IL23R Gene Research Articles

Association between Interleukin-21 and Interleukin-21 receptor gene polymorphisms with susceptibility to chronic hepatitis B virus infection and HBV spontaneous clearance in Iranian population

Hepatitis B virus (HBV) infection is a major public health concern due to the infection often leads to chronic infection, liver cirrhosis and also liver cancer. The host immune response to HBV infection and also genetic background play significant role in outcome of infection. Single nucleotide polymorphisms (SNPs) are the most important kind of variation in genetic sequences that caused by point mutations. As cytokines have major roles in viral infections, it seems that cytokine gene polymorphisms are independently associated with response to viral infections. Interleukin 21 (IL-21) plays an influential role in both innate and adaptive immune responses. Its specific receptor, IL-21R, produced and located on the surface of T, B and natural killer (NK) cells and is critical for the proliferation and differentiation of these immune effector cells. Many studies confirmed that the IL-21 involved in response to viral infections.We aimed to investigate the association of G/T IL-21 (rs2055979) and C/T IL-21R (rs3093390) gene polymorphisms with chronic hepatitis B virus infection and HBV spontaneous clearance in Iranian population. MethodsIn this study, blood samples were gathered from 320 patients with chronic HBV and 310 healthy controls and also 120 HBV spontaneous clearance individuals. Following genomic DNA extraction, genotypes of the selected SNPs determined by PCR and restriction fragment length polymorphism (RFLP) method. The results were analyzed by SPSS software using Chi-square, Logistic Regression, ANOVA and Independent Samples t-Test. ResultsAccording to our results, in IL-21R (rs3093390 C/T) gene polymorphism, allele frequency of T is statistically different in the HBV spontaneous clearance group compared to chronic HBV cases. But there is no significant difference between G/T IL-21 (rs2055979) and C/T IL-21R (rs3093390) genotypes distribution in three groups.Also we found that higher serum aspartate transaminase (AST) level in HBV spontaneous clearance group is significantly associated with TT genotype of IL-21 (rs2055979) compared to GG genotype (P value = 0.006). DiscussionOur results showed that T allele frequency in IL-21R (rs3093390 C/T) gene polymorphism could consider as a host genetic factor for HBV spontaneous clearance. Probably we can serve it as a potential prognostic genetic marker for spontaneous clearance of HBV infection.

Impact of IL1R1 and IL1R2 gene polymorphisms on risk of osteonecrosis of the femoral head from a case-control study.

AimOsteonecrosis of the femoral head (ONFH) refers to bony changes caused by osteocyte death under the effects of complicated factors, which is caused by genetic factors and certain risk factors. Our study aimed to explore whether IL1R1/IL1R2 polymorphisms influenced ONFH risk in the Chinese Han population.MethodsWe selected 286 patients and 441 controls, with 11 single‐nucleotide polymorphisms in IL1R1 and IL1R2 gene were successfully genotyped, and evaluated the associations using the chi‐squared test, Fisher's exact test, T test, and genetic model analyses. Odds ratios and 95% confidence intervals (CIs) were calculated using unconditional logistic regression.ResultsIn the allele model, rs11674595 in IL1R2 was associated with increasing the risk of ONFH, the rs10490571 and rs3917225 in IL1R1 gene were associated with an increased risk of ONFH, respectively. In the genetic model, the rs11674595 in IL1R2 gene was associated with an increased risk of ONFH in the codominant model, dominant model, and log‐additive model, respectively. The rs10490571 and rs3917225 in IL1R1 gene conferred an increased risk of ONFH in the codominant model, dominant model, and log‐additive model, respectively. We found none of the haplotypes in the IL1R2 gene was significantly associated with theONFH risk.ConclusionOur findings have demonstrated that the rs11674595 (IL1R2), rs10490571, and rs3917225 (IL1R1) were significantly associated with increasing the ONFH risk in the Chinese Han population.

Biological and genetic evaluation of IL-23/IL-17 pathway in ankylosing spondylitis patients.

Ankylosing spondylitis is the most common form of the chronic inflammatory disease group known as spondyloarthritides. Recent discoveries of the CD4+ Th17 cells and IL-23/IL-17 axis have changed the paradigms in many autoimmune diseases. In this study, we aimed to evaluate the importance of IL-23/IL-17 pathway and IL-23 receptor polymorphism in the pathogenesis of ankylosing spondylitis. Blood samples for this study were obtained from 109 ankylosing spondylitis patients and 40 healthy control subjects. Serum levels of TNF-α, IL-6, IL-17, and IL-23 were measured by the ELISA method. The IL-23R gene polymorphisms rs11209026 (Arg381Gln) and rs4131362 (Val362Ile) were performed by the Sanger Sequence method. IL-6 levels were higher in the active and inactive ankylosing spondylitis groups than in the control group. However, levels of IL-17 and IL-23 were lower in the patient group. The frequency of IL-23R gene rs11209026 and rs4131362 polymorphism were 3.7% and 8.3% in the patient, respectively. As a result, dysregulation of the IL-23 / IL-17 pathway, which is caused by reduced levels of IL-17 and IL-23 in systemic circulation in patients with ankylosing spondylitis, may contribute to the pathogenesis of the disease by systemically producing chronic autoimmune inflammation.

Teleost Type 2 Interleukin-1 Receptor (IL-1R2) from the Spotted Halibut (Verasper variegatus): 3D Structure and a Role in Immune Response

The type 2 interleukin-1 receptor (IL-1R2) is one of natural IL-1β singling inhibitors in mammals. We cloned and sequenced the IL-1R2 gene in V. variegatus (VvIL-1R2). The phylogenetic analysis showed that the molecular structure VvIL-1R2 is similar to that of its orthologues in other vertebrates. The expression levels of VvIL-1R2 are relatively high in the peripheral blood leukocytes (PBLs), gill, and spleen. In addition, peculiar expression patterns for his molecule were detected at various developmental stages, implying that in flatfishes the IL-1R2 may have be important for embryonic development and metamorphosis. In PBLs, the treatment with pathogen-associated molecular patterns (PAMPs) induced a significant and rapid up-regulation of VvIL-1R2, pointing at its involvement in the immune responses against bacterial and viral pathogens.

Pathogenic and Targetable Genetic Alterations in Resected Recurrent Undifferentiated Pleomorphic Sarcomas Identified by Targeted Next-generation Sequencing.

Undifferentiated pleomorphic sarcomas (UPSs) are difficult to treat, with a high recurrence rate. However, the genetic and molecular characterization of recurrent UPS has not been identified. In this study, we investigated the pathogenic and targetable genetic alterations in 16 paired locally pre-recurrent and post-recurrent UPS cases by targeted next-generation sequencing (466 genes). Sequence variations were most frequently found in TP53 (66%), ATRX (34%), and RB1 (28%). In addition, for the first time, recurrent IL7R gene amplification (19%) and KMT2C gene mutation (16%) were detected in UPS. Interestingly, genetic alterations varied with tumor relapse. Importantly, targetable driver variants were found in recurrent UPS. Mutated genes were correlated with the cell cycle, PI3K/mTOR and RAS/MAPK signaling pathways. TMB was also found to be increased after tumor recurrence (4.6 vs. 7.5 mutations/MB, p=0.0343). Routine use of targeted next-generation sequencing for recurrent UPS can facilitate timely therapeutic decision-making.

Dietary fish oil supplementation alters liver gene expressions to protect against LPS-induced liver injury in weanling piglets.

Here, the potential mechanisms of the protective effects of fish oil against LPS-induced liver injury in a piglet model were investigated by using RNA sequencing. Twenty-four piglets were used in a 2 × 2 factorial design, and the main factors included diet (5% corn oil or 5% fish oil) and immunological challenge (LPS or saline, on d 19). All piglets were slaughtered at 4 h after challenge, and liver samples were collected. Fish oil improved liver morphology and reduced TNF-α, IL-1β and IL-6 productions after LPS challenge. RNA sequencing analysis showed fish oil had significant effect on the expressions of genes involved in immune response during LPS-induced inflammation. Selected gene expression changes were validated using quantitative RT-PCR. Fish oil reduced the expressions of pro-inflammatory genes IL1R1, IL1RAP, CEBPB and CRP, and increased that of anti-inflammatory genes IL-18BP, NFKBIA, IFIT1, IFIT2 and ATF3. Moreover, fish oil restored the expressions of some lipid metabolism-related genes, such as ACAA1, ACACA, ACADS and ACADM, which were only decreased in pigs fed a corn oil diet after LPS challenge. Our RNA sequencing reveals novel gene-nutrient interactions following fish oil supplementation and evoked inflammation, which add to the current understanding of the benefits of n-3 polyunsaturated fatty acids against liver injury.

Gene Aberrations in Adult Patients with Ph-Negative ALL in the Czech Republic

IntroductionPhiladelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is an identified high-risk B-lineage ALL subtype, accounting for approximately 20% of adult patients with B-ALL. Ph-like ALL is characterized by poor outcome, very high risk of disease relapse and poor overall survival (OS). The leukemic cell gene expression profile of Ph-like ALL is similar to that of Ph-positive ALL. However, instead of BCR-ABL1, such patients harbor a highly diverse range of genetic alterations. The gene aberrations detected in Ph-like ALL patients are associated with JAK/STAT, Ras, Ikaros and ABL signaling pathways. These aberrations can be subdivided into five distinct subgroups based on the type of cytokine receptor or kinase fusion present: 1) rearrangements of CRLF2; 2) ABL-class gene rearrangements; 3) JAK2 and EPOR rearrangements; 4) sequence mutations or deletions activating JAK-STAT or MAPK signaling pathways and 5) other rare kinase alterations. The study aimed to define the frequency of high-risk genetic aberrations associated with Ph-like subtype in adults with Ph-negative ALL from the Czech Republic. The genetic basis in adult patients with Ph-like ALL has not been studied to date.Patients and MethodsThe molecular genetic analysis was performed in 74 Ph-negative ALL adult patients from routine hematologic practice. DNA and RNA were isolated from patient´s peripheral blood or bone marrow. The mutational analysis was focused on the detection of the P2RY8-CRLF2 fusion gene (real-time PCR) and the “hot spot” region of the JAK2 gene (PCR/Sanger sequencing) in patient´s cohort. Minimal residual disease (MRD) value was also assessed in all patients prior to the first consolidation cycle (week 11) by real-time PCR. The detection of copy number variations (MLPA method) and targeted sequencing (NGS) was performed in a selected set of patients.ResultsThe patient cohort of Ph-negative ALL consisted of 46.6% young adults (age 15 to 39 years), 35.6% adults (age 40 to 59 years), and 17.8% older adults (age 60 to 75 years). Among all patients, increasing age was associated with an inferior outcome of the disease. The difference in OS was significant for young adults compared with adults and older adults (median: 126.7, 23.5 and 22.6, respectively; P=0.0087). The above-mentioned gene aberrations were identified in 36.5% of patients with Ph-negative ALL. The 3-year OS for patients with and without gene aberrations was 36% and 49%. Copy number alterations were detected in almost a third of patient cohort in several genes (IKZF1, PAX5, BTG, ETV6, EBF1, CDKN2A/2B, and SHOX). Deletions in IKZF1 were the most frequent aberration (17.8%). Within the patient cohort, the presence of IKZF1 deletions did not influence the OS significantly. The presence of P2RY8-CRLF2 fusion gene was identified in 16.4% patients with markedly inferior OS in comparison to a patient group without detected P2RY8-CRLF2 (median: 33.2 and 126.7). Sequence mutations of TP53, IL7R, and JAK2 genes occurred in 14.3%, 2.9%, and 1.6% patients, respectively. All patients with the detected sequence variant were carriers of at least one other gene aberration. Achieving MRD negativity in patients with Ph-like aberrations tended to more favorable OS in comparison to those MRD positive, but this trend was not statistically significant enough.ConclusionsOur findings demonstrate the representation of selected gene aberrations in Ph-negative ALL adults patients. Also they have led to the introduction of molecular genetic diagnostics of Ph-like ALL to routine hematological practice in the Czech Republic. MRD negativity and younger age are the most important prognostic factors in this subgroup of patients according to our analysis.This study was supported by TA CR (TE02000058), MH CZ - DRO (FNBr, 65269705) and CEITEC 2020 (LQ1601), and MEDGENET 2020 (692298). DisclosuresFolber:Affimed: Research Funding. Doubek:Roche: Consultancy, Honoraria; Affimed: Research Funding; AbbVie: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy.

A draft of the interdisciplinary guidelines for diagnosis, methods for assessment of the degree of inflammatory activity, therapeutic efficacy, and for the use of biological agents in patients with concomitant immunoinflammatory diseases (psoriasis, psoriatic arthritis, Crohn's disease)

Psoriasis, psoriatic arthritis (PsA) and inflammatory bowel disease (IBD) are multifactorial chronic immunoinflammatory disorders with characteristic common genetic markers that determine their common pathophysiology and similar immune abnormalities. In particular, IL12/23 signaling pathway of the immune pathogenesis of the above mentioned diseases is related to the IL23R gene polymorphism. Common pathophysiological features, in their turn, produce a high risk and prevalence of comorbidity. Clinicians' unawareness of these particulars of the immunoinflammatory disorders might lead to the absence of interdisciplinary collaboration, late diagnosis of one of these disorders and polypharmacy, because each specialist (i.e., a dermatologist, a rheumatologist, a gastroenterologist) would administer his/hers treatments independently. In this context, the issues of the multidisciplinary approach to this problem are becoming highly relevant for earlier diagnosis and adequate treatment choice that is optimal for all disorders which contribute to the pathological process, taking into account common mechanism of their development. Therefore, there is the necessity to establish an interdisciplinary working group consisting of the leading specialists of the Russian Federation in rheumatology, dermatology, and gastroenterology, with a purpose to elaborate a consensus on the immunoinflammatory comorbidities. At the discretion of the Russian Association of Rheumatologists (RAR), Russian Society of Dermatovenerologists and Cosmetologists (RSDVC), Russian IBD Study Society (RIBDS), such a group has been formed of 11 experts corresponding to their scientific expertise in the area. The main aim of the Working Group was to develop a universal interdisciplinary questionnaire for detection of the signs and symptoms of the immunoinflammatory disorders (psoriasis, PsA, IBD), as well as development of a draft project of the interdisciplinary guidelines on the early diagnosis, methods of activity assessment and indications to the use of genetically engineered biological agents in patients with comorbid immunoinflammatory comorbidities (psoriasis, PsA, IBD). Procedure of the interdisciplinary guidelines elaboration . The Working Group elaborated a draft project of the up-to-date evidence-based guidelines and proposed a multidisciplinary questionnaire. An interdisciplinary expert council of specialists in dermatology, rheumatology and gastroenterology discussed each position of the proposed guidelines and was adopted by a simple majority of votes through an open voting at the Second Russian Debates “Dermatology, Rheumatology, Gastroenterology: focus on the interdisciplinary interaction” (Moscow, December 12–13, 2017). Results : 1 . A universal interdisciplinary questionnaire to detect clinical signs of immunoinflammatory disorders (psoriasis, PsA, IBD) has been created. It contains the main questions the answers to which are needed for a specialist physician (a dermatologist, a rheumatologist or a gastroenterologist) to suspect comorbidity and to refer the patient to a corresponding specialist. The questionnaire has three parts, each of them with questions to the patient aimed at the detection of the symptoms of psoriasis, PsA, and IBD. 2 . An algorithm for interaction between dermatologists, rheumatologists and gastroenterologists has been developed aimed at optimal management of patients with comorbid immunoinflammatory disorders. 3 . Goals of treatment of immunoinflammatory disorders (psoriasis, PsA, Crohn's disease) have been formulated according to the “treat-to-target” (Т2Т) concept. 4 . Criteria for assessment of activity and severity of the immunoinflammatory disorders (psoriasis, PsA, and Crohn's disease) have been formulated. 5 . The draft describes the indications for the administration of genetically engineered biological agents (GEBA), factors influencing the choice of treatment, criteria for GEBA efficacy assessment, indications to a change of a GEBA in primary or secondary treatment failure. Conclusion : In accordance with the results of discussion with specialists from various regions of the Russian Federation and with the decision of the Expert Council, it is planned to validate the questionnaire, with subsequent inclusion of the position of the draft project into the clinical guidelines on the management of patients with psoriasis, PsA, and Crohn's disease.

Association Between IL7R Promoter Polymorphisms and Multiple Sclerosis in Turkish Population.

Multiple sclerosis (MS) is a chronic progressive neurodegenerative disease that affects myelin fibers within the central nervous system resulting in neurological impairment. Although the etiology of MS is not fully understood, environmental and genetic factors are thought to play important roles. IL7R gene polymorphisms which are associated with several autoimmune diseases have also been implicated as a genetic factor for MS following genome-wide association studies. To further examine this association, we investigated the association between MS and IL7R gene - 449 (A/G), - 504 (T/C), and - 1085 (G/T) promoter polymorphisms in Turkish population. Three hundred sixty-four MS patients and 191 healthy controls were involved in this study. Three polymorphic regions in the promoter of IL7R were identified and these regions were amplified by appropriate primers. The PCR products were digested by PstI enzyme for - 504 (T/C) SNP and HphI enzyme for - 1085 (G/T) and - 449 (A/G) SNPs and genotyping was done based on digested PCR product sizes. Genotype distributions and allele frequencies of - 449 polymorphism did not show any significant association with MS directly (p = 0.120 and p = 0.490, respectively). But the genotypes of IL7R - 449 GA for AOMS and AA for EOMS were a risk factor in according to age of onset (p = 0.002, OR = 4.021, 95% CI = 1.642-9.845). Furthermore, IL7R - 449 A allele was found to be a risk factor for EOMS (p = 0.011, OR = 1.3, 95% CI = 1.107-1.527). Significant association was seen between IL7R - 504 TC heterozygote genotype and MS (p = 0.02, OR = 1.702, 95% CI = 1.169-2.478). The IL7R - 1085 (G/T) polymorphism did not show association with MS; however, the haplotype of ACG may be susceptibility to MS and RRMS (p = 0.035, OR = 1.349, 95% CI = 1.020-1.785, and p = 0.041, OR = 1.368, 95% CI = 1.012-1.850, respectively) and the haplotypes of ACG, ATT, and GTG demonstrate a protective effect in EOMS (p = 0.008, OR = 0.326, 95% CI = 0.136-0.782, p = 0.012 and p = 0.012, OR = 0.462, 95% CI = 0.249-0.859, respectively). RRMS frequency in the Turkish population was decreased and SPMS frequency was strongly increased based on comparison to results from other populations. Furthermore, male patients had an increased frequency of SPMS significantly (p = 0.033, OR = 1.667, 95% CI = 1.036-2.682). In conclusion, this is the first study to show a significant association between the IL7R promoter polymorphisms and the age of onset of MS.

IL23R-Protective Coding Variant Promotes Beneficial Bacteria and Diversity in the Ileal Microbiome in Healthy Individuals Without Inflammatory Bowel Disease.

This study aimed to characterize the mucosa-associated microbiota in ileal Crohn's disease [CD] patients and in healthy controls in terms of host genotype and inflammation status. The mucosa-associated microbiotas of intestinal pinch biopsies from 15 ileal CD patients with mild and moderate disease and from 58 healthy controls were analysed based on 16S ribosomal sequencing to determine microbial profile differences between [1] IL23R, NOD2 and ATG16L1 genotypes in healthy subjects, [2] ileal CD patients and control subjects, and [3] inflamed and non-inflamed mucosal tissue in CD patients. The protective variant of the IL23R gene [rs11209026] significantly impacted the microbial composition in the ileum of healthy subjects and was associated with an increased abundance of phylotypes within the family Christensenellaceae as well as increases in diversity and richness. Comparative analysis of healthy and non-inflamed CD microbiome samples indicated a notable decrease in the abundance of Faecalibacterium prausnitzii as well as Shannon diversity and richness. Inflamed and non-inflamed ileal samples of CD subjects had high intra-individual stability and inter-individual variability, but no significant alterations in diversity, richness or taxa were identified. Calprotectin correlated positively with the abundance of Proteobacteria and negatively with diversity in the samples from healthy subjects. The observation of low diversity and low abundance of beneficial bacteria in healthy control subjects carrying the IL23R [rs11209026] wild-type GG genotype indicates that the gut microbiome is influenced by host genetics and is altered prior to disease diagnosis. Faecal calprotectin may be a potential non-invasive screening tool for dysbiosis in subjects without disorders of intestinal inflammation.

NEW PATHOGENIC VARIANT ON IL-7R GENE ASSOCIATED WITH SCID

Introduction T-B+NK+ Severe Combined Immunodeficiency (SCID) due to mutations in the genes encoding the IL-7 receptor represent about 10% of American SCID cases. We report a patient found to have a c.675C>A (p.Tyr225*) homozygous mutation in exon 5. This variant is not present in population databases, and has not been reported in the literature in individuals with IL-7 receptor disease. Case Description Our medical center received a referral for abnormal T-cell receptor excision circle (TREC) results on a newborn screen. The patient's mother had an uncomplicated pregnancy, and there was no consanguinity or family history concerning for a primary immune deficiency. Lymphocyte subsets revealed an absence of T cells, along with present, but diminished B-cells and Natural-Killer cells. The patient had an absent thymic shadow on chest X-ray. He was also found to have poor mitogenic responses. FISH for DiGeorge syndrome was negative for deletions in 22q11.2 and 22q13, and testing for ADA deficiency was negative. Genetic testing resulted in a c.675C>A (p.Tyr225*) homozygous mutation. The patient has had a confirmed infection with Rhinovirus. He is currently on bacterial and fungal prophylaxis, and receiving immune globulin while awaiting bone marrow transplantation. Discussion A homozygous mutation in IL7R, Exon 5, c.675C>A (p.Tyr225*) creates a premature translational stop signal in the IL7R gene, resulting in an absent or disrupted protein product. Loss of function variants of IL7R are known to be pathogenic. This case reinforces the need for researchers to functionally evaluate all mutations found in patients.

Parity-dependent association between IL-12Râ2 and IL-23R gene polymorphisms and clinical mastitis in Chinese Holstein cows

Interleukin-12 (IL-12) and interleukin-23 (IL-23) are proinflammatory cytokines produced by macrophages and dendritic cells in response to infection with intracellular pathogens. Given the importance of IL-12 and IL-23 for modulating inflammation and the host immune response, the IL-12 and IL-23 receptor genes may be suitable candidate genes for studying disease resistance in dairy cattle. DNA samples of twenty Chinese Holstein cows were selected randomly for PCR amplification and sequencing, and used for SNP discovery in the bovine IL-12Râ2 and IL-23R promoter regions. One SNP (c.-246G>T, rs385343195) in IL-12Râ2 and 2 SNPs [c.-856A>G (rs109216732) and c.-207T>C (rs109571825)] in IL-23R were identified. Identified SNPs were genotyped in 866 Chinese Holstein cows and associations between SNPs or haplotypes and clinical mastitis infection were analyzed by logistic regression model. Significant associations between rs385343195 (IL-12Râ2 gene) and haplotypes of SNPs rs385343195-rs109216732-rs109571825 (TGC and TAT), and clinical mastitis infection were detected depending on parity, and this provides insight into the complex mechanisms of immunity to infections. Further investigations are required to reveal the mechanisms of IL-12Râ2 and IL-23R in mastitis susceptibility in cattle.

Association of IL4R-rs1805016 and IL6R-rs8192284 polymorphisms with clinical dengue in children from Colombian populations.

Etiologic studies provide evidence that IL-4R and IL-6R receptors may play important roles in the regulatory mechanisms of the development of clinical dengue, especially in children which is a segment of the population with high severe dengue risk. Moreover, the allele frequencies and genetic associations may be influenced by the populational genetic background. Therefore, we performed a case-control study to evaluate possible associations between SNPs in IL4R and IL6R genes and clinical dengue in children from two Colombian populations. We genotyped the rs1805016 (IL4R) and rs8192284 (IL6R) by PCR-RFLP method, in 298 symptomatic children and 648 asymptomatic controls. Three individual genetic ancestral proportions (APs) (European, Amerindian, African) were inferred by genotyping 29 AIMs (Ancestry informative markers). The variables gender, APs, and the population of origin were used like confusion variables. We found IL4R-rs1805016 GG genotype and G-allele carriers and IL6R-rs8192284 AA genotype associated with clinical dengue in the pooled and Huila samples. Nevertheless, we found no association of these polymorphisms in the sample of Antioquia. For the first time, we report SNPs in IL4R and IL6R genes associated with clinical dengue, which contributes to understanding the genetic susceptibility to dengue disease. Moreover, these results may be influenced by genetic background and must be evaluated through functional analysis.

Transcription factor Zbtb38 downregulates the expression of anti-inflammatory IL1r2 in mouse model of rheumatoid arthritis

DNA methylation is a decisive regulator of gene expression. Differentially methylated promoters were described in rheumatoid arthritis (RA), but we do not know how these epimutations can trigger a proinflammatory cytokine milieu. B cell-focused DNA methylome studies identified a group of genes that had undergone disease-associated changes in a murine model of RA. An arthritis-specific epimutation (hypomethylation) was detected in the promoter region of the Zbtb38 gene, which encodes a transcriptional repressor. Gene expression studies revealed that hypomethylation of the Zbtb38 promoter was accompanied by disease-specific repressor expression, and two anti-inflammatory factors interleukin 1 receptor 2 gene (IL1r2) and interleukin-1 receptor antagonist (IL1rn) were among the downregulated genes. We hypothesized that Zbtb38 repressor could induce downregulated expression of these anti-inflammatory genes and that this could significantly contribute to arthritis pathogenesis. Our studies demonstrate that Zbtb38 forms a molecular bridge between an arthritis-associated epimutation (DNA hypomethylation in Zbtb38 promoter) and transcriptional silencing of the IL1r2 gene in B cells. In this way, disease-associated DNA hypomethylation can support autoimmune arthritis by interfering with an anti-inflammatory pathway.

Genomic analysis reveals genes affecting distinct phenotypes among different Chinese and western pig breeds

The differences in artificial and natural selection have been some of the factors contributing to phenotypic diversity between Chinese and western pigs. Here, 830 individuals from western and Chinese pig breeds were genotyped using the reduced-representation genotyping method. First, we identified the selection signatures for different pig breeds. By comparing Chinese pigs and western pigs along the first principal component, the growth gene IGF1R; the immune genes IL1R1, IL1RL1, DUSP10, RAC3 and SWAP70; the meat quality-related gene SNORA50 and the olfactory gene OR1F1 were identified as candidate differentiated targets. Further, along a principal component separating Pudong White pigs from others, a potential causal gene for coat colour (EDNRB) was discovered. In addition, the divergent signatures evaluated by Fst within Chinese pig breeds found genes associated with the phenotypic features of coat colour, meat quality and feed efficiency among these indigenous pigs. Second, admixture and genomic introgression analysis were performed. Shan pigs have introgressed genes from Berkshire, Yorkshire and Hongdenglong pigs. The results of introgression mapping showed that this introgression conferred adaption to the local environment and coat colour of Chinese pigs and the superior productivity of western pigs.

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.

The role of IL-23/IL-17 axis in human kidney allograft rejection.

Th17 cell subset has been implicated in autoimmune diseases, tumor immunity and, transplant rejection. In order to investigate the role of IL-17/IL-23 pathway in allograft outcome, intragraft expression of IL-17mRNA and single nucleotide polymorphisms (SNPs) of IL-17A, IL-17F, IL-17RC, and IL23R genes were evaluated with a quantification of IL-17A, IL-17F, and IL-23 plasma levels. This study revealed that recipients with acute rejection (AR) had a significant increase in IL-17AmRNA expression levels after transplantation compared to controls (P=0.037). Moreover, IL-17A plasma levels were significantly higher in AR group; pretransplantation (Day-1 [D-1]): P=0.00022 and posttransplantation (Day 7 [D7]): P<10-14 . IL-17F and IL-23 plasma levels were significantly higher in AR at D7 only (47.86vs. 22.99pg/ml; and 33.82vs. 18.811pg/ml; P=0.015 and P<10-17 , respectively). Using receiver-operating characteristic curves, D7 IL-17A and IL-23 plasma levels exhibited excellent sensitivities and specificities for predicting AR. Genetic study revealed no association between IL-17A, IL-17F, IL-17RC, and IL23R studied SNPs and AR. Nevertheless, a significant improvement of graft survival was found in kidney transplant recipients carrying IL-17F-rs763780*A/A, IL-17RC*G/G, and *G/A genotypes. Besides, IL-17AmRNA levels were significantly higher in patients carrying the IL-23R*G/G genotype comparatively to those with *G/A genotype. Based on these findings, significant increase of IL-17A mRNA and protein levels in AR recipients that are genetically controlled highlights the role of this cytokine that can be a useful clinical biomarker to predict early acute renal allograft rejection.

Involvement of the IL23/Th17 Pathway in the Pathogenesis of Tunisian Pemphigus Foliaceus.

Pemphigus foliaceus (PF) is a rare autoimmune skin disease caused by anti-Dsg1 pathogenic autoantibodies. It is considered as a Th2-mediated disease. Likewise, Th17 cells were recently described in the pathogenesis of the disease but their role is still unclear. We aimed to unravel the eventual implication of the IL23/Th17 pathway in the development of PF. A case-control study was conducted on 115 PF patients and 201 healthy controls using PCR-RFLP and AS-PCR methods. SNPs in IL23R, RORγt, IL17A, IL17F, IL17AR, TNFa, and STAT3 genes were genotyped. mRNA expression of IL23R and RORγt was evaluated using Q-PCR. The frequency of circulating Th17 cells was analyzed by flow cytometry. Genetic associations between IL23R>rs11209026, IL17A>rs3748067, IL17F>rs763780, and TNFa>rs1800629 and the susceptibility to PF were reported. Moreover, we revealed a significant increased frequency of circulating CD4+IL17+ cells as well as higher mRNA levels of RORγt and IL23R in PBMCs of patients. However, no significant increase of RORγt and IL23R mRNA expression was observed in lesional skin biopsies. In spite of the little size of specimens, our results provide converging arguments for the contribution of the IL23/Th17 pathway in the pathogenesis of PF.

Association of IL17 and IL23R gene polymorphisms with rheumatic heart disease in South Indian population

ABSTRACTBackground: IL-23/Th17 signaling pathway plays a crucial role in the cell-mediated immune response against bacterial infections and also in the pathogenesis of inflammatory and autoimmune diseases. Recent studies indicate that Th17 cell-associated cytokines are involved in the progression and maintenance of valvular lesions in rheumatic heart disease (RHD). Variants in the genes of cytokines that are potentially involved in Th17 response may influence interindividual differences in their expression levels, thereby contributing to the pathogenesis of immune-mediated diseases such as RHD.Objective: The aim of the study is to investigate the association of IL17A, IL17F, and IL23R gene variants with the risk perception of RHD.Methods: A total of 225 individuals (99 RHD patients and 126 healthy siblings) were recruited for the study. The IL17A (rs2275913), IL17F (rs763780), and IL23R (rs10889677) polymorphisms were determined by polymerase chain reaction restriction fragment length polymorphisms and amplification-refractory mutation system-polymerase chain reaction methods, respectively.Results: The frequency of IL17A (rs2275913) A/A genotype was significantly high in pooled RHD patients (odds ratio [OR] = 2.76; pc = 0.021), rheumatic fever (RF) patients (OR = 14.5; pc = 0.0001), and mitral valvular lesions patients (OR = 2.74; pc = 0.039) when compared to healthy siblings. However, the IL17F (rs763780) and IL23R (rs10889677) polymorphisms did not show any association with RHD.Conclusions: The results suggest that IL17A (rs2275913) polymorphism is associated with the development of RF/RHD in South Indian population. Further studies are required to substantiate the association of these genes with the disease risk.

Correlations of IL-23R gene polymorphism with clinicopathological characteristics and prognosis of hepatocellular carcinoma patients after interventional therapy

In this study, we summarized the association of IL-23R gene polymorphisms with hepatocellular carcinoma (HCC). A total of 270 HCC patients were selected as HCC group, and 251 healthy individuals served as the control group. PCR-RFLP was performed to detect IL-23R gene polymorphism, including rs17375018 and rs11805303. Survival rate and risk factors of HCC were identified. The findings suggested that IL-23R rs17375018 was correlated with genetic susceptibility to HCC, and GC haplotype was closely linked with the risk factors of HCC. Moreover, rs17375018 polymorphism was related to portal vein tumor thrombus (PVTT) and alcohol consumption in HCC patients, while prognosis was better in HCC patients with AA genotype of rs17375018 polymorphism. Lastly, GG genotype in rs17375018, PVTT and TNM stage III and IV were identified as independent risk factors for HCC. In conclusion, IL-23R rs17375018 polymorphism might serve as a prognostic factor in patients with HCC after interventional therapy.