the pathogenesis of Crohn's disease (CD). In this study, we investigated whether genetic variants of the IL-10 gene were associated with CD in a New Zealand population. Three single nucleotide polymorphisms (SNPs) in the promoter region of IL-10 (rs1800871, rs1800872, and rs1800896) and a flanking SNP, rs3024505, were genotyped in a well-characterized New Zealand dataset consisting of 342 CD cases and 610 controls. Furthermore, we measured serum IL-10 levels in a number of the CD patients and controls and examined whether a relationship existed between these polymorphisms and serum IL-10 levels. We demonstrated an association with CD for SNPs rs3024505 and rs1800896, and phenotypic analysis indicated an association of rs3024505 with an early age at first diagnosis, stricturing CD behavior, and requirement for bowel resection. We also observed that IL-10 concentration was significantly higher in CD patients than in the controls and that the T allele of rs1800896, the A allele of rs1800871, and the T allele of rs1800872 were associated with increased serum IL-10 levels.

Introduction

Crohn's disease (CD) is a form of inflammatory bowel disease (IBD), characterized by chronic, relapsing gastrointestinal inflammation. It results from multiple genetic and multiple environmental risk factors, operating additively and interactively. One such genetic factor is the interleukin (IL)-10 gene. IL-10 is an important immunosuppressor cytokine, involved in the regulation of many aspects of the immune response. It inhibits the production of proinflammatory cytokines and T helper 1 cytokines, downregulates the expression of major histocompatibility complex class II and costimulatory molecules on antigen-presenting cells, and promotes the development of regulatory T cells [1]. The importance of IL-10 in IBD pathogenesis was initially suggested by the observation that IL-10-deficient mice develop enterocolitis when they are not kept in a germ-free environment [2].

The most commonly studied genetic variants in the IL-10 gene are 3 promoter polymorphisms: -592C/A (rs1800872), -819C/T (rs1800871), and -1082 G/A (rs1800896), which give rise to 3 well-conserved haplotypes (GCC, ACC, and ATA). Although some studies have reported an association with CD for these promoter single nucleotide polymorphisms (SNPs) [3], [4], most studies have been unable to confirm this [5], [6], [7], [8], [9], [10].

Recently, a genome-wide association study (GWAS) indicated a strong association between the other form of IBD, ulcerative colitis (UC), and SNP rs3024505 flanking the IL-10 gene. A modest association between the SNP and CD was also reported in this study [11]. More recently SNP rs3024505 was found to be associated with both early-onset CD and UC in a GWAS [12].

We investigated whether rs3024505 and the 3 IL-10 promoter polymorphisms were associated with CD in a well-characterized case–control New Zealand dataset. Furthermore, we measured serum IL-10 levels in a number of CD patients and controls and examined whether a relationship existed between these polymorphisms and serum IL-10 levels.

Section snippets

Study population

The Auckland CD Project is a population-based study of genetic and environmental determinants of CD etiology. CD patients were recruited between May 2005 and April 2007 through local doctors and surgeries in Auckland, New Zealand, as well as other North Island centers, by media campaigns (e.g., local newspaper and television). Controls were recruited by the same means. Participants consented to collection of peripheral blood or a buccal swab for DNA extraction and genotyping and answered

Association analysis

SNP rs1800896 deviated from HWE in the controls (p = 0.0006). To ensure genotyping errors did not exist in our data, the genotyping was repeated using an alternative primer and probe set and our genotypes were confirmed to be correct. Also, the frequency of the T allele, 0.491, does not differ greatly from the HapMap CEU population frequency of 0.469. Deviations from HWE may have resulted by chance or it is possible that the SNP is associated with a currently unknown factor that varies across

Discussion

In this study we attempted to replicate the reported associations of IL-10 with CD in a New Zealand population. We did not find evidence for an association with 2 of the promoter SNPs: -592 (rs1800872) and -819 (rs1800871), but were able to demonstrate associations for the promoter SNP -1082 (rs1800896) as well as SNP rs3024505 flanking the IL-10 gene. Furthermore, phenotypic analysis demonstrated an association of rs3024505 with an early age at first diagnosis, CD behavior (stricturing), and

Acknowledgments

We thank the many patients with Crohn's disease and the control subjects who participated in this study. We also thank Karen Munday, Philippa Dryland, and Virginia Parslow for subject recruitment. Nutrigenomics New Zealand is a collaboration among AgResearch Ltd, Plant and Food Research, and The University of Auckland with funding through the Foundation for Research Science and Technology.

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Biomarkers for the Prediction and Diagnosis of Fibrostenosing Crohn's Disease: A Systematic Review
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Intestinal strictures are a common complication of Crohn’s disease (CD). Biomarkers of intestinal strictures would assist in their prediction, diagnosis, and monitoring. Herein we provide a comprehensive systematic review of studies assessing biomarkers that may predict or diagnose CD-associated strictures.
We performed a systematic review of PubMed, EMBASE, ISI Web of Science, Cochrane Library, and Scopus to identify citations pertaining to biomarkers of intestinal fibrosis through July 6, 2020, that used a reference standard of full-thickness histopathology or cross-sectional imaging or endoscopy. Studies were categorized based on the type of biomarker they evaluated (serum, genetic, histopathologic, or fecal).
Thirty-five distinct biomarkers from 3 major groups were identified: serum (20 markers), genetic (9 markers), and histopathology (6 markers). Promising markers include cartilage oligomeric matrix protein, hepatocyte growth factor activator, and lower levels of microRNA-19-3p (area under the curves were 0.805, 0.738, and 0.67, respectively), and multiple anti-flagellin antibodies (A4-Fla2 [odds ratio, 3.41], anti Fla-X [odds ratio, 2.95], and anti-CBir1 [multiple]). Substantial heterogeneity was observed and none of the markers had undergone formal validation. Specific limitations to acceptance of these markers included failure to use a standardized definition of stricturing disease, lack of specificity, and insufficient relevance to the pathogenesis of intestinal strictures or incomplete knowledge regarding their operating properties.
There is a lack of well-defined studies on biomarkers of intestinal stricture. Development of reliable and accurate biomarkers of stricture is a research priority. Biomarkers can support the clinical management of CD patients and aid in the stratification and monitoring of patients during clinical trials of future antifibrotic drug candidates.
Association between IL-10 rs3024505 and susceptibility to inflammatory bowel disease: A systematic review and meta-analysis
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Citation Excerpt :
However, at a later disease stage, individuals with T or C alleles of rs3024505 have similar serum IL-10 concentrations, although those with the T allele have a higher risk of IBD [14]. Furthermore, findings regarding the association of serum IL-10 concentrations with IBD, UC, and CD, are inconsistent [14-17]. In general, low serum levels of IL-10 are known to increase the severity of CD compared with high serum levels [15,47].
Inflammatory bowel disease (IBD) is a chronic inflammatory disease that affects the small intestine, colon, and rectum. We evaluated associations between the interleukin 10 (IL-10) rs3024505 polymorphism and IBD, ulcerative colitis (UC), and Crohn's disease (CD) by meta-analysis. All peer-reviewed manuscripts concerning the relationship between IL-10_rs3024505 and IBD identified by searing the PubMed, Cochrane Library, EMBASE, and Chinese Medical Database were examined. The association between IL-10_rs3024505 and IBD was evaluated in allele (AG), recessive (RG), dominant (DG), homozygous (HMG), and heterozygous (HTG) genetic models. Associations were also conducted on IBD subtypes, CD and UC, and ethnicity (Non-Europeans and Europeans) subgroups. The meta-analysis included 13 studies, 8552 cases (IBD patients), and 12,830 healthy controls. Subgroup analysis of IBD (UC and CD) revealed heterogeneity in AG, DG, and HTG but no heterogeneity in RG or HMG. Moreover, AG, DG, and HTG did not show publication bias in IBD, CD, or UC, but RG and HMG exhibited publication bias. No heterogeneity and no publication bias were found among the five genetic models by a subgroup analysis of Non-Europeans and European ethnicities. The minor allele(T) of rs3024505 was significantly related to IBD: 1.37 (1.30–1.45) for AG, 2.06 (1.74–2.45) for RG, 1.39 (1.27–1.52) for DG, 2.25 (1.89–2.67) for HMG, and 1.32 (1.23–1.40) for HTG (all P < 0.00001). In the subgroup analysis of ethnicity, there was a significant effect of rs3024505 on IBD in Europeans but not non-Europeans: 1.38 (1.31–1.46) for AG, 2.07 (1.73–2.48) for RG, 1.39 (1.31–1.49) for DG, 2.26 (1.89–2.71) for HMG, and 1.33 (1.24–1.42) for HTG in Europeans (all P < 0.00001). Sensitivity analysis showed no dominant study in Europeans, but one study had a dominant impact in Non-Europeans. In conclusion, IL-10_rs3024505 polymorphism confers susceptibility to CD and UC in Europeans, but its impact should have conducted more studies in Non-Europeans.
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Inflammatory bowel diseases (IBDs) are chronic problems of gastrointestinal tract (GIT) with poorly understood aetiology. Patients with any of the two common entities, Crohn's disease (CD) or ulcerative colitis (UD) have significant increased risk of gastrointestinal and extra-intestinal malignancies. Particularly, the colorectal cancer (CRC) and lymphomas are the most frequently associated cancers with IBD. Although the incidence of CRC has declined in the European countries during last 30 years yet the risk among IBD patients remains higher than the healthy people. In the present study, we have described many common factors influencing the onset and advancement of IBD and CRC including the alterations in gut microbiota, changes in the interleukin pathways and tumour necrosis factor. The other common factors are patient age, race, genetics, family history, diet composition, obesity and level of vitamins and minerals in the body. These multiple factors contribute to the higher incidence of CRC among IBD patients.
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Two single nucleotide polymorphisms (SNPs), −819C > T in the IL-10 gene (rs1800871) and −308G > A in the TNF-α gene (rs1800629) located within the promoter region may affect the expression of cytokine genes. The −308A allele of the rs1800629 polymorphism and the −819A allele of the rs1800871 polymorphism are associated with increased cytokine levels (Abraham and Kroeger, 1999; Wang et al., 2011). The SNPs located in the TNF-α and IL-10 genes were studied due to the scarcity of studies showing their relationship to suicidal behaviour.
Mental disorders (MeDi) and suicide attempts (SA) are influenced by environmental and genetic factors. Genetic polymorphism studies have identified some candidate genes for suicidal behaviour in people with MeDi.
To evaluate MeDi and SA in relation to the presence of rs2020933 (5-HTT), rs1800871 (IL-10) and rs1800629 (TNF-α) polymorphisms.
A questionnaire for identification and general data, a brief quality of life assessment (WHOQOL-brief), the scale of suicide ideation by Beck and the MINI International Neuropsychiatric Interview were used in this study. DNA was obtained using buccal mucosa swab samples, and genotyping was performed using real-time polymerase chain reaction. A total of 306 patients were assessed with MeDi; 161 patients had MeDi and a history of SA, and 145 patients had MeDi and no history of SA. The study had 175 subjects in the control group.
The TNF-α rs1800629 -308A/G genotype was significantly associated with function as a protection factor in the control group compared with MeDi without SA. The TNF-α rs1800629 -308G allele appeared as risk factor for MeDi compared to the control group, for female gender. Additionally, the −308A/G + A/A genotype appeared as protection factor for the control group compared to the group with MeDi. For TNF-α, the −308G allele appeared as risk factor for the number of SA (1 time) compared to the control group.
The IL-10 (rs1800871) and 5-HTT (rs2020933) SNPs were considered to have inadequate statistical power. The rs1800629 (TNF-α) polymorphism may be associated with MeDi without SA, MeDi in females and the number of SA (1 time) in the studied group.
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The effect of IL-10 genetic variation and interleukin 10 serum levels on Crohn's disease susceptibility in a New Zealand population

Abstract

Introduction

Section snippets

Study population

Association analysis

Discussion

Acknowledgments

Cell

Am J Hum Genet

Mol Genet Metab

Lancet

Interleukin-10 and the interleukin-10 receptor

Annu Rev Immunol

Interleukin-10 polymorphisms in Spanish patients with IBD

Inflamm Bowel Dis

Interleukin-10 (IL-10) genotypes in inflammatory bowel disease

Tissue Antigens

Role of polymorphisms in the interleukin-10 gene in determining disease susceptibility and phenotype in inflammatory bowel disease

Dig Dis Sci

Inflammatory bowel disease: the role of inflammatory cytokine gene polymorphisms

Mediat Inflamm

The role of cytokine gene polymorphisms in determining disease susceptibility and phenotype in inflammatory bowel disease

Am J Gastroenterol