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Pastras P, Aggeletopoulou I, Papantoniou K, Triantos C. Targeting the IL-23 Receptor Gene: A Promising Approach in Inflammatory Bowel Disease Treatment. Int J Mol Sci 2025; 26:4775. [PMID: 40429917 DOI: 10.3390/ijms26104775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2025] [Revised: 05/09/2025] [Accepted: 05/14/2025] [Indexed: 05/29/2025] Open
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's Disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation of the gastrointestinal tract. A key component of the inflammatory pathway in IBD is interleukin 23 (IL-23), which promotes the differentiation and maintenance of Th17 cells. These cells are major contributors to intestinal inflammation and the release of pro-inflammatory cytokines. A dysregulated IL-23/Th17 axis can lead to excessive gut inflammation. Notably, IL-23 affects Th17 cell responses differently in UC and CD, fostering IL-17 production in UC and interferon-gamma (IFN-γ) production in CD. Genetic studies have pinpointed specific variants of the IL-23 receptor (IL23R) gene that confer protection against IBD. The R381Q (rs11209026) variant has been linked to a reduced risk of developing both CD and UC. Additionally, other variants, such as G149R (rs76418789) and V362I (rs41313262), inhibit IL23R function by disrupting intracellular trafficking and protein stability. This disruption results in decreased phosphorylation of downstream signal transducers, such as STAT3 and STAT4, and reduced IL23R expression on the cell surface, ultimately dampening the activation of pro-inflammatory pathways. The protective effects of these genetic variants underscore the IL-23/IL23R pathway as a significant therapeutic target in IBD management. Therapies designed to modulate this pathway have the potential to reduce pro-inflammatory cytokine production and enhance anti-inflammatory mechanisms. Ongoing research into the IL23R gene and its variants continues to provide valuable insights, paving the way for more targeted and effective treatments for IBD patients.
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Affiliation(s)
- Ploutarchos Pastras
- Division of Gastroenterology, Department of Internal Medicine, University of Patras, 26504 Patras, Greece
| | - Ioanna Aggeletopoulou
- Division of Gastroenterology, Department of Internal Medicine, University of Patras, 26504 Patras, Greece
| | - Konstantinos Papantoniou
- Division of Gastroenterology, Department of Internal Medicine, University of Patras, 26504 Patras, Greece
| | - Christos Triantos
- Division of Gastroenterology, Department of Internal Medicine, University of Patras, 26504 Patras, Greece
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Barac IS, Văcăraș V, Iancu M, Mureșanu DF, Procopciuc LM. Interleukins (IL-23 and IL-27) serum levels: Relationships with gene polymorphisms and disease patterns in multiple sclerosis patients under treatment with interferon and glatiramer acetate. Heliyon 2023; 9:e17427. [PMID: 37484355 PMCID: PMC10361377 DOI: 10.1016/j.heliyon.2023.e17427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 04/22/2023] [Accepted: 06/16/2023] [Indexed: 07/25/2023] Open
Abstract
Background interleukin 23 (IL-23) is an important factor involved in the survival and proliferation of T helper 17 cells (Th17), known for their implication in multiple sclerosis (MS). By contrast, IL-27 regulates and modulates the function of T lymphocytes, in particular as a suppressor of Th17 differentiation. The aims of the study were i) to test the association of cytokines with the clinical and genetic characteristics in each of the multiple sclerosis groups (CIS - clinically isolated syndrome, RRMS - relapsing-remitting MS and SPMS - Secondary progressive MS) and ii) to evaluate the association between serum levels of IL-23 and IL-27 with T4730C (IL-27), A964G (IL-27) and R381Q (IL-23) gene polymorphisms in RRMS patients. Methods Blood samples were obtained from 82 patients diagnosed with MS under treatment with glatiramer acetate (GA), interferon beta (IFN) 1 A and 1 B. IL-23 and IL-27 serum concentrations were measured by enzyme-linked immunosorbant assay (ELISA). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used in order to determine the genotypes for R381Q (IL-23) polymorphisms, T4730C (IL-27) and A964G (IL-27). Results Patients with SPMS, RRMS and CIS respectively differed significantly regarding age distribution (p = 0.003) but the studied MS groups were similar regarding age at disease onset (p = 0.528) and treatment type (p = 0.479). A significant increase of mean serum IL-27 was noticed in cases with early onset (age at disease onset <28 years) of RRMS (mean difference: 4.2 pg/ml, 95% CI: 0.8-5.3 pg/ml), compared to cases with later onset of RRMS (age at disease onset ≥28 years). RRMS patients with wild GG genotype of R381Q (IL-23) showed a significant increase of mean serum IL-23 than patients with variant AG genotype (mean difference: 115.1 pg/ml, 95% CI: 8.6-221.6 pg/ml). A trend for a higher increase in means of serum IL-23 (p = 0.086) was observed in RRMS patients carriers of AA genotype of A964G (IL-27) polymorphism in comparison with patients with AG or GG genotypes. We found no significant monotonic correlation of IL-27, IL-23 serum levels with age at disease onset (years) and duration of disease (p > 0.05) in the CIS and SPMS group respectively but a significant correlation between IL-23 and the duration of disease-modifying treatment was noticed only in the SPMS group. Conclusions The results of the current study suggest an association between IL-23 levels and the R381Q gene polymorphism and also a relationship between IL-27 serum levels and early age at disease onset in RRMS patients.
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Affiliation(s)
- Ioana S. Barac
- Department of Clinical Neurosciences, “Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, 400012, Romania
| | - Vitalie Văcăraș
- Department of Clinical Neurosciences, “Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, 400012, Romania
| | - Mihaela Iancu
- Department of Medical Informatics and Biostatistics, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj‐Napoca, Cluj‐Napoca, 400012, Romania
| | - Dafin F. Mureșanu
- Department of Clinical Neurosciences, “Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, 400012, Romania
| | - Lucia M. Procopciuc
- Department of Biochemistry, “Iuliu Hațieganu" University of Medicine and Pharmacy Cluj-Napoca, Cluj-Napoca, 400012, Romania
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Markelova M, Senina A, Khusnutdinova D, Siniagina M, Kupriyanova E, Shakirova G, Odintsova A, Abdulkhakov R, Kolesnikova I, Shagaleeva O, Lyamina S, Abdulkhakov S, Zakharzhevskaya N, Grigoryeva T. Association between Taxonomic Composition of Gut Microbiota and Host Single Nucleotide Polymorphisms in Crohn's Disease Patients from Russia. Int J Mol Sci 2023; 24:ijms24097998. [PMID: 37175705 PMCID: PMC10178390 DOI: 10.3390/ijms24097998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 04/25/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Crohn's disease (CD) is a chronic relapsing inflammatory bowel disease of unknown etiology. Genetic predisposition and dysbiotic gut microbiota are important factors in the pathogenesis of CD. In this study, we analyzed the taxonomic composition of the gut microbiota and genotypes of 24 single nucleotide polymorphisms (SNP) associated with the risk of CD. The studied cohorts included 96 CD patients and 24 healthy volunteers from Russia. Statistically significant differences were found in the allele frequencies for 8 SNPs and taxonomic composition of the gut microbiota in CD patients compared with controls. In addition, two types of gut microbiota communities were identified in CD patients. The main distinguishing driver of bacterial families for the first community type are Bacteroidaceae and unclassified members of the Clostridiales order, and the second type is characterized by increased abundance of Streptococcaceae and Enterobacteriaceae. Differences in the allele frequencies of the rs9858542 (BSN), rs3816769 (STAT3), and rs1793004 (NELL1) were also found between groups of CD patients with different types of microbiota communities. These findings confirm the complex multifactorial nature of CD.
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Affiliation(s)
- Maria Markelova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Anastasia Senina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Dilyara Khusnutdinova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Maria Siniagina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Elena Kupriyanova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | | | | | - Rustam Abdulkhakov
- Hospital Therapy Department, Kazan State Medical University, 420012 Kazan, Russia
| | - Irina Kolesnikova
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia
| | - Olga Shagaleeva
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia
| | - Svetlana Lyamina
- Molecular Pathology of Digestion Laboratory, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, 127473 Moscow, Russia
| | - Sayar Abdulkhakov
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Natalia Zakharzhevskaya
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia
| | - Tatiana Grigoryeva
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
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Barac IS, Iancu M, Văcăraș V, Cozma A, Negrean V, Sâmpelean D, Mureșanu DF, Procopciuc LM. Potential Contribution of IL-27 and IL-23 Gene Polymorphisms to Multiple Sclerosis Susceptibility: An Association Analysis at Genotype and Haplotype Level. J Clin Med 2021; 11:jcm11010037. [PMID: 35011777 PMCID: PMC8745323 DOI: 10.3390/jcm11010037] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/17/2021] [Accepted: 12/18/2021] [Indexed: 11/30/2022] Open
Abstract
(1) Background: interleukin 23 (IL-23) and interleukin 27 (IL-27) modulate the activity of T helper 17 cells (Th17) with critical roles in autoimmune diseases and multiple sclerosis (MS). The genes responsible for cytokine generation are highly influenced by the presence of single nucleotide polymorphisms (SNP) in main regions such as regulatory sequences or in promoter regions, contributing to disease susceptibility and evolution. The present study analyzed the associations of IL-23 and IL-27 SNPs with susceptibility to multiple sclerosis. (2) Methods: We performed a case-control study including 252 subjects: 157 patients diagnosed with MS and 95 controls. We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to determine the genotypes for IL-27 T4730C (rs 181206), IL-27 A964G (rs 153109), and IL-23 receptor gene (IL-23R) G1142A (rs 11209026). (3) Results: The IL27-T4730C gene polymorphism was significantly associated with an increased odds of MS under the dominant genetic model (TC + CC variant genotypes, adjusted odds ratio OR = 4.06, 95% CI: 2.14–7.83, p-value = 0.000007, Q-value = 0.000063). Individuals carrying the IL-27 A924G variant (AG + GG) genotype presented higher odds of MS compared to non-carriers under the dominant model (adjusted OR = 1.93, 95% CI: 1.05–3.51, p-value = 0.0324, Q-value = 0.05832) and the allelic genetic model (unadjusted p-value = 0.015, OR = 1.58, 95% CI: 1.09–2.28), while IL-23-R381Q SNP conferred a decreased odds of MS under a codominant model of inheritance (adjusted OR = 0.26, 95% CI: 0.08–0.92, p-value = 0.0276, Q-value = 0.058) and an allelic model (unadjusted p-value = 0.008, OR = 0.23, 95% CI: 0.07–0.75). In an additive model with adjustment for age group (≤40 years vs. >40 years), sex and smoking, patients carrying the G-C (A964G, T4730C) haplotype had a 3.18 increased risk (95% CI: 1.74–5.81, p < 0.001) to develop multiple sclerosis. (4) Conclusions: The results of the current study showed a significant relationship of IL-27-A964G and IL-27-T4730C polymorphisms with increased risk of MS, and also the protective role of the IL-23-R381Q polymorphism. Moreover, the haplotype-based analysis proposed the mutant G-C (A924G, T4730C) as a significant risk haplotype for the development of MS.
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Affiliation(s)
- Ioana S. Barac
- Department of Clinical Neurosciences, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400000 Cluj-Napoca, Romania; (I.S.B.); (D.F.M.)
| | - Mihaela Iancu
- Department of Medical Informatics and Biostatistics, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400012 Cluj-Napoca, Romania
- Correspondence: (M.I.); (V.V.); Tel.: +40-0740-130-888 (M.I.); +40-0728-730-373 (V.V.)
| | - Vitalie Văcăraș
- Department of Clinical Neurosciences, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400000 Cluj-Napoca, Romania; (I.S.B.); (D.F.M.)
- Correspondence: (M.I.); (V.V.); Tel.: +40-0740-130-888 (M.I.); +40-0728-730-373 (V.V.)
| | - Angela Cozma
- Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400000 Cluj-Napoca, Romania; (A.C.); (V.N.); (D.S.)
| | - Vasile Negrean
- Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400000 Cluj-Napoca, Romania; (A.C.); (V.N.); (D.S.)
| | - Dorel Sâmpelean
- Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400000 Cluj-Napoca, Romania; (A.C.); (V.N.); (D.S.)
| | - Dafin F. Mureșanu
- Department of Clinical Neurosciences, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400000 Cluj-Napoca, Romania; (I.S.B.); (D.F.M.)
| | - Lucia M. Procopciuc
- Department of Biochemistry, “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, 400000 Cluj-Napoca, Romania;
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He M, Li C, Tang W, Kang Y, Zuo Y, Wang Y. Machine learning gene expression predicting model for ustekinumab response in patients with Crohn's disease. Immun Inflamm Dis 2021; 9:1529-1540. [PMID: 34469062 PMCID: PMC8589399 DOI: 10.1002/iid3.506] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Background Recent studies reported the responses of ustekinumab (UST) for the treatment of Crohn's disease (CD) differ among patients, while the cause was unrevealed. The study aimed to develop a prediction model based on the gene transcription profiling of patients with CD in response to UST. Methods The GSE112366 dataset, which contains 86 CD and 26 normal samples, was downloaded for analysis. Differentially expressed genes (DEGs) were identified first. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were administered. Least absolute shrinkage and selection operator regression analysis was performed to build a model for UST response prediction. Results A total of 122 DEGs were identified. GO and KEGG analyses revealed that immune response pathways are significantly enriched in patients with CD. A multivariate logistic regression equation that comprises four genes (HSD3B1, MUC4, CF1, and CCL11) for UST response prediction was built. The area under the receiver operator characteristic curve for patients in training set and testing set were 0.746 and 0.734, respectively. Conclusions This study is the first to build a gene expression prediction model for UST response in patients with CD and provides valuable data sources for further studies.
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Affiliation(s)
- Manrong He
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chao Li
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Wanxin Tang
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yingxi Kang
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yongdi Zuo
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yufang Wang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Miyoshi J, Matsuura M, Hisamatsu T. Safety evaluation of ustekinumab for moderate-to-severe ulcerative colitis. Expert Opin Drug Saf 2021; 21:1-8. [PMID: 34511011 DOI: 10.1080/14740338.2021.1980536] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Ustekinumab is a human IgG1 kappa monoclonal antibody that targets the p40 subunit of interleukin (IL)-12 and IL-23 and blocks the binding of these cytokines to the IL-12Rβ1 chain of their receptors. Ustekinumab is approved for treating moderate-to-severe ulcerative colitis (UC). AREAS COVERED We reviewed the mechanism of action, pharmacokinetics, efficacy, and safety of ustekinumab. Future challenges for optimizing UC treatment with ustekinumab are discussed. EXPERT OPINION Ustekinumab has favorable clinical efficacy and safety profiles for moderately-to-severely active UC. Ustekinumab is the first biologic for targeting IL-12/IL-23 pathways. Therefore, ustekinumab can be a therapeutic option following the failure of other biologics, including anti-tumor necrosis factor-α antagonists and anti-α4ß7 integrin antagonists. However, the positioning of ustekinumab in the therapeutic strategy for UC remains unclear. The efficacy of combinations of ustekinumab and immunomodulators over ustekinumab monotherapy has not been supported in studies. Ustekinumab is a human immunoglobulin G monoclonal antibody with low immunogenicity. Therefore, ustekinumab monotherapy, which should be safe, could be sufficient for treating UC. Further studies are required to understand the efficacy and safety of ustekinumab in patients with UC, particularly in special situations, and to optimize UC treatment with ustekinumab.
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Affiliation(s)
- Jun Miyoshi
- Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo, Japan 181-8611
| | - Minoru Matsuura
- Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo, Japan 181-8611
| | - Tadakazu Hisamatsu
- Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo, Japan 181-8611
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Raja TW, Veeramuthu D, Savarimuthu I, Al-Dhabi NA. Current Trends in the Treatment of Systemic Lupus Erythematosus. Curr Pharm Des 2020; 26:2602-2609. [PMID: 32066358 DOI: 10.2174/1381612826666200211122633] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 12/21/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Systemic lupus erythematosus (SLE) is an autoimmune disease in mankind. SLE's downregulation of T and B lymphocytes could cause the development of autoantibodies, which in turn attack cell surface, nuclear, and cytoplasmic molecules, creating immune complexes that harm tissues. OBJECTIVE The objective of the present review is to evaluate SLE's present therapeutic policies and raise consciousness about the disease. METHODS New therapies are rare for SLE. This is due to the complexity of the disease and its various manifestations. Three techniques are used to develop biological treatments for the illness: B-cell modulation, T-cell regulation and cytokine inhibition. This paper reviews the present trends in SLE therapy. RESULTS Each arm of the immune system is a prospective therapeutic development target for this disease; it involves B-cells, T-cells, interferon (IFN) and cytokines. To date, only one of these agents is been approved for use against lupus, belimumab which comes under B-cell therapy. Both the innate and the adaptive immune systems are the objectives. Currently, although there is no full SLE remedy, drug therapy can minimize organ injury and control active disease, which relies on immunosuppressants and glucocorticoids. CONCLUSION It is possible to access SLE treatment in the form of T-cell, B-cell and anticytokine therapies. In these therapies, antibodies and antigens interactions play a major part. Another medication for treating SLE is the non-steroidal anti-inflammatory drug such as hydroxychloroquine. Glucocorticoids (GCs) are another antiinflammatory treatment that suppresses the growth of cytokines related to inflammation and prevents the recruitment of leukocyte by reducing endothelial cell permeability.
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Affiliation(s)
- Tharsius W Raja
- Division of Ethnopharmacology, Entomology Research Institute, Loyola College, Chennai-600034, Tamil Nadu, India
| | - Duraipandiyan Veeramuthu
- Division of Ethnopharmacology, Entomology Research Institute, Loyola College, Chennai-600034, Tamil Nadu, India
| | | | - Naif A Al-Dhabi
- Department of Botany and Microbiology, College of Sciences, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
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Quiroz-Cruz S, Posada-Reyes B, Alatorre-García T, Del Real-Calzada CM, García-Samper X, Escobar-Gutiérrez A, Vázquez-Chacón CA, Martínez-Guarneros JA, Cruz-Rivera M, Vaughan G, Fonseca-Coronado S. Genetic polymorphisms present in IL10, IL23R, NOD2, and ATG16L1 associated with susceptibility to inflammatory bowel disease in Mexican population. Eur J Gastroenterol Hepatol 2020; 32:10-16. [PMID: 31651650 DOI: 10.1097/meg.0000000000001540] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVE Ulcerative colitis and Crohn's disease are the two clinical forms of inflammatory bowel disease (IBD). Diverse studies have shown the association of single nucleotide polymorphism (SNP) in molecules of the immune system and the occurrence of IBD. Here, several SNPs of the immune system with controversial results for their association with UC and CD were evaluated in a Mexican population. METHODS SNPs rs1800896, rs3024505 (IL-10); rs11209026 (IL23R); rs2066844, rs2066845 (NOD-2), and rs2241880 (ATG16L1) were assessed in 93 patients with IBD and 200 healthy controls by hybridization probes and quantitative PCR. RESULTS The AG genotype for rs1800896 was associated with an increased risk for both UC and CD (P = 0.005 and P = 0.026, respectively); whereas the AA genotype presents a negative association (P = 0.011 for UC, and 0.0038 for CD). For this SNP, G allele was associated with risk of UC (P = 0-043) but not for CD. For the rs3024505 in IL-10, T allele was associated with UC (P = 0.011). Moreover, this allele was associated with early onset of UC (P = 0.033) and with the use of steroid treatment (P = 0.019). No significant differences for NOD2 (rs2066844T and rs2066845C), IL23R (rs11209026), and ATG16L1 (rs22411880) were found between cases and controls and the homozygous TT genotype for rs2066844 and CC for rs2066845 were not observed. CONCLUSION Our results show both genotypic and phenotypic associations of IL-10 SNPs with IBD but not with the other immune-related SNPs studied in this Mexican cohort.
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Affiliation(s)
- Sarai Quiroz-Cruz
- Unidad de Investigación Multidisciplinaria, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México
| | - Berenice Posada-Reyes
- Unidad de Investigación Multidisciplinaria, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México
| | - Thalia Alatorre-García
- Unidad de Investigación Multidisciplinaria, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México
| | - Carlos Manuel Del Real-Calzada
- Servicio de Gastroenterología, Hospital de especialidades, Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social
| | - Xóchitl García-Samper
- Servicio de Gastroenterología, Hospital Adolfo López Mateos, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado
| | - Alejandro Escobar-Gutiérrez
- Coordinación de Investigación, Instituto de Diagnóstico y Referencia Epidemiológicos, Secretaria de Salud, Ciudad de México
| | - Carlos Arturo Vázquez-Chacón
- Coordinación de Investigación, Instituto de Diagnóstico y Referencia Epidemiológicos, Secretaria de Salud, Ciudad de México
| | | | | | - Gilberto Vaughan
- Facultad de Ciencias de la Salud, Centro de Investigación en Ciencias de la Salud (CICSA), Universidad Anáhuac, México Norte, México
| | - Salvador Fonseca-Coronado
- Unidad de Investigación Multidisciplinaria, Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México
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Borecki K, Zawada I, Salkić NN, Karakiewicz B, Adler G. Relationship between the IL23R SNPs and Crohn's Disease Susceptibility and Phenotype in the Polish and Bosnian Populations: A Case-Control Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:1551. [PMID: 31052515 PMCID: PMC6539781 DOI: 10.3390/ijerph16091551] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 04/26/2019] [Accepted: 04/28/2019] [Indexed: 12/22/2022]
Abstract
It is suggested that IL-23/IL-17 axis and single nucleotide polymorphisms (SNPs) of IL23R may have crucial role in pathogenesis of Crohn's disease (CD). Thus, we sought to assess the IL23R SNPs contribution to susceptibility and phenotype of CD. We recruited 117 CD subjects and 117 controls from Poland and 30 CD subjects and 30 controls from Bosnia and Herzegovina (B&H). Two common IL23R SNPs: rs1004819, rs7517847 were genotyped using TaqMan SNP assays. In the Polish population it was found that allele rs1004819: A increases the risk of CD, while allele rs7517847: A is protective against disease development. In Poles the co-carriage of two IL23R risk genotypes was associated with increased risk of CD. A significantly increased risk of CD early onset was observed in Poles carrying at least one rs7517847: G allele. It was also found that IL23R SNPs may be associated with structuring/penetrating CD behavior, as alleles rs1004819: A and rs7517847: G were significantly less frequent in patients without complications, from Poland and B&H, respectively. Allele rs1004819: A was also significantly more frequent in Poles with penetrating CD. These results confirm IL23R SNPs contribution to CD susceptibility in the Polish population and suggest their impact on early age of onset and more severe disease course.
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Affiliation(s)
- Krzysztof Borecki
- Department of Studies in Antropogenetics and Biogerontology, Pomeranian Medical University, Żołnierska 48, 71-210 Szczecin, Poland.
| | - Iwona Zawada
- Department of Gastroenterology, Pomeranian Medical University, Unii Lubelskiej 1, 71-252 Szczecin, Poland.
| | - Nermin Nusret Salkić
- Department of Gastroenterology and Hepatology, University Clinical Center Tuzla, Trnovac bb, 75000 Tuzla, Bosnia and Herzegovina.
| | - Beata Karakiewicz
- Department of Public Health, Pomeranian Medical University, Żołnierska 48, 71-210 Szczecin, Poland.
| | - Grażyna Adler
- Department of Studies in Antropogenetics and Biogerontology, Pomeranian Medical University, Żołnierska 48, 71-210 Szczecin, Poland.
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Imam T, Park S, Kaplan MH, Olson MR. Effector T Helper Cell Subsets in Inflammatory Bowel Diseases. Front Immunol 2018; 9:1212. [PMID: 29910812 PMCID: PMC5992276 DOI: 10.3389/fimmu.2018.01212] [Citation(s) in RCA: 194] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 05/15/2018] [Indexed: 12/30/2022] Open
Abstract
The gastrointestinal tract is a site of high immune challenge, as it must maintain a delicate balance between tolerating luminal contents and generating an immune response toward pathogens. CD4+ T cells are key in mediating the host protective and homeostatic responses. Yet, CD4+ T cells are also known to be the main drivers of inflammatory bowel disease (IBD) when this balance is perturbed. Many subsets of CD4+ T cells have been identified as players in perpetuating chronic intestinal inflammation. Over the last few decades, understanding of how each subset of Th cells plays a role has dramatically increased. Simultaneously, this has allowed development of therapeutic innovation targeting specific molecules rather than broad immunosuppressive agents. Here, we review the emerging evidence of how each subset functions in promoting and sustaining the chronic inflammation that characterizes IBD.
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Affiliation(s)
- Tanbeena Imam
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Sungtae Park
- Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
| | - Mark H Kaplan
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Matthew R Olson
- Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States.,Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
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Peng LL, Wang Y, Zhu FL, Xu WD, Ji XL, Ni J. IL-23R mutation is associated with ulcerative colitis: A systemic review and meta-analysis. Oncotarget 2017; 8:4849-4863. [PMID: 27902482 PMCID: PMC5354875 DOI: 10.18632/oncotarget.13607] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 11/12/2016] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES Since a genome-wide association study revealed that Interleukin-23 receptor (IL-23R) gene is a candidate gene for Ulcerative Colitis (UC), many studies have investigated the association between the IL-23R polymorphisms and UC. However, the results were controversial. The aim of the study was to determine whether the IL-23R polymorphisms confer susceptibility to UC. METHODS A systematic literature search was carried out to identify all potentially relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of association. RESULTS A total of 33 studies in 32 articles, including 10,527 UC cases and 15,142 healthy controls, were finally involved in the meta-analysis. Overall, a significant association was found between all UC cases and the rs11209026A allele (OR = 0.665, 95% CI = 0.604~0.733, P < 0.001). Similarly, meta-analyses of the rs7517847, rs1004819, rs10889677, rs2201841, rs11209032, rs1495965, rs1343151 and rs11465804 polymorphisms also indicated significant association with all UC (all P < 0.05). Stratification by ethnicity revealed that the rs11209026, rs7517847, rs10889677, rs2201841 andrs11465804 polymorphisms were associated with UC in the Caucasian group, but not in Asians, while the rs1004819 and rs11209032 polymorphisms were found to be related to UC for both Caucasian and Asian groups. However, subgroup analysis failed to unveil any association between the rs1495965 and rs1343151 polymorphisms and UC in Caucasians or Asians. CONCLUSIONS The meta-analysis suggests significant association between IL-23R polymorphisms and UC, especially in Caucasians.
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Affiliation(s)
- Ling-Long Peng
- Department of Science and Education, The Second People's Hospital of Wuhu, Wuhu, Anhui 241000, China
| | - Ying Wang
- Department of Environmental Health, Suzhou Municipal Center for Disease Prevention and Control, Suzhou, Jiangsu 215004, China
| | - Feng-Ling Zhu
- Department of Science and Education, The Second People's Hospital of Wuhu, Wuhu, Anhui 241000, China
| | - Wang-Dong Xu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Xue-Lei Ji
- Department of Science and Education, The Second People's Hospital of Wuhu, Wuhu, Anhui 241000, China
| | - Jing Ni
- The Teaching Centre for Preventive Medicine, School of Public Health, Anhui Medical University, Hefei, Anhui 230032, China
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Bilsborough J, Targan SR, Snapper SB. Therapeutic Targets in Inflammatory Bowel Disease: Current and Future. ACTA ACUST UNITED AC 2016. [DOI: 10.1038/ajgsup.2016.18] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Abdollahi E, Tavasolian F, Momtazi-Borojeni AA, Samadi M, Rafatpanah H. Protective role of R381Q (rs11209026) polymorphism in IL-23R gene in immune-mediated diseases: A comprehensive review. J Immunotoxicol 2016; 13:286-300. [PMID: 27043356 DOI: 10.3109/1547691x.2015.1115448] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Interleukin-23 (IL-23) is a regulator of cellular immune responses involved in controlling infection and autoimmune diseases. Strong evidence has shown that IL-23 plays a role in the maintenance of immune responses by influencing the proliferation and survival of IL-17-producing T-helper (TH)-17 cells. The critical role of the IL-23/TH17 axis in immune-mediated diseases has emerged from different studies. It has also been seen that polymorphisms in the IL-23 receptor (IL-23R) gene might influence IL-23 responses. Interestingly, a functional single nucleotide polymorphism (SNP) in the IL-23 receptor gene (IL-23R; rs11209026, 1142 G wild-type A reduced function, Arg381Gln, R381Q) seems to confer a measure of protection against development of inflammatory bowel disease (IBD; Crohn's disease, ulcerative colitis), ankylosing spondylitis, rheumatoid arthritis, psoriasis, thyroiditis, recurrent spontaneous abortion and asthma, suggesting that a perturbation in the IL-23 signaling pathway is likely to be relevant to the pathophysiology of these diseases. The aim of this review was to provide an evaluation of what is currently known about the protective role of R381Q variant in IL-23R gene in immune-based diseases.
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Affiliation(s)
- Elham Abdollahi
- a Department of Medical Immunology , School of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran ;,b Shahid Sadoughi University of Medical Science , Yazd , Iran ;,c Student Research Committee, Mashhad University of Medical Sciences , Mashhad , Iran
| | - Fataneh Tavasolian
- d Department of Immunology , School of Medical Sciences, Tarbiat Modares University , Tehran , Iran
| | - Amir Abbas Momtazi-Borojeni
- c Student Research Committee, Mashhad University of Medical Sciences , Mashhad , Iran ;,e Department of Medical Biotechnology , Mashhad University of Medical Sciences , Mashhad , Iran
| | - Morteza Samadi
- f Department of Immunology , Shahid Sadoughi University , Yazd , Iran ;,g Reproductive Immunology Research Center, Shahid Sadoughi University , Yazd , Iran
| | - Houshang Rafatpanah
- h Research Center for HIV/AIDS, HTLV1 and Viral Hepatitis, Iranian Academic for Education, Culture and Research (ACECR), Mashhad Branch , Mashhad , Iran ;,i Inflammation/Inflammatory Diseases Research Center, Mashhad University of Medical Sciences , Mashhad , Iran
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Xu WD, Xie QB, Zhao Y, Liu Y. Association of Interleukin-23 receptor gene polymorphisms with susceptibility to Crohn's disease: A meta-analysis. Sci Rep 2015; 5:18584. [PMID: 26678098 PMCID: PMC4683513 DOI: 10.1038/srep18584] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 11/20/2015] [Indexed: 02/05/2023] Open
Abstract
Studies investigating the association between Interleukin-23 receptor (IL-23R) gene polymorphisms and Crohn’s disease (CD) report conflicting results. Thus, a meta-analysis was carried out to assess the association between the IL-23R polymorphisms and CD. A systematic literature search was conducted to identify all relevant studies. Pooled odds ratio (ORs) with 95% confidence interval (CIs) was used to estimate the strength of association. Finally, a total of 60 case-control studies in 56 articles, involving 22,820 CD patients and 27,401 healthy controls, were included in the meta-analysis. Overall, a significant association was found between all CD and the rs7517847 polymorphism (OR = 0.699, 95% CI = 0.659 ~ 0.741, P < 0.001). Meta-analysis of the rs11209026, rs1343151, rs10489629 and rs11465804 polymorphisms indicated the same pattern as for rs7517847. Meta-analysis showed an association between the rs10889677A allele and CD (OR = 1.393, 95% CI = 1.328 ~ 1.461, P < 0.001). Similarly, meta-analysis of the rs2201840, rs1004819, rs1495965 and rs11209032 polymorphisms revealed the same pattern as that shown by meta-analysis of rs10889677. Stratification by ethnicity revealed that IL-23R gene polymorphisms were associated with CD in the Caucasian group, but not in Asians. In summary, the meta-analysis suggests a significant association between IL-23R polymorphisms and CD, especially in Caucasians.
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Affiliation(s)
- Wang-Dong Xu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, Sichuan, 610041, PR China
| | - Qi-Bing Xie
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, Sichuan, 610041, PR China
| | - Yi Zhao
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, Sichuan, 610041, PR China
| | - Yi Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, 37 Guoxue Road, Chengdu, Sichuan, 610041, PR China
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Liu M, Zhu W, Wang J, Zhang J, Guo X, Wang J, Song J, Dong W. Interleukin-23 receptor genetic polymorphisms and ulcerative colitis susceptibility: A meta-analysis. Clin Res Hepatol Gastroenterol 2015; 39:516-25. [PMID: 25497273 DOI: 10.1016/j.clinre.2014.10.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 09/13/2014] [Accepted: 10/17/2014] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The interleukin-23 receptor (IL-23R) polymorphism has been implicated in susceptibility to ulcerative colitis (UC), but the results remain inconclusive. This study was designed to evaluate whether IL-23R polymorphisms were associated with UC susceptibility. METHODS CNKI, WanFang Data, PubMed, MEDLINE, Web of Science, Google Scholar, EBSCO, CBM database and EMBASE were searched until 31 June 2014 for eligible studies on eight IL-23R polymorphisms: rs11209026, rs7517847, rs1209032, rs2201841, rs1343151, rs1088967, rs1495965 and rs1004819. Meta-analysis from all eligible case-control studies was performed to assess the purported associations. Meta-analysis was performed by using the RevMan 5.2 software and STATA package version 12.0. RESULTS Sixteen studies with 5438 cases and 7380 controls were included. Overall, our analysis found that variant minor alleles for single nucleotide polymorphisms (SNPs) rs11209026 (Arg381Gln) (dominant model: GG+TG vs. TT, P=0.02, OR=0.71, 95%CI: 0.53-0.94); rs7517847 (recessive model: GG vs. TT, P=0.04, OR=0.80, 95%CI: 0.65-0.99) and rs11209032 [dominant model: GA+AA vs. GG (P=0.04, OR=1.31, 95% CI: 1.01-1.26); AA vs. GG: (P=0.04, OR=1.21, 95% CI: 1.01-1.45)] of IL-23R were associated with UC risk. In stratification analysis by ethnicity, we observed that the rs11209026 and rs7517847 polymorphism of IL-23R could protect against development of UC among Caucasian populations [rs11209026: dominant model (P=0.01, OR=0.69, 95%CI: 0.52-0.92); rs7517847: GG vs. TT (P=0.002, OR=0.69, 95%CI: 0.54-0.87); recessive model (P=0.004, OR=0.73, 95% CI: 0.59-0.90)]; the rs11209032 were associated with a greater risk for UC in Caucasian populations [dominant model (P=0.04, OR=1.13, 95%CI: 1.00-1.26)]; the rs1088967 were associated with a lower risk for UC among Asian populations [dominant model (P=0.04, OR=0.73, 95%CI: 0.54-0.99)]. Moreover, meta-analysis revealed no association between the four alleles of the rs2201841, rs1004819, rs1495965 and rs1343151 polymorphisms and the risk of developing UC in Caucasian and Asian populations. CONCLUSION Our meta-analysis supports that two polymorphisms (rs11209026 and rs7517847) in the IL-23 gene may be considered to be protective factors against developing UC among Caucasian populations; while the rs11209032 polymorphisms may increase the risk of UC among Caucasian populations; furthermore, the rs1088967 polymorphisms in the IL-23 gene may be considered to be protective factors against developing UC among Asian populations. Further large case-control studies especially concerning ethnicity differences and genotype-phenotype interaction should be performed to clarify possible roles of IL-23R in UC.
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Affiliation(s)
- Min Liu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 430060 Wuhan, Hubei, PR China
| | - Wenqian Zhu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 430060 Wuhan, Hubei, PR China
| | - Jun Wang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 430060 Wuhan, Hubei, PR China
| | - Jixiang Zhang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 430060 Wuhan, Hubei, PR China
| | - Xufeng Guo
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 430060 Wuhan, Hubei, PR China
| | - Jing Wang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 430060 Wuhan, Hubei, PR China
| | - Jia Song
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 430060 Wuhan, Hubei, PR China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, 430060 Wuhan, Hubei, PR China.
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Interleukin-23R rs7517847 T/G Polymorphism Contributes to the Risk of Crohn's Disease in Caucasians: A Meta-Analysis. J Immunol Res 2015; 2015:279849. [PMID: 26090488 PMCID: PMC4451526 DOI: 10.1155/2015/279849] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Revised: 01/05/2015] [Accepted: 01/12/2015] [Indexed: 12/13/2022] Open
Abstract
The association between Interleukin-23R gene polymorphism and Crohn's disease (CD) in Caucasians is still controversial. Thus, a meta-analysis was performed to evaluate the correlation between this gene variant and CD risk. We retrieved the available data from EMBASE and PUBMED until May 1, 2014, and evaluated the effect of rs7517847 in Caucasians. The significant associations were confirmed between rs7517847 and CD risk in dominant models (TT/TG versus GG: OR = 1.652, 95% CI 1.277, 2.137), allelic model (T allele versus G allele: OR = 1.327, 95% CI 1.198, 1.469), homozygote comparison (TT versus GG: OR = 1.890, 95% CI 1.465, 2.437), heterozygote comparison (TG versus GG: OR = 1.509, 95% CI 1.161, 1.960), and recessive model (TT versus TG/GG: OR = 1.409, 95% CI 1.279, 1.552). In conclusion, this meta-analysis demonstrates that rs7517847 is associated with the risk of CD in Caucasians. These findings show that IL-23R genes confer susceptibility to CD in the Caucasians.
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Serbati N, Senhaji N, Diakite B, Badre W, Nadifi S. IL23R and ATG16L1 variants in Moroccan patients with inflammatory bowel disease. BMC Res Notes 2014; 7:570. [PMID: 25159710 PMCID: PMC4162942 DOI: 10.1186/1756-0500-7-570] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2014] [Accepted: 08/14/2014] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Inflammatory bowel diseases (IBD) are chronic diseases of the gastrointestinal tract. Although their pathogenesis is unclear, the combination of genetic predisposition and environmental components are believed to be the main cause of these diseases. Recently, many variants in interleukin 23 receptor (IL23R) and autophagy-related 16-like 1 (ATG16L1) genes have been associated with the disease. Our objective was to assess the frequency of ATG16L1 (T300A) and IL23R (L310P) variants in Moroccan IBD (Crohn's disease and Ulcerative Colitis) patients and to evaluate a possible effect of these variants on disease's phenotype and clinical course. METHODS 96 Moroccan IBD patients and 114 unrelated volunteers were genotyped for ATG16L1 (T300A) and IL23R (L310P) variants by PCR-restriction fragment length polymorphism. RESULTS This is the first report on the prevalence of ATG16L1 (T300A) and IL23R (L310P) variants in a Moroccan group. We found that IL23R (L310P) variant conferred a protective effect for crohn's disease (CD) but not ulcerative colitis (UC) patients. The presence of ATG16L1 (T300A) mutated alleles was associated with CD type but not with disease onset. In addition, the carriage of T300A variant alleles conferred a protective effect in UC. CONCLUSION Our results showed that the prevalence of ATG16L1 and IL23R variants was not significantly different between patients and controls. However a possible role of ATG16L1 (T300A) on CD phenotype was suggested.
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Affiliation(s)
- Nadia Serbati
- Laboratory of Medical Genetics- Medical school of Casablanca, Faculté de Médecine et de Pharmacie de Casablanca, 19, rue Tarik ibn ziad, Casablanca, Morocco.
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Magyari L, Kovesdi E, Sarlos P, Javorhazy A, Sumegi K, Melegh B. Interleukin and interleukin receptor gene polymorphisms in inflammatory bowel diseases susceptibility. World J Gastroenterol 2014; 20:3208-22. [PMID: 24695754 PMCID: PMC3964393 DOI: 10.3748/wjg.v20.i12.3208] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 12/20/2013] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), represents a group of chronic inflammatory disorders caused by dysregulated immune responses in genetically predisposed individuals. Genetic markers are associated with disease phenotype and long-term evolution, but their value in everyday clinical practice is limited at the moment. IBD has a clear immunological background and interleukins play key role in the process. Almost 130 original papers were revised including meta-analysis. It is clear these data are very important for understanding the base of the disease, especially in terms of clinical utility and validity, but text often do not available for the doctors use these in the clinical practice nowadays. We conducted a systematic review of the current literature on interleukin and interleukin receptor gene polymorphisms associated with IBD, performing an electronic search of PubMed Database from publications of the last 10 years, and used the following medical subject heading terms and/or text words: IBD, CD, UC, interleukins and polymorphisms.
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Yu P, Shen F, Zhang X, Cao R, Zhao X, Liu P, Tu H, Yang X, Shi R, Zhang H. Association of single nucleotide polymorphisms of IL23R and IL17 with ulcerative colitis risk in a Chinese Han population. PLoS One 2012; 7:e44380. [PMID: 22984500 PMCID: PMC3439435 DOI: 10.1371/journal.pone.0044380] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2012] [Accepted: 08/06/2012] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Previous studies implicated that IL23R and IL17 genes play an important role in autoimmune inflammation. Genome-wide association studies have also identified multiple single nucleotide polymorphisms (SNPs) in the IL23R gene region associated with inflammatory bowel diseases. This study examined the association of IL23R and IL17A gene SNPs with ulcerative colitis susceptibility in a population in China. METHODOLOGY A total of 270 ulcerative colitis and 268 healthy controls were recruited for the analyses of 23 SNPs in the IL23R and IL17A regions. Genomic DNA was extracted and analysis of these 23 SNPs using ligase detection reaction allelic (LDR) technology. Genotype and allele associations were calculated using SPSS 13.0 software package. PRINCIPAL FINDINGS Compared to the healthy controls, the variant alleles IL23R rs7530511, and rs11805303 showed a statistically significant difference for ulcerative colitis susceptibility (0.7% vs 3.3%, P = 0.002; 60.4% vs 53.2%, P = 0.0017, respectively). The linkage disequilibrium (LD) patterns of these SNPs were measured and three LD blocks from the SNPs of IL23R and one block from those of IL17A were identified. A novel association with ulcerative colitis susceptibility occurred in haplotypes of IL23R (Block1 H3 P = 0.02; Block2 H2 P = 0.019; Block3 H4 P = 0.029) and IL17A (H4 P = 0.034). Pair-wise analyses showed an interaction between the risk haplotypes in IL23R and IL17A (P = 0.014). CONCLUSIONS Our study demonstrated that rs7530511, and rs11805303 of IL23R were significantly associated with ulcerative colitis susceptibility in the Chinese population. The most noticeable finding was the linkage of IL23R and IL17A gene region to ulcerative colitis risk due to the gene-gene interaction.
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Affiliation(s)
- Pengli Yu
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Fangcheng Shen
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaofei Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Risheng Cao
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiaodan Zhao
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Pengfei Liu
- Department of Gastroenterology, the People's Hospital of Jiangyin, Jiangyin, China
| | - Huiming Tu
- Department of Gastroenterology, the Fourth People's Hospital of Wuxi, Wuxi, China
| | - Xiaozhong Yang
- Department of Gastroenterology, the First Hospital of Huaian, Huaian, China
| | - Ruihua Shi
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hongjie Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Bondurant KL, Lundgreen A, Herrick JS, Kadlubar S, Wolff RK, Slattery ML. Interleukin genes and associations with colon and rectal cancer risk and overall survival. Int J Cancer 2012; 132:905-15. [PMID: 22674296 DOI: 10.1002/ijc.27660] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2011] [Accepted: 05/10/2012] [Indexed: 12/20/2022]
Abstract
Interleukins are a group of cytokines that contribute to growth and differentiation, cell migration, and inflammatory and anti-inflammatory responses by the immune system. In our study, we examined genetic variation in genes from various anti-inflammatory and proinflammatory interleukins to determine association with colon and rectal cancer risk and overall survival. Data from two population-based incident studies of colon cancer (1,555 cases and 1,956 controls) and rectal cancer (754 cases and 954 controls) were used. After controlling for multiple comparisons, single nucleotide polymorphisms (SNPs) from four genes, IL3, IL6R, IL8, IL15, were associated with increased colon cancer risk, and CXCR1 and CXCR2 were significantly associated with increased rectal cancer risk. Only SNPs from genes within the IL-8 pathway (IL8, CXCR1 and CXCR2) showed a significant association with both colon and rectal cancer risk. Several SNPs interacted significantly with IL8 and IFNG SNPs and with aspirin/non-steroidal anti-inflammatory drug (NSAID), cigarette smoking, estrogen use and BMI. For both colon and rectal cancer, increasing numbers of risk alleles were associated with increased hazard of death from cancer; the estimated hazard of death for colon cancer for the highest category of risk alleles was 1.74 (95% confidence interval [CI] 1.18-2.56) and 1.96 (95% CI 1.28-2.99) for rectal cancer. These data suggest that interleukin genes play a role in risk and overall survival for colon and rectal cancer.
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Affiliation(s)
- Kristina L Bondurant
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
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Naser SA, Arce M, Khaja A, Fernandez M, Naser N, Elwasila S, Thanigachalam S. Role of ATG16L, NOD2 and IL23R in Crohn’s disease pathogenesis. World J Gastroenterol 2012; 18:412-24. [PMID: 22346247 PMCID: PMC3270503 DOI: 10.3748/wjg.v18.i5.412] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2011] [Revised: 08/08/2011] [Accepted: 08/27/2011] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease is a group of diseases that includes Crohn’s disease (CD) and ulcerative colitis. CD is characterized as a chronic inflammatory disease of the gastrointestinal tract, ranging from the mouth to the anus. Although there are gross pathological and histological similarities between CD and Johne’s disease of cattle, the cause of CD remains controversial. It is vital to understand fully the cause of this disease because it affects approximately 500 000 people in North America and Europe. It ranges from 27 to 48 cases per 100 000 people. There are many theories on the cause of CD ranging from possible association with environmental factors including microorganisms to imbalance in the intestinal normal flora of the patients. Regardless of the environmental trigger, there is strong evidence that a genetic disposition is a major key in acquiring CD. Many studies have proven the link between mutations in the ATG16L, NOD2/CARD15, IBD5, CTLA4, TNFSF15 and IL23R genes, and CD. The purpose of this review is to examine all genetic aspects and theories of CD, including up to date multiple population studies performed worldwide.
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Bossini-Castillo L, Martin JE, Broen J, Gorlova O, Simeón CP, Beretta L, Vonk MC, Callejas JL, Castellví I, Carreira P, García-Hernández FJ, Fernández Castro M, Coenen MJH, Riemekasten G, Witte T, Hunzelmann N, Kreuter A, Distler JHW, Koeleman BP, Voskuyl AE, Schuerwegh AJ, Palm Ø, Hesselstrand R, Nordin A, Airó P, Lunardi C, Scorza R, Shiels P, van Laar JM, Herrick A, Worthington J, Denton C, Tan FK, Arnett FC, Agarwal SK, Assassi S, Fonseca C, Mayes MD, Radstake TRDJ, Martin J. A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations. Hum Mol Genet 2011; 21:926-33. [PMID: 22076442 DOI: 10.1093/hmg/ddr522] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
A single-nucleotide polymorphism (SNP) at the IL12RB2 locus showed a suggestive association signal in a previously published genome-wide association study (GWAS) in systemic sclerosis (SSc). Aiming to reveal the possible implication of the IL12RB2 gene in SSc, we conducted a follow-up study of this locus in different Caucasian cohorts. We analyzed 10 GWAS-genotyped SNPs in the IL12RB2 region (2309 SSc patients and 5161 controls). We then selected three SNPs (rs3790567, rs3790566 and rs924080) based on their significance level in the GWAS, for follow-up in an independent European cohort comprising 3344 SSc and 3848 controls. The most-associated SNP (rs3790567) was further tested in an independent cohort comprising 597 SSc patients and 1139 controls from the USA. After conditional logistic regression analysis of the GWAS data, we selected rs3790567 [P(MH)= 1.92 × 10(-5) odds ratio (OR) = 1.19] as the genetic variant with the firmest independent association observed in the analyzed GWAS peak of association. After the first follow-up phase, only the association of rs3790567 was consistent (P(MH)= 4.84 × 10(-3) OR = 1.12). The second follow-up phase confirmed this finding (P(χ2) = 2.82 × 10(-4) OR = 1.34). After performing overall pooled-analysis of all the cohorts included in the present study, the association found for the rs3790567 SNP in the IL12RB2 gene region reached GWAS-level significant association (P(MH)= 2.82 × 10(-9) OR = 1.17). Our data clearly support the IL12RB2 genetic association with SSc, and suggest a relevant role of the interleukin 12 signaling pathway in SSc pathogenesis.
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Affiliation(s)
- Lara Bossini-Castillo
- Instituto de ParasitologÍa y Biomedicina López-Neyra, IPBLN-CSIC, Granada 18100, Spain.
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No association between interleukin 23 receptor gene polymorphisms and systemic lupus erythematosus. Rheumatol Int 2011; 30:33-8. [PMID: 19306001 DOI: 10.1007/s00296-009-0893-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2008] [Accepted: 03/04/2009] [Indexed: 12/17/2022]
Abstract
The objective of this study was to elucidate whether polymorphisms of the interleukin 23 receptor gene (IL23R) are associated with susceptibility to systemic lupus erythematosus (SLE) in a Korean population. We recruited 602 SLE patients and 991 healthy controls. Seven single nucleotide polymorphisms (rs1004819, rs7517847, rs10489629, rs2201841, rs1343151, rs11209032, and rs1495965) were selected for genotyping among previously reported variants used in a genome-wide association study of inflammatory bowel disease. Polymorphic sites were genotyped using the TaqMan assay. The genotype distributions of IL23R polymorphisms and haplotypes were compared between the SLE patients and healthy controls using multiple logistic regression models. None of the IL23R genetic variants differed significantly between SLE patients and healthy controls, which suggests that IL23R polymorphisms play no role in the susceptibility to SLE in the Korean population. Electronic supplementary material The online version of this article (doi:10.1007/s00296-009-0893-8) contains supplementary material, which is available to authorized users.
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Duffin KC, Woodcock J, Krueger GG. Genetic variations associated with psoriasis and psoriatic arthritis found by genome-wide association. Dermatol Ther 2010; 23:101-13. [PMID: 20415816 DOI: 10.1111/j.1529-8019.2010.01303.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Psoriasis and psoriatic arthritis are immune disorders with a complex polygenic basis. HLA-Cw6, which lies in the major histocompatibility region on chromosome 6, is considered the major genetic determinant of psoriasis. Recent genome-wide association studies have identified new variants outside of the MHC with relevance to the immunology of psoriasis. Variants in or near genes that encode subunits of cytokines (IL12B, IL23A) or cytokine receptors (IL23R) are interesting given that the gene product of IL12B, p40, is the target of a recently approved monoclonal antibody therapy for psoriasis (ustekinumab). Association with psoriasis and psoriatic arthritis has been found in TNFAIP3 and TNFIP1, ubiquitin ligases in the NF-kappaB pathway, and IL13, a Th2 cytokine. Copy number variation of human beta-defensin and late cornified envelope genes also associate with psoriasis. Many of these genetic variations also associate with immune disorders considered psoriatic co-morbidities, including Crohn's disease and diabetes.
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Diaz-Gallo LM, Palomino-Morales RJ, Gómez-García M, Cardeña C, Rodrigo L, Nieto A, Alcain G, Cueto I, López-Nevot MA, Martin J. STAT4 gene influences genetic predisposition to ulcerative colitis but not Crohn's disease in the Spanish population: a replication study. Hum Immunol 2010; 71:515-519. [PMID: 20153791 DOI: 10.1016/j.humimm.2010.02.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2009] [Revised: 01/21/2010] [Accepted: 02/01/2010] [Indexed: 12/12/2022]
Abstract
Recently, the signal transducer and activator of transcription 4 (STAT4) gene has been associated with multiple autoimmune diseases. Interestingly, a recent work showed that the T allele of the rs7574865 STAT4 SNP was associated with inflammatory bowel disease (IBD) in a Spanish population. The aim of the present study was to reevaluate the role of the STAT4 rs7574865 polymorphism on IBD. The present case-control study included 498 Crohn's disease (CD) patients, 402 ulcerative colitis (UC) patients, and 1296 healthy matched controls. Genotyping was performed using a PCR system with a pre-developed TaqMan allelic discrimination assay for the rs7574865 STAT4 SNP. Moreover, a meta-analysis was performed with the previous work in a Spanish population and the current study, including a final sample size of 1574 IBD patients (820 with CD and 754 with UC) and 2012 healthy controls. No evidence of association was found for the current case-control study (CD: p = 0.23, OR = 0.9, 95% CI = 0.75-1.1; UC: p = 0.17, OR = 1.14, 95% CI = 0.95-1.38). However, the meta-analysis showed that the STAT4 rs7574865 T allele was significantly associated with susceptibility to UC (p = 0.012 pooled; OR = 1.20, 95% CI = 1.04-1.39) but not CD (p = 0.71 pooled; OR = 0.93, 95% CI = 0.65-1.34). Our data suggest that the rs7574865 STAT4 SNP is a genetic susceptibility variant for UC but not CD in the Spanish population.
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26
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Leng RX, Pan HF, Chen GM, Wang C, Qin WZ, Chen LL, Tao JH, Ye DQ. IL-23: A Promising Therapeutic Target for Systemic Lupus Erythematosus. Arch Med Res 2010; 41:221-5. [DOI: 10.1016/j.arcmed.2010.02.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2009] [Accepted: 02/05/2010] [Indexed: 12/18/2022]
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27
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Lin Z, Poritz L, Franke A, Li TY, Ruether A, Byrnes KA, Wang Y, Gebhard AW, MacNeill C, Thomas NJ, Schreiber S, Koltun WA. Genetic association of nonsynonymous variants of the IL23R with familial and sporadic inflammatory bowel disease in women. Dig Dis Sci 2010; 55:739-46. [PMID: 19294505 DOI: 10.1007/s10620-009-0782-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2008] [Accepted: 02/26/2009] [Indexed: 12/15/2022]
Abstract
PURPOSE To replicate the association of IL23R R381Q (rs11209026) with inflammatory bowel disease (IBD), examine the effect of the two nonsynonymous variations, Q3H and L310P, on IBD, and to study gender distribution of these variants in IBD patients. RESULTS IL23R R381Q was associated with Crohn's disease (CD) (P = 0.010), but not with ulcerative colitis (UC); L310P was associated with UC (P = 0.004), but not with CD; no association was observed for Q3H with CD or UC. A female-specific association of R381Q with CD (P = 0.041), and of L310P with UC (P = 0.008) was observed. CONCLUSION We replicated the association of IL23R R381Q with CD but not UC, and we observed an association of L310P with UC, but not CD, in a central Pennsylvania population. Further analysis of the distribution of IL23R variants revealed that these effects were largely female-specific. The results suggest that IL23R R381Q confers protection against CD and that L310P confers protection against UC in females.
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Affiliation(s)
- Zhenwu Lin
- Department of Surgery, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA.
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Li Y, Mao Q, Shen L, Tian Y, Yu C, Zhu WM, Li JS. Interleukin-23 receptor genetic polymorphisms and Crohn's disease susceptibility: a meta-analysis. Inflamm Res 2010; 59:607-14. [PMID: 20157760 DOI: 10.1007/s00011-010-0171-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2009] [Revised: 01/22/2010] [Accepted: 02/01/2010] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVE This study was designed to evaluate whether interleukin-23 receptor (IL-23R) polymorphisms were associated with Crohn's disease (CD) susceptibility. METHODS PubMed, MEDLINE, and Embase were searched for studies that investigated the IL-23R variants and CD risk. Meta-analysis from all eligible case-control studies was performed to assess the purported associations. RESULTS Our analysis found that variant minor alleles for single nucleotide polymorphisms (SNPs) rs11209026 (Arg381Gln) (P < 0.00001, OR = 0.43, 95% CI (0.37-0.50)) and rs7517847 (G/G vs. T/T, P < 0.00001, OR = 0.49, 95% CI (0.38-0.64); G/G vs. T/G + T/T, (P < 0.00001, OR = 0.56, 95% CI (0.44-0.72); T/G + G/G vs. T/T, (P < 0.00001, OR = 0.71, 95% CI (0.64-0.79) of IL-23R were inversely associated with CD risk; sensitivity analysis also indicated that Caucasian population with a variant of Arg381Gln has a decreased risk for developing CD (P < 0.00001, OR = 0.43, 95% CI (0.36-0.50)). CONCLUSION Our meta-analysis supports that two polymorphisms (Arg381Gln and rs7517847) within the IL-23R gene may be considered to be protective factors against developing CD. Further large case-control studies especially concerning ethnicity differences and genotype-phenotype interaction should be performed to clarify possible roles of IL-23R in CD.
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Affiliation(s)
- Yi Li
- Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
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29
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Sventoraityte J, Zvirbliene A, Franke A, Kwiatkowski R, Kiudelis G, Kupcinskas L, Schreiber S. NOD2, IL23R and ATG16L1 polymorphisms in Lithuanian patients with inflammatory bowel disease. World J Gastroenterol 2010; 16:359-64. [PMID: 20082483 PMCID: PMC2807958 DOI: 10.3748/wjg.v16.i3.359] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the frequency of NOD2, IL23R and ATG16L1 genetic variants in a case-control panel for inflammatory bowel disease (IBD) from Lithuania.
METHODS: One hundred and eighty unrelated IBD patients [57 Crohn’s disease (CD) and 123 ulcerative colitis (UC)] and 186 healthy controls were genotyped for the following known genetic susceptibility variants: NOD2 - Arg702Trp (rs2066844), Gly908Arg (rs2066845) and Leu1007insC (rs2066847), as well as IL23R - Arg381Gln (rs11209026) and ATG16L1 - Thr300Ala (rs2241880).
RESULTS: The effect that carriership of at least one NOD2 risk allele predisposes to CD was replicated in the Lithuanian population (41.1% CD vs 16.9% controls, P = 2 × 10-4, OR = 3.48, 95% CI: 1.81-6.72). In the allelic single marker analysis, Leu1007insC was strongly associated with CD (21.4% CD vs 4.7% controls, P = 3.687 × 10-8, OR = 5.54, 95% CI: 2.85-10.75). Neither the other two NOD2 variants, nor the known variants in IL23R and ATG16L1 were found to be risk factors for CD, UC or IBD. However, our relatively small study population was underpowered to demonstrate such weak to moderate disease associations.
CONCLUSION: The results support a strong association between CD susceptibility and the Leu1007insC variant in NOD2 in the Lithuanian study population.
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Melum E, Franke A, Karlsen TH. Genome-wide association studies - A summary for the clinical gastroenterologist. World J Gastroenterol 2009; 15:5377-96. [PMID: 19916168 PMCID: PMC2778094 DOI: 10.3748/wjg.15.5377] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Genome-wide association studies (GWAS) have been applied to various gastrointestinal and liver diseases in recent years. A large number of susceptibility genes and key biological pathways in disease development have been identified. So far, studies in inflammatory bowel diseases, and in particular Crohn’s disease, have been especially successful in defining new susceptibility loci using the GWAS design. The identification of associations related to autophagy as well as several genes involved in immunological response will be important to future research on Crohn’s disease. In this review, key methodological aspects of GWAS, the importance of proper cohort collection, genotyping issues and statistical methods are summarized. Ways of addressing the shortcomings of the GWAS design, when it comes to rare variants, are also discussed. For each of the relevant conditions, findings from the various GWAS are summarized with a focus on the affected biological systems.
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31
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Single-nucleotide polymorphisms and expression of IL23R in Chinese ankylosing spondylitis patients. Rheumatol Int 2009; 30:955-9. [DOI: 10.1007/s00296-009-1085-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2008] [Accepted: 08/05/2009] [Indexed: 10/20/2022]
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32
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Márquez A, Orozco G, Martínez A, Palomino-Morales R, Fernández-Arquero M, Mendoza JL, Taxonera C, Díaz-Rubio M, Gómez-García M, Nieto A, López-Nevot MA, de la Concha EG, Martín J, Urcelay E. Novel association of the interleukin 2-interleukin 21 region with inflammatory bowel disease. Am J Gastroenterol 2009; 104:1968-75. [PMID: 19471255 DOI: 10.1038/ajg.2009.224] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Genome-wide association studies have reported the role of the interleukin (IL) 2-IL21 chromosomal region at 4q27 in several autoimmune conditions. Mice deficient in IL-2 develop a disease with clinical and histological similarity to ulcerative colitis (UC) in humans. Modest evidence of linkage with UC was tentatively proposed for the IL2 gene more than a decade ago. Therefore, we decide to investigate the association of polymorphisms in the IL-2 axis (IL2, IL2RA, and IL2RB genes) with inflammatory bowel diseases (IBDs). METHODS Seven hundred and twenty-eight white Spanish unrelated IBD patients (356 Crohn's disease (CD) and 372 UC) and 549 ethnically matched controls were included in a case-control study. In addition, a Spanish replication cohort with 562 CD and 430 UC patients and 1,310 controls were analyzed. Eight single-nucleotide polymorphisms previously associated with different autoimmune diseases were analyzed using TaqMan chemistry. RESULTS The IL2-rs6822844 polymorphism modified CD predisposition (P=0.002; odds ratio, OR (95% confidence interval, CI)=0.61 (0.44-0.84)); this was replicated in the other Spanish cohort, resulting in a strong protective effect of the minor allele in the merged samples (P=0.0002; OR (95% CI)=0.70 (0.58-0.85)). A similar effect of rs6822844 was detected for UC. Another marker, rs11938795, also showed evidence of an association with CD (P=0.006; OR (95% CI)=0.73 (0.58-0.92)). CONCLUSIONS Polymorphisms within the IL2-IL21 linkage disequilibrium (LD) block show a novel association with IBD, this is concordant with suggestive previous results of whole genome analyses in CD and type 1 diabetes. Our data agree with the effect previously observed for other conditions and delineate a shared underlying mechanism.
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Affiliation(s)
- Ana Márquez
- Immunology Department, Hospital Clínico San Carlos, Madrid 28040, Spain
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Zhang L, Jarvis LB, Baek HJ, Gaston JSH. Regulatory IL4+CD8+ T cells in patients with ankylosing spondylitis and healthy controls. Ann Rheum Dis 2009; 68:1345-51. [PMID: 18647857 DOI: 10.1136/ard.2008.088120] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
OBJECTIVES Interleukin (IL)4+CD8+ regulatory T cells (Treg) obtained from peripheral blood mononuclear cells (PBMCs) from patients with ankylosing spondylitis (AS) by coculture with autologous dendritic cells (DC) have been previously described. In the present work, the proportions of IL4+CD8+ T cells in PB from patients with AS and controls are examined; in addition the conditions required for the generation of IL4+CD8+ Treg cells and their frequency in T cell lines from patients with AS and controls are investigated. METHODS CD8+ T cells were either stimulated non-specifically ex vivo and intracellular cytokines examined, or cocultured with DC and other stimuli, for 2 weeks. The resulting lines were analysed for cytokine expression. Clones derived from these lines were tested for regulatory function. RESULTS PBMCs from patients with AS and from human leukocyte antigen (HLA)-B27+ healthy controls contained a higher frequency of IL4+CD8+ T cells than those from HLA-B27- controls. Likewise, CD8+ T cell lines obtained by coculture with DC contained a higher ratio of IL4+ to interferon (IFN)gamma+ cells when obtained from patients with AS or HLA-B27+ controls. T cell clones obtained from these lines showed regulatory activity. Outgrowth of IL4+ CD8+ T cells required contact with DC, but not maturation with lipopolysaccharide (LPS); allogeneic DC were also effective. Coculture with lymphoblastoid cells, or anti-CD3/CD28 microbeads, produced only expansion of IFN gamma-producing CD8+ T cells. CONCLUSIONS The higher proportion of CD8+ cells which can produce IL4 in PB and in expanded CD8+ T cell lines suggests an altered pattern of CD8+ T cell differentiation in AS and in HLA-B27+ healthy individuals. This predisposition to generate IL4+CD8+ T cells may play a role in pathogenesis of spondyloarthritis.
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Affiliation(s)
- L Zhang
- Department of Rheumatology and Immunology, Changzheng Hospital, Shanghai, China
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Sáfrány E, Pazár B, Csöngei V, Járomi L, Polgár N, Sipeky C, Horváth IF, Zeher M, Poór G, Melegh B. Variants of the IL23R gene are associated with ankylosing spondylitis but not with Sjögren syndrome in Hungarian population samples. Scand J Immunol 2009; 70:68-74. [PMID: 19522770 DOI: 10.1111/j.1365-3083.2009.02265.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Recently, associations were found between several autoimmune diseases and functional variants of interleukin-23 receptor (IL23R) gene; here, we studied the possible association of nine polymorphisms of IL23R with ankylosing spondylitis (AS) and with Sjögren syndrome (SS). In our study, we genotyped groups of patients with AS (n = 206), SS (n = 156) and healthy controls (n = 235) for rs11805303, rs10889677, rs1004819, rs2201841, rs11209032, rs11209026, rs10489629, rs7517847 and rs7530511 variants using PCR-RFLP methods. We observed significant increase in the carriage of the T allele of rs11805303 and the A allele of rs1004189 in the AS group compared with the controls. For the rs10889677 variant, the prevalence of the AA genotype and for the rs2201841, the CC genotype showed a more than two-fold increase in the AS group compared with the controls. By contrast, the GA heterozygous genotype of rs11209026 variant showed a significant decrease in AS patients compared with controls. Haplotype analysis revealed association of four IL23R haplotypes with AS. There was no difference in the distribution of any of the examined IL23R variants between controls and SS patients. In conclusion, we confirmed the susceptibility or protective associations of IL23R polymorphisms with AS in a Hungarian population and first demonstrated the involvement of the rs11805303 intronic single nucleotide polymorphisms, which was tested so far only for other autoimmune diseases.
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Affiliation(s)
- E Sáfrány
- Department of Medical Genetics, University of Pécs, Pécs
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Takaku T, Calado RT, Kajigaya S, Young NS. Interleukin-23 receptor (IL-23R) gene polymorphisms in acquired aplastic anemia. Ann Hematol 2009; 88:653-7. [PMID: 19165485 PMCID: PMC3438141 DOI: 10.1007/s00277-008-0666-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2008] [Accepted: 12/04/2008] [Indexed: 01/07/2023]
Abstract
Acquired aplastic anemia (AA) is a rare disease with a complex pathogenesis. In most cases, T cell-mediated immune destruction of hematopoietic cells results in peripheral blood pancytopenia and bone marrow hypoplasia. A subset of the heterodimeric interleukin-23 receptor gene (IL-23R) is significantly associated with autoimmune-mediated diseases. To examine whether IL-23R single nucleotide polymorphisms (SNPs) might contribute to AA, we selected three IL-23R SNPs with amino acid changes (rs11209026: p.Arg381Gln; rs41313262: p.Val362Ile; and rs11465797: p.Thr175Asn) and compared their frequencies in 279 AA patients and 184 ethnically matched healthy controls. The three SNP prevalences were similar between the AA patients and controls. The Arg381Gln variant, which has a strong protective effect against inflammatory bowel disease, showed no association with AA. Furthermore, IL-23 levels in sera were measured in the AA patients and in controls, and there were no significant differences among them. Our results indicate that these three IL-23R SNPs and serum IL-23 level have no apparent impact on susceptibility to AA.
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Affiliation(s)
- Tomoiku Takaku
- Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD, USA.
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Palomino-Morales RJ, Oliver J, Gómez-García M, López-Nevot MA, Rodrigo L, Nieto A, Alizadeh BZ, Martín J. Association of ATG16L1 and IRGM genes polymorphisms with inflammatory bowel disease: a meta-analysis approach. Genes Immun 2009; 10:356-364. [PMID: 19491842 DOI: 10.1038/gene.2009.25] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2008] [Revised: 02/12/2009] [Accepted: 02/18/2009] [Indexed: 12/18/2022]
Abstract
The aim of this study was to determine the role of the ATG16L1 (rs2241880) and IRGM (rs13361189 and rs4958847) genes polymorphism in Crohn's disease (CD) and ulcerative colitis (UC). Our study included 557 CD and 425 UC patients and 672 ethnically matched Spanish controls and a meta-analysis with the data published to date. The polymorphisms were genotyped using predesigned TaqMan single nucleotide polymorphism genotyping assays. There was a statistically significant difference in the distribution of the ATG16L1 rs2241880 G allele between CD patients and controls in the Spanish population: P=6.5 x 10(-9), odds ratio (OR)=1.62. Although no differences were observed between UC patients and controls in the Spanish cohort, a meta-analysis demonstrated that the ATG16L1 G allele increase significantly risk for UC (P=0.0003, pooled OR=1.08). In addition, our meta-analysis data showed that IRGM rs13361189 and rs4958847 polymorphisms were associated with CD (rs13361189 C allele P=1.07 x 10(-19), pooled OR=1.34; rs4958847 A allele P=2.78 x 10(-17), pooled OR=1.31) and UC (rs13361189 P=0.0069, pooled OR=1.16; rs4958847 P=0.014, pooled OR=1.13). In conclusion, our results confirm the ATG16L1 rs2241880 and IRGM rs13361189 and rs4958847 polymorphisms as important markers for CD susceptibility and indicate that these variants are also associated with UC.
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Krupoves A, Seidman EG, Mack D, Israel D, Morgan K, Lambrette P, Costea I, Deslandres C, Grimard G, Law L, Levy E, Amre DK. Associations between ABCB1/MDR1 gene polymorphisms and Crohn's disease: a gene-wide study in a pediatric population. Inflamm Bowel Dis 2009; 15:900-8. [PMID: 19107781 DOI: 10.1002/ibd.20849] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Functional studies support the involvement of the MDR1 gene in the pathways leading to Crohn's disease (CD). Two common single nucleotide polymorphisms (SNPs), C3435T and G2677T/A, thought to alter the function of the corresponding P-glycoprotein, have shown inconsistent associations with CD. We investigated whether DNA variants in the MDR1 gene were associated with susceptibility for CD and specific phenotypes in children. METHODS A case-control study was conducted at 3 gastroenterology clinics across Canada. Children with CD and population- or hospital-based controls were included. CD cases were classified using the Montreal Classification. Thirteen tag-SNPs and the C3435T variant in the MDR1 gene were genotyped. Single-SNP allelic, genotype as well as gene-wide haplotype associations with CD and its phenotypes at diagnosis were assessed. RESULTS A total of 270 CD cases and 336 controls were studied. Most cases were male (56.3%), had disease location L3+/-L4 (58.1%), and an inflammatory phenotype B1+/-p (88.5%). Allelic association analysis revealed that SNP rs17327442 was significantly associated with overall susceptibility to CD (odds ratio [OR] = 0.72, 95% confidence interval [CI] = 0.50-0.99, P = 0.04) but this association did not withstand corrections for multiple testing (q-value = 0.56). Genotype-phenotype analysis indicated that 2 SNPs (rs10248420, P = 0.007, q-value = 0.07; rs2032583, P = 0.01, q-value = 0.07) were significantly associated with colonic disease. Five SNPs, rs1128503 (P = 0.02), rs1202184 (P = 0.008), rs1202186 (P = 0.02), rs2091766 (P = 0.03), and rs2235046 (P = 0.03) were nominally associated with noninflammatory CD. Specific haplotypes comprising of the tag-SNPs were significantly associated with either colonic or noninflammatory CD. CONCLUSIONS Our comprehensive gene-wide analysis suggests that the MDR1 gene may be associated with clinical phenotypes of CD in children.
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Genetic variants in IL-23R and ATG16L1 independently predispose to increased susceptibility to Crohn's disease in a Canadian population. J Clin Gastroenterol 2009; 43:444-7. [PMID: 19276991 DOI: 10.1097/mcg.0b013e318168bdf0] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
GOALS To establish the relevance of variants in the IL-23R and ATG16L1 genes in inflammatory bowel disease (IBD). AIM Three recent genome wide association studies have identified variants in the IL-23R and ATG16L1 genes, which modulate susceptibility to Crohn's disease (CD). METHODS We genotyped 1028 IBD patients, including 443 CD and 347 ulcerative colitis (UC) non-Jewish cases, 238 (183 CD and 55 UC) Jewish cases, and 1005 ethnically matched control subjects for 18 and 11 variants, respectively, in the IL-23R and ATG16L1 genes, including the IL-23R (R381Q) and ATG16L1 (T216A) variants, previously associated with CD. RESULTS Single nucleotide polymorphisms within each of 3 haplotype blocks across the IL-23R gene were associated with an increased risk of CD. Notably, the minor allele of the IL-23R R381Q variant was present in 2.9% of cases and 6.0% controls (P=0.0001, odds ratio=0.48, 95% confidence interval 0.33-0.69). Homozygosity for the minor (T) allele of the ATG16L1 T216A polymorphism was strongly protective for CD (P=0.0001, odds ratio=0.51, 95% confidence interval 0.38-0.68). No phenotypic associations were detected and no interactions between the genes to increase disease risk were established. CONCLUSIONS We confirm the association of CD with variants in the IL-23R and ATG16L1 genes and the more modest association of the IL-23R R381Q variant with UC. Our results also suggest that these variants act independently of one another to influence risk and pathogenesis of IBD.
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Martins AJ, Colquhoun P, Reid G, Kim SO. Reduced expression of basal and probiotic-inducible G-CSF in intestinal mononuclear cells is associated with inflammatory bowel disease. Inflamm Bowel Dis 2009; 15:515-25. [PMID: 19058228 DOI: 10.1002/ibd.20808] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Granulocyte-colony stimulating factor (G-CSF) is a pleiotropic cytokine involved in the hematopoiesis of granulocytes, neuroprotection, and immunomodulation. Previously, we have shown that probiotic Lactobacillus rhamnosus GR-1 induces G-CSF production from bone marrow-derived macrophages. Whether this probiotic also induces G-CSF in intestinal mononuclear cells is unknown. METHODS G-CSF release in response to L. rhamnosus GR-1 was analyzed in isolated intestinal lamina propria mononuclear cells from inflammatory bowel disease (IBD) and non-IBD patients. The effects of G-CSF on proinflammatory cytokine production in human peripheral blood mononuclear cells and intestinal tissue from C57BL/6 wildtype and G-CSF receptor knockout mice was examined. RESULTS Normal mouse or human intestinal lamina propria cells constitutively express high levels of G-CSF, of which production was further enhanced by exogenous L. rhamnosus GR-1. However, cells obtained from IBD patients showed reduced G-CSF production under basal conditions and also lower production after exogenous GR-1 treatments. Intestinal tissue samples isolated from G-CSF receptor-deficient mice constitutively expressed higher levels of TNFalpha, IL-23, and IL-12 than those from wildtype mice, and pretreatment of G-CSF suppressed lipopolysaccharide (LPS)-induced IL-23 in human peripheral blood mononuclear cells. CONCLUSIONS These results suggest that high G-CSF production induced by commensals such as L. rhamnosus is important in maintaining normal immunological homeostasis in the intestine and defects in the production of G-CSF are associated with IBD.
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Affiliation(s)
- Andrew J Martins
- Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada
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Civitavecchia G, Renda MC, Ruggeri RF, Maggio A, Renna S, Orlando A, Cottone M. IL-23R determines susceptibility in Crohn's disease in a Mediterranean area. Inflamm Bowel Dis 2009; 15:317-8. [PMID: 18626976 DOI: 10.1002/ibd.20591] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Einarsdottir E, Koskinen LLE, Dukes E, Kainu K, Suomela S, Lappalainen M, Ziberna F, Korponay-Szabo IR, Kurppa K, Kaukinen K, Adány R, Pocsai Z, Széles G, Färkkilä M, Turunen U, Halme L, Paavola-Sakki P, Not T, Vatta S, Ventura A, Löfberg R, Torkvist L, Bresso F, Halfvarson J, Mäki M, Kontula K, Saarialho-Kere U, Kere J, D'Amato M, Saavalainen P. IL23R in the Swedish, Finnish, Hungarian and Italian populations: association with IBD and psoriasis, and linkage to celiac disease. BMC MEDICAL GENETICS 2009; 10:8. [PMID: 19175939 PMCID: PMC2642807 DOI: 10.1186/1471-2350-10-8] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/03/2008] [Accepted: 01/28/2009] [Indexed: 12/24/2022]
Abstract
Background Association of the interleukin-23 receptor (IL23R) with inflammatory bowel disease (IBD) has been confirmed in several populations. IL23R also associates with psoriasis, suggesting that the gene may be an important candidate for many chronic inflammatory diseases. Methods We studied association of single-nucleotide variants in IL23R with IBD in Swedish patients, in both Crohn's disease (CD) and ulcerative colitis (UC) subsets. The same genetic variants were also studied in Finnish patients with psoriasis or celiac disease, and in Hungarian and Italian patients with celiac disease. Results Association of IL23R with IBD was replicated in our Swedish patients, and linkage and association of the IL23R region with psoriasis was found in the Finnish population. The IL23R region was also linked to celiac disease in Finnish families, but no association of IL23R variants with celiac disease was found in the Finnish, Hungarian or Italian samples. Conclusion Our study is the first to demonstrate association of IL23R with CD and UC in Swedish patients with IBD. It is also the first study to report linkage and association of the IL23R region with psoriasis in the Finnish population. Importantly, this is the first report of linkage of the IL23R region to celiac disease, a chronic inflammatory condition in which IL23R has not been previously implicated.
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Affiliation(s)
- Elisabet Einarsdottir
- Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
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Park JH, Kim YJ, Park BL, Bae JS, Shin HD, Bae SC. Lack of association between interleukin 23 receptor gene polymorphisms and rheumatoid arthritis susceptibility. Rheumatol Int 2008; 29:781-6. [PMID: 19034457 DOI: 10.1007/s00296-008-0770-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2008] [Accepted: 11/04/2008] [Indexed: 01/05/2023]
Abstract
The recent discovery of interleukin 23 (IL-23), its receptor, and the underlying signal transduction pathway has improved our understanding of cellular immunity. Several studies suggest that IL-23 is an essential promoter of chronic joint inflammation. In this report, we assess the possible association of interleukin 23 receptor (IL23R) polymorphisms and haplotypes with rheumatoid arthritis (RA). The study was conducted on 1,204 RA patients and 979 healthy controls. Seven polymorphisms were selected from previous IBD reports. The seven SNPs (rs1004819, rs7517847, rs10489629, rs2201841, rs1343151, rs11209032 and rs1495965) were genotyped using the TaqMan assay. Comparison of RA and control subjects revealed no statistically significant differences in the distribution of the IL23R genotypes and haplotypes. Our results clearly indicate that IL23R gene polymorphisms do not play a significant role in susceptibility to RA in the Korean population. Accordingly, we conclude that IL23R gene polymorphisms cannot be applied as an effective genetic marker for RA susceptibility.
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Affiliation(s)
- Jeong Ha Park
- Division of Rheumatology, Department of Internal Medicine, Hanyang University College of Medicine, The Hospital for Rheumatic Diseases, Hanyang University, 17 Haengdang-Dong, Seongdong-Gu, Seoul, 133-792, South Korea
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Quinn JMW, Sims NA, Saleh H, Mirosa D, Thompson K, Bouralexis S, Walker EC, Martin TJ, Gillespie MT. IL-23 inhibits osteoclastogenesis indirectly through lymphocytes and is required for the maintenance of bone mass in mice. THE JOURNAL OF IMMUNOLOGY 2008; 181:5720-9. [PMID: 18832731 DOI: 10.4049/jimmunol.181.8.5720] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
IL-23 stimulates the differentiation and function of the Th17 subset of CD4(+) T cells and plays a critical role in chronic inflammation. The IL-23 receptor-encoding gene is also an inflammatory disease susceptibility gene. IL-23 shares a common subunit with IL-12, a T cell-dependent osteoclast formation inhibitor, and we found that IL-23 also dose-dependently inhibited osteoclastogenesis in a CD4(+) T lymphocyte-dependent manner. When sufficiently enriched, gammadelta T cells also mediated IL-23 inhibition. Like IL-12, IL-23 acted synergistically with IL-18 to block osteoclastogenesis but, unlike IL-12, IL-23 action depended on T cell GM-CSF production. IL-23 did not mediate IL-12 action although IL-12 induced its expression. Male mice lacking IL-23 (IL-23p19(-/-)) had approximately 30% lower bone mineral density and tibial trabecular bone mass (bone volume (BV)/total volume (TV)) than wild-type littermates at 12 wk and 40% lower BV/TV at 26 wk of age; male heterozygotes also had lower bone mass. Female IL-23p19(-/-) mice also had reduced BV/TV. IL-23p19(-/-) mice had no detectable osteoclast defect in trabecular bone but IL-23p19(-/-) had thinner growth plate hypertrophic and primary spongiosa zones (and, in females, less cartilage remnants) compared with wild type. This suggests increased osteoclast action at and below the growth plate, leading to reduced amounts of mature trabecular bone. Thus, IL-23 inhibits osteoclast formation indirectly via T cells in vitro. Under nonpathological conditions (unlike inflammatory conditions), IL-23 favors higher bone mass in long bones by limiting resorption of immature bone forming below the growth plate.
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Rueda B, Orozco G, Raya E, Fernandez-Sueiro JL, Mulero J, Blanco FJ, Vilches C, González-Gay MA, Martin J. The IL23R Arg381Gln non-synonymous polymorphism confers susceptibility to ankylosing spondylitis. Ann Rheum Dis 2008; 67:1451-4. [PMID: 18199597 DOI: 10.1136/ard.2007.080283] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVES Recent results have shown that the IL23R gene, coding for a subunit of the interleukin-23 receptor, is strongly associated with autoimmunity. The aim of the current study was to investigate, for the first time, the possible involvement of the IL23R gene in genetic susceptibility to ankylosing spondylitis (AS). METHODS We carried out a case-control association study in which 365 patients with AS and 500 blood bank donors were included. Eight single nucleotide polymorphisms (SNPs) spanning the IL23R gene were selected as genetic markers for our association study and were genotyped using a Taqman 5' allelic discrimination assay. RESULTS Interestingly, we observed association of two of eight IL23R genotyped SNPs. The strongest effect was conferred by the non-synonymous rs11209026 (Arg381Gln) SNP (odds ratio 0.46 95% confidence interval 0.2 to 0.7 p = 0.001). Similarly, the IL23R rs1343151 SNP showed association with AS genetic susceptibility (odds ratio 0.68 95% confidence interval 0.55 to 0.83 p = 0.0002). After a conditional case-control test we observed that the effect of these two genetic variants was independent of linkage disequilibrium. CONCLUSIONS These results suggest that the IL23R gene seems to be involved in AS genetic predisposition.
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Affiliation(s)
- B Rueda
- Instituto de Parasitología y Biomedicina López-Neyra, CSIC, Granada, Spain
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Márquez A, Mendoza JL, Taxonera C, Díaz-Rubio M, De La Concha EG, Urcelay E, Martínez A. IL23R and IL12B polymorphisms in Spanish IBD patients: no evidence of interaction. Inflamm Bowel Dis 2008; 14:1192-6. [PMID: 18383521 DOI: 10.1002/ibd.20463] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Recent genomic surveys have identified IL23R and IL12B as susceptibility loci for inflammatory bowel disease (IBD). Our aim in the present study was to ascertain whether the IL23R and IL12B associations with IBD are also observed in our population, and to analyze possible genetic interactions between polymorphisms at IL12B and IL23R, ligand and receptor, respectively. METHODS In all, 707 IBD patients (344 with Crohn's disease and 363 with ulcerative colitis) and 547 healthy controls from the same ethnic origin (Caucasian Spaniards) were included in the present study. Two single nucleotide polymorphisms (SNPs) in IL23R (rs7517847 and rs11209026) and 2 in IL12B (rs3212227 and rs6887695) genes were analyzed by TaqMan technology. Genetic frequencies were compared with a chi-square test. Interaction between genes was analyzed by case-only comparisons. RESULTS The data show an association of both IL23R SNPs with overall IBD (statistically stronger, rs7517847; odds ratio [OR] = 0.79, 95% confidence interval [CI]: 0.67-0.94, minor allele frequencies: 0.355 in IBD patients versus 0.410 in controls; P = 0.005), somewhat stronger in Crohn's disease (OR = 0.74, 95% CI: 0.61-0.91) than in ulcerative colitis (OR = 0.84, 95% CI: 0.69-1.03). IL12B rs6887695 showed a weak association with IBD (OR = 1.24, 95% CI: 1.04-1.47, minor allele frequencies: 0.375 in IBD patients versus 0.326 in controls, P = 0.012), stronger in UC (OR = 1.31, 95% CI: 1.07-1.60, P = 0.007). No statistically significant differences were apparent when patients were stratified according to clinical characteristics. No interaction was observed between any of the polymorphisms studied at IL12B and IL23R. CONCLUSIONS Our study confirms the association of IL23R and IL12B with IBD in the Spanish population, but no interaction between either loci could be detected.
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Affiliation(s)
- Ana Márquez
- Clinical Immunology Department, Hospital Clínico San Carlos, Madrid, Spain
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Latiano A, Palmieri O, Valvano MR, D’Incà R, Cucchiara S, Riegler G, Staiano AM, Ardizzone S, Accomando S, Angelis GLD, Corritore G, Bossa F, Annese V. Replication of interleukin 23 receptor and autophagy-related 16-like 1 association in adult- and pediatric-onset inflammatory bowel disease in Italy. World J Gastroenterol 2008; 14:4643-4651. [PMID: 18698678 PMCID: PMC2738788 DOI: 10.3748/wjg.14.4643] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2008] [Revised: 07/14/2008] [Accepted: 07/21/2008] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate gene variants in a large Italian inflammatory bowel disease (IBD) cohort, and to analyze the correlation of sub-phenotypes (including age at diagnosis) and epistatic interaction with other IBD genes. METHODS Total of 763 patients with Crohn's disease (CD, 189 diagnosed at age < 19 years), 843 with ulcerative colitis (UC, 179 diagnosed < 19 years), 749 healthy controls, and 546 healthy parents (273 trios) were included in the study. The rs2241880 [autophagy-related 16-like 1 (ATG16L1)], rs11209026 and rs7517847 [interleukin 23 receptor (IL23R)], rs2066844, rs2066845, rs2066847 (CARD15), rs1050152 (OCTN1), and rs2631367 (OCTN2) gene variants were genotyped. RESULTS The frequency of G allele of ATG16L1 SNP (Ala197Thr) was increased in patients with CD compared with controls (59% vs 54% respectively) (OR = 1.25, CI = 1.08-1.45, P = 0.003), but not in UC (55%). The frequency of A and G (minor) alleles of Arg381Gln, rs11209026 and rs7517847 variants of IL23R were reduced significantly in CD (4%, OR = 0.62, CI = 0.45-0.87, P = 0.005; 28%, OR = 0.64, CI = 0.55-0.75, P < 0.01), compared with controls (6% and 38%, respectively). The A allele (but not G) was also reduced significantly in UC (4%, OR = 0.69, CI = 0.5-0.94, P = 0.019). No association was demonstrated with sub-phenotypes and interaction with CARD15, and OCTN1/2 genes, although both gene variants were associated with pediatric-onset disease. CONCLUSION The present study confirms the association of IL23R polymorphisms with IBD, and ATG16L1 with CD, in both adult- and pediatric-onset subsets in our study population.
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Abstract
PURPOSE OF REVIEW Gut is exposed to enteric bacteria and food antigens but maintains its homeostasis without the development of acute or chronic inflammation in normal situations. Abnormal innate immunity to enteric flora may develop into intestinal inflammation such as inflammatory bowel disease. This paper reviews recent studies on innate immunity in gut homeostasis and inflammation, identifying novel susceptible genes and clarifying the interaction between epithelial cells and immune cells such as intestinal macrophages and dendritic cells, as well as the interaction between NOD2 and toll-like receptor. RECENT FINDINGS Crosstalk between epithelial cells and monocytic cells such as macrophages and dendritic cells plays an important role in gut homeostasis. Dysregulation of this crosstalk leads to decreased epithelial integrity and chronic intestinal inflammation. Macrophages and dendritic cells also regulate bacterial flora for the maintenance of intestinal homeostasis. Interleukin-23 derived from these cells is a key cytokine in inflammatory bowel disease pathogenesis. Interactions between NOD2 and toll-like receptor signaling pathways may cause abnormal immune responses and decreased bacterial clearance. Genome-wide scanning has identified innate immunity-related genes as inflammatory bowel disease susceptibility genes. SUMMARY Recent studies on gut innate immunity in animal models have greatly advanced our knowledge of inflammatory bowel disease pathogenesis. For further progress, human studies and clarification of the functions of the identified susceptibility genes are needed.
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Abstract
PURPOSE OF REVIEW Genetic factors play an important role in the pathogenesis of inflammatory bowel disease. In this review, we will provide an update on the rapid advances in the discovery of inflammatory bowel disease, primarily Crohn's disease, associated genes. RECENT FINDINGS Seven recently published Crohn's disease genome-wide association studies have confirmed prior findings related to the nucleotide-binding oligomerization domain 2 (NOD2) gene and the IBD5 locus. In addition, 10 novel loci have been identified and well replicated. SUMMARY Several promising associations between Crohn's disease and gene variants have been identified and replicated, the two most widely replicated being variants in the IL23R and ATG16L1 genes. These findings highlight and further support the importance of the immune system and its interactions with the intestinal microflora in the pathogenesis of inflammatory bowel disease.
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Abstract
PURPOSE OF REVIEW To inform readers of recent advances in our understanding of the development and function of Th17 T cells and emerging data suggesting that the interleukin-23/interleukin-17 axis may be involved in the pathogenesis of spondyloarthritis. RECENT FINDINGS The discovery of CD4+ Th17 T cells and the interleukin-23/interleukin-17 axis has challenged existing paradigms and the role of Th1 T cells in many autoimmune diseases. The development and cytokine profile of Th17 T cells differs in mice and humans. In humans, interleukin-23 synergizes with interleukin-6 and interleukin-1 to promote Th17 development. In mice, transforming growth factor-beta and interleukin-6 are critical, whereas interleukin-23 is more important at later stages promoting interleukin-17 production. In mice, CD4+ cells producing interferon-gamma appear to be distinct from interleukin-17-producing cells, while in humans cells secreting both cytokines have been observed. Growing evidence from animal models, cytokine analyses of patient fluids, and whole-genome association studies suggest that the interleukin-23/interleukin-17 axis plays an important role in spondyloarthritis pathogenesis. Possible links between an HLA-B27-induced unfolded protein response and activation of the interleukin-23/interleukin-17 axis have been observed in animal models and may contribute to the development of the spondyloarthritis phenotype. SUMMARY Activation of the interleukin-23/interleukin-17 axis in spondyloarthritis has important therapeutic implications.
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Affiliation(s)
- Gerlinde Layh-Schmitt
- William S. Rowe Division of Rheumatology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, Ohio, USA
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Manel N, Unutmaz D, Littman DR. The differentiation of human T(H)-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORgammat. Nat Immunol 2008; 9:641-9. [PMID: 18454151 PMCID: PMC2597394 DOI: 10.1038/ni.1610] [Citation(s) in RCA: 1057] [Impact Index Per Article: 62.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2008] [Accepted: 03/24/2008] [Indexed: 02/06/2023]
Abstract
T(H)-17 cells are interleukin 17 (IL-17)-secreting CD4+ T helper cells involved in autoimmune disease and mucosal immunity. In naive CD4+ T cells from mice, IL-17 is expressed in response to a combination of IL-6 or IL-21 and transforming growth factor-beta (TGF-beta) and requires induction of the nuclear receptor RORgammat. It has been suggested that the differentiation of human T(H)-17 cells is independent of TGF-beta and thus differs fundamentally from that in mice. We show here that TGF-beta, IL-1beta and IL-6, IL-21 or IL-23 in serum-free conditions were necessary and sufficient to induce IL-17 expression in naive human CD4+ T cells from cord blood. TGF-beta upregulated RORgammat expression but simultaneously inhibited its ability to induce IL-17 expression. Inflammatory cytokines relieved this inhibition and increased RORgammat-directed IL-17 expression. Other gene products detected in T(H)-17 cells after RORgammat induction included the chemokine receptor CCR6, the IL-23 receptor, IL-17F and IL-26. Our studies identify RORgammat as having a central function in the differentiation of human T(H)-17 cells from naive CD4+ T cells and suggest that similar cytokine pathways are involved in this process in mice and humans.
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Affiliation(s)
- Nicolas Manel
- The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA
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