IL23R Gene Research Articles

IL6R Gene Polymorphic Variant rs2228145(C >A) as a Marker of Genetic Liability to Nonalcoholic Steatohepatitis in the Russian Population of Karelia.

Association of IL6R gene polymorphic variant rs2228145(C>A) with the development of nonalcoholic steatohepatitis in Karelia residents is detected. The risk of nonalcoholic steatohepatitis is more than 2-fold higher in carriers of CC genotype by rs2228145 polymorphic marker than in carriers of other genotypes. Plasma levels of IL-6 and the content of IL6R gene transcripts in the peripheral blood leukocytes are higher in patients with nonalcoholic steatohepatitis than in normal subjects. No relationships between rs2228145 polymorphism and the level of IL-6 and content of IL6 and IL6R mRNA were detected. Gene IL6R polymorphic variant rs2228145(C>A) seems to be involved in genetic predisposition of the population of Karelia to nonalcoholic steatohepatitis. However, biochemical and molecular mechanisms underlying the relationship of rs2228145 with the development of nonalcoholic steatohepatitis are not yet studied.

Group 3 innate lymhoid cells are absent in DOCK8-defective HIES patients

Abstract Innate lymphoid cell (ILC) subsets ILC1, ILC2 and ILC3 mirror image the functions helper CD4+ T cell subsets, Th1, Th2 and Th17, respectively; rely on similar transcription factors for their development, and produce similar effector cytokines. Thus, they have recently been shown to be crucial for protective immunity in mice. More importantly, in several chronic inflammatory diseases activated or increased frequency of ILCs have been reported in the circulation or affected tissues of patients. Our previous work with Dock8-defective Dock8pri/pri mice revealed that Dock8 is required for the development/function and survival of murine ILC3s. Thus Dock8pri/pri mice lacked ILC3s and was susceptible to Citrobacter rodentium infections. However to date, whether DOCK8 regulates ILC3 development or functions in humans has not been addressed. In the current study, using 11 DOCK8 mutant patients from across Turkey, we show, for the first time, that humans with DOKC8 deficiency lack peripheral ILC3s. Reduction in blood ILC3 could be verified by flow cytometry. Additionally, sorted total blood ILC population obtained from HIES patients with DOCK8 mutations shows diminished ILC3-specific Gm-csf, AhR and il23r gene expression in line with ILC3 loss. The defect is dramatic in ILC3s and less so in ILC2s in circulation. Flow cytometric examination of 11 patients revealed full restroration of ILC3s following hematopoietic stem cell transplantation. We also show that sorted peripheral ILC precursor population obtained from DOCK8 mutant patients has impaired capacity to proliferate in ILC1-ILC2-ILC3 polarizing conditions. This is the first report in the literature to show a selective deletion of ILC3s in HIES patients with DOCK8 mutations.

Prognostic Significance of IL-17,And IL-13 Along With IL-23R Gene Polymorphisms in Patients with Rheumatoid Arthritis in Iraqi Patients

Rheumatoid arthritis is a systemic disease with very complex pathogenesis and feature of chronic synovitis. The biological effect of polymorphism on expression and functionality of IL-23R such as SNP can have functional and phenotypic consequences that make Il-23R as a risk factor for RA disease. Moreover recently there is a new trends to find out a new noninvasive prognostic biomarker for RA disease which may help in fallowing up disease. Thus the aim of present work is to find out if there prognostic value for IL-13 and IL-17in Rheumatoid arthritis through linking its expression level with disease activity score (DAS). Also To study if there is a role for IL-23R 11209026 gene polymorphism in disease susceptibility in Iraqi community by using healthy volunteer as a control group. To achieve this goal a Case control study has been conducted on 40 patient and 40 matched apparently health control. serum IL-17 and IL-13 concentration were measure by enzyme Linked immunosorbent assay According to manufactural instruction,measurement of disease activity was determine according to DAS 28 Score.RFLP PCR was used to study SNP of IL-23R gene polymorphism for patient and control group. Data were summarized, presented and analyzed using statistical package for social science (SPSS version 23). Result of present study found there was significant association between serum IL-17 and IL-13 level and RA disease (P<0, 001; and P<0, 001respectively). Moreover,there is significant positive correlation between expression level of both IL-17 and IL-13 with DAS28 (0.044,and 0.034 respectively). According to Receptor operating Curve both of IL-17 and IL-13 found to have high specificity and sensitivity 100%. Regarding to IL-23 R gene polymorphism,there was no significant correlation between rs11209026 gene polymorphism and susceptibility to rheumatoid arthritis patients in Iraqi community. Thus,present study showed that the concentrations of IL-13 and IL-17 significantly correlated with disease severity and DAS 28 which reflect their prognostic value in RA. Moreover,present study demonstrated that there was no significant association between Il-23R gene rs11209026 polymorphism and susceptibility to RA in Iraqi population.

Acute coronary syndrome: Relationship between genetic variants and TIMI risk

Acute Coronary Syndrome (ACS) is a multifactorial disease, including the genetic factor, caused by coronary artery obstruction by atheroma. Some genetic variants have been described as risk factors for this disease. Its early diagnosis and stratification of risk of death by Thrombolysis in Myocardial Infarction (TIMI) are important. Therefore, we evaluated variants in the IL6R (c950-1722C>T), TNFa (c.-488G>A), LEPR (c.2673+1118C>T) and IL1b (c.-598T>C) genes in relation to TIMI risk, cytokine serum levels, and risk factors for ACS. We selected 200 patients with ACS, 50 without ACS from the Real Hospital Português, Recife - PE, and 295 blood donors at the Fundação de Hematologia e Hemoterapia de Pernambuco (Hemope). Variants were determined by DNA sequencing or enzymatic cleavage. Cytokine levels were measured by ELISA. The most frequent risk factors found in the patients were dyslipidemia and hypertension, this latter associated with high TIMI risk (p = 0.003). Genotype frequencies of IL6R and TNFa differed between patients with ACS and the blood donors (p = 0.0002 and p = 0.01, respectively), and TNF-α levels differed between genotypes. The TT genotype of the IL6R gene is as a possible protective factor for ACS because it was significantly more present in blood donors (32.2%) than in patients with ACS (18.0%), and was more frequent in low TIMI risk (22.9%) than in the intermediate (20.2%) or high (4.9%). In patients with ACS, the TT genotype in IL6R was related to a lower concentration of c-reactive protein (p = 0.03) and troponin (p = 0.02), showing a less inflammatory reaction and tissue damage. The differences in the frequencies of variants in genes of medical interest among the groups show the importance of studies in specific populations groups to establish the relationship between genes and diseases.

Macrophages Represent the Major Pool of Interleukin-7 Receptor-α Expressing Immune Cells in Patients with Myocarditis

Myocarditis is an inflammatory heart disease which involves a large number of cytokine receptors. In order to identify potential key signalling cascades we screened a number of receptors by Western blot and found high expression of the interleukin-7 (IL-7) receptor-α (IL-7Rα). Since IL-7 is usually required for the development of B as well as T lymphocytes we wanted to determine the major cell type(s) expressing this receptor. Importantly, immune cells might be also a source of IL-7.

A pilot study of single nucleotide polymorphisms in the interleukin-6 receptor and their effects on pre- and post-transplant serum mediator level and outcome after allogeneic stem cell transplantation.

Interleukin (IL)-6 is an important regulator of immunity and inflammation in many diseases. Single nucleotide polymorphisms (SNPs) in the IL-6 gene influence outcome after allogeneic stem cell transplantation (ASCT), but the possible importance of SNPs in the IL-6 receptor has not been examined. We therefore investigated whether SNPs in the IL-6R gene influenced biochemical characteristics and clinical outcomes after ASCT. We examined the IL-6 promoter variant rs1800975 and the IL-6R SNPs rs4453032, rs2228145, rs4129267, rs4845374, rs4329505, rs4845617, rs12083537, rs4845618, rs6698040 and rs4379670 in a 101 population-based cohort of allotransplant recipients and their family donors. Patients being homozygous for the major alleles of the IL-6R SNPs rs2228145 and rs4845618 showed high pretransplant CRP serum levels together with decreased sIL-6R levels; the decreased IL-6R levels persisted 6 months post-transplant. In contrast, patients being homozygous for the minor allele of the IL-6R SNP rs4379670 showed decreased pretransplant CRP levels. Furthermore, the IL-6R rs4845618 donor genotype showed an association with severe acute graft-versus-host disease (GVHD), whereas the donor genotype of the IL-6 SNP rs1800795 was associated with decreased survival 100 days post-transplant. Finally, the recipient genotype of the IL-6R SNP rs4329505 showed a strong association with 2-years non-relapse mortality, and this effect was also highly significant in multivariate analysis. IL-6 and IL-6R SNPs influence the clinical outcome after allogeneic stem cell transplantation.

MOLECULAR GENETIC TESTING OF ACCP-POSITIVE PATIENTS WITH RHEUMATOID ARTHRITIS AND HIGH INFLAMMATORY DISEASE ACTIVITY (A REMARCA STUDY)

Rheumatoid arthritis (RA) is a multifactorial disease, in which the interaction of the genetic component and environmental factors, determines not only the development of the disease, but also its pronounced clinical polymorphism. We assume that the high inflammatory activity of RA may be determined by the genes, the products of which trigger inflammatory processes. Objective: to investigate allele and genotype distribution of gene polymorphic variants in active anti-cyclic citrullinated peptide (aCCP)-positive patients with RA from the REMARCA program versus a control group of healthy blood donors. Subjects and methods . A molecular genetic study enrolled 146 aCCP-positive patients from the REMARCA program and a control group of 314 healthy blood donors without autoimmune diseases and their presence in the history, who were matched with the study group for gender and sex. The polymorphic variants of the genes PTPN22 (+1858C>T, rs2476601), TNFAIP3 (rs6920220, rs10499194), CTLA4 (+49A>G, rs231775), TNFА (-308A>G, rs1800629), IL6 (-174G>C, rs1800795), IL6R (+358A>C, rs8192284), IL10 (-592A>C, rs1800872, -892 C>T, rs1800871, -1082 A>G, rs1800896), and MCP1/CCL2 (+2518A>G, rs1024611) were genotyped by a real-time polymerase chain reaction assay. Results and discussion. The genotype and allele frequencies of polymorphic variants of the genes CTLA4 (+49A>G), IL-6R (+358A>C), and IL10 (592A>C) in the RA group significantly differed from those in the control group. When comparing with the control group, the minor alleles of the CTLA4 and IL10 genes were markers for the risk of aCCP-positive RA with a high inflammatory activity (OR=1.4 [1.1; 1.9], p=0.02 and OR=1.9 [1.4; 2.5]; p=0.0001, respectively). At the same time, the minor C allele of the IL6R gene served as a marker of protection (OR=0.7 [0.5; 0.9]; p=0.03). Logistic regression analysis revealed that there was a statistically significant correlation of the high inflammatory activity indices SDAI, CDAI, and DAS28 with the minor homozygous GG genotype of the CTLA4 gene (OR=2.5 [1.1; 6.0]; p=0.03, OR=2.6 [1.1–6.4], p=0.03 and OR=3.4 [1.3–8.8]; p=0.01, respectively). In addition, the inflammatory activity indices SDAI and CDAI rather than DAS28-ESR were associated with at least one minor A allele (the AA/AC genotypes) of the IL10 gene (OR=2.4 [1.2; 5.1], p=0.02 and OR=2.2 [1.1; 4.7]; p=0.03, respectively). The levels of ESR and CRP were not associated with the examined polymorphisms. Conclusion. The findings may suggest that there is a relationship of the polymorphisms of the genes CTLA4 (+49A>G, rs231775), IL6R (+358A>C, rs8192284), and IL10 (-592A>C, rs1800872) to high inflammatory activity in the group of aCCP-positive patients from the REMARCA study.

IL12B, IL23A, IL23R and HLA-C*06 genetic variants in psoriasis susceptibility and response to treatment

The role of interleukin-23 is crucial in the pathogenesis of psoriasis, and IL23A, IL12B and IL23R genetic variants have been associated with the disease in genome-wide association studies. In the current paper we have conducted a confirmation study of the abovementioned genetic factors in a case-control analysis of 507 psoriatic patients and 396 controls from a Polish population, and subsequently analyzed the impact of genetic variants on response to topical and NB-UVB therapy in a subset of 306 patients. Case-control analysis revealed an association of IL12B rs3212227 and IL23R rs11209026 minor allele carrier status with reduced odds for psoriasis (OR = 0.66, 95%CI: 0.50–0.87, and OR = 0.41, 95%CI: 0.26–0.67, respectively), while HLA-C*06 allele carriers were more frequent in patients group (OR = 4.56, 95%CI: 3.41–6.10). The studied polymorphic variants of IL12B, IL23A, and IL23R genes did not influence therapy outcome, i.e. there were no significant differences in PASI reduction between patients with different genotypes. However, HLA-C*06 carriers showed poorer response to the applied treatment, when compared to non-carriers. The results of the current study confirm an association between IL12B and IL23R genetic polymorphism and psoriasis vulgaris (with a protective effect of minor alleles). HLA-C*06 carriers show reduced effectiveness of topical/NB-UVB therapy, and that observation could be potentially used in treatment personalization.

Knockout of zebrafish interleukin 7 receptor (IL7R) by the CRISPR/Cas9 system delays retinal neurodevelopment

Interleukin 7 receptor (il7r), a transmembrane receptor, belongs to the type I cytokine receptor family. Il7r is involved in the pathogenesis of neurodegenerative disorders, such as multiple sclerosis. Targeted knockdown of il7r leads to delayed myelination, highlighting the potential role of il7r in the development of the nervous system. Zebrafish is an ideal model for the study of neurogenesis; moreover, the il7r gene is highly conserved between zebrafish and human. The aim of the present study was to investigate the novel function of il7r in neurogenesis. First, an il7r−/− homozygous mutant line was generated by clustered regularly interspaced short palindromic repeats (CRISPR)-associated 9 (CRISPR/Cas9) technology. Second, the gross development of il7r−/− mutants revealed remarkably smaller eyes and delayed retinal neurodifferentiation. Third, microarray analysis revealed that genes associated with the phototransduction signalling pathway were strongly down-regulated in il7r−/− mutants. Finally, the results from behavioural tests indicated that visual function was impaired in il7r−/− mutant larvae. Overall, our data demonstrate that a lack of il7r retards the development of the retina. Thus, il7r is an essential molecule for maintaining normal retinal development in zebrafish.

Genetic susceptibility to invasive pneumococcal disease

BackgroundThe pathogenesis of IPD remains unknown, especially among middle-aged individuals without risk factors (WRF). ObjectivesThe aim of the present study was to investigate the role of single nucleotide polymorphisms (SNP) within key genes involved in innate immune response on IPD susceptibility. MethodsForty-three SNPs within 10 immunological genes were investigated in a cohort of 144 Caucasian IPD patients and 280 ethnically matched controls. ResultsThe allele distribution of the NFKBIA rs1050851 and NFKBIE rs2282151 variants were associated with IPD susceptibility (χ2 = 4.23, p = 0.04 and χ2 = 5.13, p = 0.02, respectively). Additionally, the genotype distribution of NFKBIZ rs645781 (χ2 = 8.25, p = 0.02) and IL1R1 rs3917254 (χ2 = 6.70, p = 0.04) were also associated with IPD risk. When only IPD-WRF patients were considered; the allele distribution of IL1R1 rs2160227 (χ2 = 5.62, p = 0.03), rs13020778 (χ2 = 5.73, p = 0.02), rs3917267 (χ2 = 3.72, p = 0.05) and IL4 rs2227284 (χ2 = 3.76, p = 0.05) and the genotype distribution of IL10 rs3024509 (χ2 = 7.70, p = 0.02), IL1R1 rs3917254 (χ2 = 13.40, p = 0.001), NFKBIZ rs645781 (χ2 = 13.86, p = 0.001) and rs677011 (χ2 = 9.06, p = 0.01) variants were associated with IPD risk. ConclusionsWe found several associations between variants in the IL1R1, IL4, IL10, NFKBIE, NFKBIA, and NFKBIZ genes and risk of IPD. If validated, these biomarkers may help to identify people with higher risk of IPD.

Lack of association between rheumatoid arthritis and genetic variants rs10889677, rs11209026 and rs2201841 of IL-23R gene

IntroductionRheumatoid arthritis (RA) is an autoimmune diseases, where different genetic variants in cytokine genes may play a pathogenic role. A GWAS in autoimmune diseases highlighted the IL-23R gene as a one of the susceptibility factors. We examined three candidate single nucleotide polymorphisms (SNPs) rs10889677, rs11209026 and rs2201841 of the IL-23R gene, as well as determined their possible association with RA in a Polish population. Patients and methodsThe IL-23R gene polymorphisms were genotyped for 422 RA patients and 348 healthy individuals using TaqMan SNP genotyping assay. ResultsThe genotypes frequency did not deviate from HWE in each examined group. A comparison of the allele as well as genotype frequencies of the IL-23R polymorphisms under codominant, dominant and recessive genetic model revealed no significant differences between RA patients and healthy subjects. We also demonstrated that IL-23R rs2201841 and rs11209026 as well as rs11209026 and rs10889677 were in complete linkage disequilibrium (D′=1.0). Our genotype-phenotype analysis demonstrated that in carriers of rs10889677C and/or rs2201841A allele the RF, extra-articular manifestations and erosion were more frequent present than in patients with rs10889677A and/or rs2201841A allele, although this association was not significant. DiscussionPresent findings indicated that the autoimmune disease-associated genetic variants in IL-23R gene are not associated with RA in the Polish population.

Genetic Susceptibility to Asthma and Genetic Interactions in the 5q31-q33 and 16p11 Regions in Sudanese Families

Background: Asthma is a complex disorder with heterogeneous phenotypes attributed to the interactions of many genes and the environment. Numerous genetic studies have mapped asthma susceptibility genes to a region on chromosome 5q31-q33. This study aimed to determine the association of 10 candidate polymorphisms in IL-4, IL-5, IL-9, IL-13 and IL-4R genes in 5q31-q33 region with susceptibility to asthma in Sudanese families.Method: Fifty two multi cases families consisting of 141 known cases of asthma and 129 healthy individuals from Khartoum state were genotyped for seven SNPs on 5q31-33 region located in four candidate genes; IL4, IL5 IL13, IL9 and three SNPs in IL4Rα on chromosome 16p using multiplex PCR with Mass ARRAY system. Multiple logistic regression was used to test for association of asthma. P-value needed to achieve statistical significance taking multiple testing into account is P=0.005 (=0.05/10 (number of SNPs genotyped)). However, since SNPs within genes showed some degree of linkage disequilibrium and SNPs were selected as major SNPs for association with Asthma in other populations. Therefore, P £ 0.01 (=0.05/5 genes) can used as the P-value required to achieve correction for multiple testing.Result: Genotype and allelic frequencies of all SNPs were similar in both asthmatics and healthy subjects. Stepwise logistic regression demonstrated that SNP IL-13 rs2069743 was markedly associated with Asthma (P=0.008) and same SNP added significant main effects to IL-4 rs2070874 or IL-9 rs31563, whereas the reverse was not true, indicating that the main effect for association with asthma in this population is most strongly tagged by SNP IL-13 rs2069743.Conclusion: There is strong genetic association of SNPs in 5q31-q33 and 16p11 region and asthma.

The Diagnostic and Prognostic Role of Interleukin 12B and Interleukin 6R Gene Polymorphism in Patients With Ankylosing Spondylitis.

Interleukin 23 (IL-23) pathway and IL-1 cluster genes play prominent role in the etiopathology of ankylosing spondylitis (AS). The aim of this study was to investigate the diagnostic and prognostic role of 5 single-nucleotide polymorphisms related to IL-23 pathway and IL-1 cluster genes in AS patients. Four hundred thirty-one patients with AS and 206 age- and sex-matched healthy controls were recruited in this prospective cohort study. Five potential single-nucleotide polymorphisms (IL-23R [rs11209026], IL-12B [rs6871626], TYK2 [rs6511701], IL-6R [rs4129267], and IL-1R2 [rs2192752]) related to IL-23 pathway and IL-1 cluster genes by analyzing previous studies were genotyped. Among 431 total AS patients, 198 active cases were treated and followed up for 24 weeks. Frequencies of IL-12B AA (rs6871626) and IL-6R TT (rs4129267) genotypes were increased in AS patients compared with healthy controls (both P < 0.001), and IL-12B A (rs6871626) as well as IL-6R T (rs4129267) allele increased the risk of AS independently (both P < 0.001). The Bath Ankylosing Spondylitis Disease Activity Index score was found to be elevated in AS patients with IL-12B AA (rs6871626) compared with patients with the CA and CC genotypes (P = 0.002 and P < 0.001, respectively), and the Bath Ankylosing Spondylitis Functional Index score was also increased in AS patents with IL-12B AA (rs6871626) than in those with the CA and CC genotypes (P = 0.001 and P < 0.001). In addition, IL-6R T (rs4129267) allele could predict a worse ASAS-20 (Assessment of SpondyloArthritis international Society) response at week 24 as an independent factor by multivariate logistic regression analysis with additive model (P = 0.011). Interleukin 12B (rs6871626) and IL-6R (rs4129267) gene polymorphisms could serve as promising biomarkers for diagnosis and prognosis in AS patients.

IL23R gene variants in relation to IL17A levels and clinical phenotype in patients with ankylosing spondylitis.

BackgroundIL23 receptor (IL23R) binding by IL23 is required for the maturation of CD4+ cells into Th17 cells and subsequent generation of IL17A and TNF. As IL23R variations contribute to AS susceptibility, we investigated the effect of IL23R variants on cytokine levels and disease measures in an AS cohort.MethodsThis was a cross-sectional study of AS patients (n = 334, 90% B27+, age 45 years). IL23R genotyping for three non-synonymous single-nucleotide polymorphisms (rs11209026, protective allele A; rs10489629, protective allele A; and rs11209032, risk allele A) was done by Taqman RT-PCR. IL23, IL17A, TNF and IL6 concentrations were determined by sandwich ELISA. Genotypic associations were analysed with non-parametric methods.ResultsTwenty-two AS patients (6.6%) carried the protective rs11209026 A allele, whereas 206 (61.7%) carried the rs11209032A risk allele (P = 0.03). Two patients homozygous for rs11209026A had late onset, no co-morbidity and undetectable cytokine levels. IL23R genotypes and five common haplotypes were unrelated with age at onset, BASFI or co-morbidity (all P >0.2). There was no overall difference in the concentration of IL17A (184 vs 233 pg/ml, P > 0.2) or IL23 (276 vs 262 pg/ml, P > 0.4) between AS patients and controls, but a global haplotype association (P = 0.01) was observed for IL23 concentrations.ConclusionHomozygosity for rs11209026A is rare in AS patients, but may ameliorate the clinical presentation. IL17A and IL23 levels are similar in controls and AS patients. IL23R variants influence IL23 levels but not IL17A levels in AS patients, suggesting that IL23R impacts more on cell types other than Th17 cells.

Association of IL-23R gene rs7517847 T&gt;G SNP and susceptibility to systemic lupus erythematosus: A systematic review and meta-analysis

Previous articles have evaluated the association between IL-23R gene rs7517847 T>G SNP and systemic lupus erythematosus (SLE). Nevertheless, the results of these studies have been inconclusive. The current study is a meta-analysis that assesses the association between IL-23R gene rs7517847 T>G SNP and SLE susceptibility. Literature searches of Medline, Web of Science, and EMBASE databases were performed to recognize all eligible studies published before August, 2016, and the search was updated in July, 2017. The identified studies were independently reviewed by two authors for eligibility based on inclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to assess the strength of association in the allelic model, dominant model, recessive model, heterozygotes contrast, and homozygotes contrast. Because evidence of heterogeneity was detected across the studies, the data was pooled using a random-effects model. A sum of four case-control studies with 1348 SLE patients and 1754 healthy subjects were considered in this study. In the combined analysis, no significant association between the IL-23R gene rs7517847 T>G SNP and SLE disease risk was found in any of the genetic models (dominant model: OR = 0.95, 95% CI = 0.72-1.18; allelic model: OR = 1.08, 95% CI = 0.95-1.21; recessive model: OR = 1.13, 95% CI = 0.80-1.46; TG vs. TT: OR = 0.86, 95% CI = 0.63-1.08; and GG vs. TT: OR = 1.20, 95% CI = 0.81-1.60). Moreover, no publication bias was observed in any genetic models (p> 0.05). First, this study was based on unadjusted ORs. Second, the number of included case-control articles was small. Third, only published English language studies were imported to this meta-analysis. The current meta-analysis suggests that the IL-23R gene rs7517847 T>G SNP might not be related with risk of SLE. More studies are essential to confirm these results. No association was found between the IL-23R gene rs7517847 T>G SNP and SLE risk.

Genetic profile of patients with early onset inflammatory bowel disease

Inflammatory Bowel disease (IBD) is a widespread pathological condition with clinical heterogeneity and with different levels of severity. Although IBD usually occurs in young adults, onset in childhood and infancy are described in patients within the 10th and second year of age. By genome-wide association studies and meta-analysis, several genetic loci have been identified associated with an increased risk of developing IBD in Western populations with variants that may alter the normal mucosal immunity in the gastrointestinal tract.The clinical complexity and the heterogeneity of the IBD phenotype probably reflect the presence of genetic heterogeneity where different genes or combinations of them may be involved, together with environmental factors. We hypothesized that patients with early onset IBD could have either more severe genetic variants in genes associated with IBD or multiple variants in different genes. Under the multifactorial diseases is crucial to consider the small contribution of a single variant in all not only to other small variations in the same gene but also in different genes belonging to the same pathway.We performed direct gene sequencing looking for 94 variations in NOD2, ATG16L1, IL23R, IL10R, IL10 and XIAP genes previously shown as correlated with IBD both in multifactorial and in Mendelian models. All variants identified are known in literature as being associated with IBD except for three variants in the genes NOD2, IL10 and IL10RB that even though present in online databases have never been involved in association studies on IBD patients. Moreover, we coupled genetic variants identification with an accurate “in silico” analysis to verify their predictive impact on the protein structure and function. The in-silico prediction of these variants results as benign therefore even if they exhibit a very low frequency in control population being benign, they cannot be considered pathogenic as monogenic disease but fall within the multifactorial range.The variants identified in our study partially reflect the association data described in the literature but there are no significant differences with the onset of disease (VEO vs EO-IBD).

Polymorphisms in the canine IL7R 3′UTR are associated with thymic output in Labrador retriever dogs and influence post-transcriptional regulation by microRNA 185

Interleukin-7 (IL-7) and its receptor (IL-7R) are essential for T cell development in the thymus, and changes in the IL-7/IL-7R pathway have been implicated in age-associated thymic involution which results in a reduction of naïve T cell output. The aim of this study was to investigate the relationship between IL7 and IL7R genetic variation and thymic output in dogs. No single nucleotide polymorphisms (SNPs) were identified in the canine IL7 gene, but a number were present in the canine IL7R gene. Polymorphisms in the IL7R exon 8 and 3′UTR were found to be associated with signal joint T cell receptor excision circle (sj-TREC) values (a biomarker of thymic output) in young and geriatric Labrador retrievers. Additionally, one of the SNPs in the IL7R 3′UTR (SNP 14 c.1371 + 446 A > C) was found to cause a change in the seed-binding site for microRNA 185 which, a luciferase reporter assay demonstrated, caused changes in post-transcriptional regulation, and therefore might be capable of influencing IL-7R expression. The research findings suggest a genetic link between IL7R genotype and thymic output in dogs, which might impact on immune function as these animals age and provide further evidence of the involvement of IL-7/IL-7R pathway in age-associated thymic involution.

Interleukin gene polymorphisms in Chinese Han population with breast cancer, a case-control study.

Cytokines are known as important regulators of the cancer involved in inflammatory and immunological responses. This fact and plethora of gene polymorphism data prompted us to investigate IL1 gene polymorphisms in breast cancer (BC) patients. Totally, 530 patients with BC and 628 healthy control women were studied. The genetic polymorphisms for IL1 were analyzed by Massarray Sequencing method. Three single nucleotide polymorphisms (SNPs) identified in IL1B, IL1R1 gene are thought to influence breast cancer risk. The results of the association between IL-1B, IL1R1 polymorphisms and breast cancer risk have significant. We found that the variant TT genotype of rs10490571 was associated with a significantly increased breast cancer risk (TT vs. CC: OR = 2.82, 95% CI = 1.12–7.08, P = 0.047 for the codominant model). For rs16944 (AG vs. GG: OR = 0.60, 95% CI = 0.41–0.90, P = 0.034 for the codominant model) and rs1143623 (CG vs. CC: OR = 0.65, 95% CI = 0.45–0.94, P = 0.023 for the codominant model) have significant associations were found in genetic models. In conclusion, the present analysis suggests a correlation of polymorphic markers within the IL-1 gene locus with the risk in developing breast cancer. Taken together with our finding that IL1B, IL1R1 gene three SNP are also associated with the risk for the disease, we suggest that inflammation via innate and adaptive immunity contributes to multifactorial hereditary predisposition to pathogenesis of the breast cancer.

Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort

ObjectiveInterleukin 6 (IL-6) levels are commonly elevated in patients with depression and psychosis and in people who are at risk of developing these disorders. A common, functional variant in the IL6R gene (IL6R Asp358Ala; rs2228145 A > C) is known to dampen down inflammation by impairing IL6R signaling. We have examined the association of Asp358Ala with diagnosis of depression and psychosis, serum IL-6, CRP levels, and a number of risk factors commonly linked with inflammation, depression or psychosis. We predicted that if IL-6 were related to depression/psychosis risk causally, rather than due to confounding, Asp358Ala would be associated with risk of these disorders, serum IL-6, CRP levels, but not with any of the confounders. MethodWe used data from the population-based ALSPAC birth cohort. Serum IL-6 and CRP levels were measured at age 9 years. Psychotic disorder, ICD-10 diagnosis of severe depressive episode, and total depression score were assessed at age 18 years. IL6R Asp358Ala was genotyped using the Illumina HumanHap550 quad genome-wide SNP genotyping platform. Risk factors assessed include sex, body mass index, social class, ethnicity, maternal education, birth weight, gestational age, maternal post-natal depression, childhood psychological and behavioral problems, and total IQ score. ResultsAsp358Ala was associated with decreased risk of severe depression and/or psychosis; adjusted odds ratio for those with CC, compared with AA, genotype was 0.38 (95% CI, 0.15–0.94). The variant was associated with increased serum IL-6 levels (P = 5.5 × 10−22) but decreased serum CRP levels (P = 3.5 × 10−5), consistent with an anti-inflammatory effect downstream of IL-6. Asp358Ala was not associated with total depression score. Asp358Ala was not associated with any of the other risk factors commonly linked with inflammation, depression or psychosis (all P > 0.20). ConclusionsThe findings provide further evidence that the IL-6/IL6R pathways are involved in pathogenesis of severe depression and psychosis, and may be novel therapeutic targets. Previously reported associations between IL-6, depression and psychosis are unlikely to be fully explained by confounding. Based on a small number of cases, findings from the current study need replication in other samples.

Genetic polymorphism in ATG16L1 gene is associated with adalimumab use in inflammatory bowel disease

BackgroundThe role of single nucleotide polymorphisms (SNPs) associated with inflammatory bowel disease (IBD) is gaining interest. With the advent of novel therapies, personalized treatment in IBD is a future goal. We wondered whether IBD-associated SNPs are able to predict response to anti-TNFα treatment.MethodsData on treatment use and primary response, loss of response and side effects to anti-TNFα treatments were retrieved for 570 IBD patients. rs13361189 (IRGM), rs10210302 (ATG16L1), rs2066844, rs2066845, rs2066847 (NOD2), rs35873774 (XBP1), rs11175593 (LRRK2), rs11465804 (IL23R), rs2301436 (CCR6), rs744166 (STAT3) and rs4821544 (NCF4) SNP status were determined.ResultsNo associations were found between genetic variants of the LRRK2, CCR6, IL23R and NCF4 genes and response to anti-TNFα. For NOD2 and XBP1 associations were found, however, these associations were not strong enough to survive multiple testing corrections. Strikingly, patients carrying the ATG16L1 T300A variant were more likely to be treated with adalimumab, even after correction for disease phenotype, disease behavior and age (p = 0.004, OR 2.8, CI 1.6–5.0).ConclusionsGenetic polymorphisms in the known IBD-associated gene ATG16L1 correlate with requirement of treatment, suggesting a different IBD disease phenotype in these patients. Further investigation will need to elucidate the implications of these findings and identify the underlying disease characteristics.