IL23R Gene Research Articles

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.

Genetic polymorphism related to monocyte-macrophage function is associated with graft-versus-host disease

Despite detailed human leukocyte antigen (HLA) matching and modern immunosuppressive therapy, severe graft-versus-host disease (GvHD) remains a major hurdle for successful allogeneic hematopoietic stem cell transplantation (HSCT). As the genetic diversity in GvHD complicates the systematic discovery of associated variants across populations, we studied 122 GvHD-associated single nucleotide polymorphisms (SNPs) in 492 HLA-matched sibling HSCT donor-recipient pairs from Finland and Spain. The association between these candidate SNPs and grade III–IV acute GvHD and extensive chronic GvHD was assessed. The functional effects of the variants were determined using expression and cytokine quantitative trait loci (QTL) database analyses. Clear heterogeneity was observed in the associated markers between the two populations. Interestingly, the majority of markers, such as those annotated to IL1, IL23R, TLR9, TNF, and NOD2 genes, are related to the immunological response by monocytes-macrophages to microbes, a step that precedes GvHD as a result of intestinal lesions. Furthermore, cytokine QTL analysis showed that the GvHD-associated markers regulate IL1β, IFNγ, and IL6 responses. These results support a crucial role for the anti-microbial response in GvHD risk. Furthermore, despite apparent heterogeneity in the genetic markers associated with GvHD, it was possible to identify a biological pathway shared by most markers in both populations.

Association between interleukin-6/6R gene polymorphisms and coronary artery disease in Russian population: influence of interleukin-6/6R gene polymorphisms on inflammatory markers.

This study determined the genotype effects of interleukin (IL)-6/IL-6R single nucleotide polymorphisms (SNPs) on circulating levels of different cytokines in healthy and coronary artery disease (CAD) patients with different allele frequencies. In the control patients, rs1800795 showed significant differences in IL-18 concentrations between CC and CG and CC and GG genotypes (P=0.003 and 0.004, respectively). Furthermore, circulatory IL-1β was significantly different between GC and GG genotypes from the same SNP (P=0.038). In the diseased patients, significance was determined only for IL-2 (P=0.021) between the C and G homozygote allele carriers of rs1800795. The diseased GC and GG genotype carriers were statistically different for IL-2 (P=0.049) from the rs1800796 and for IL-4 (P=0.049) from the rs2228044. IL-4 was also statistically significant between the GC and CC genotypes from the rs2228043 of the IL-6R gene (P=0.025). The last combination of genotypes in the same gene for the same SNP was statistically significant for IL-10 (P=0.036). According to the logistic regression, only gender (odds ratio [OR] =2.43) and triglycerides (OR =1.98) could be taken as determinants of CAD, while examined SNPs genotypes were not identified as risk factors for CAD. In general, the IL-6 polymorphism genotypes were mainly associated with inflammatory cytokines, while the IL-6R polymorphism genotypes were associated with anti-inflammatory cytokines.

Association of IL-23R gene single nucleotide polymorphism; rs 11209026 with incidence and severity of ankylosing spondylitis in a cohort of Egyptian patients

The aim of the present study was to investigate the possible association between incidence and severity of ankylosing spondylitis (AS) in a cohort of Egyptians and Interleukin-23Receptor (IL23R) genesingle nucleotide polymorphism(rs11209026). Methods:The study included thirty-two AS patients and forty volunteers who serves asa control group. The studied polymorphismwas genotyped using 5′ Nuclease assay. Results: A statistically significant difference was detected between both studied groups as regards different IL23R genesingle nucleotide polymorphism(rs11209026) genotypes. Heterozygous genotype was the most prevailing among both cases and controls. At a cutoff level of 110pg/mL, a statically significant difference was observed between cases and controls as regards serum IL23 level. Conclusions:In Egyptians, IL-23R single nucleotide polymorphism (rs11209026) appears to be associated with ankylosing spondylitis occurrence not severity, while higher levels of IL-23 might be associated with disease severity.

The chromatin accessibility signature of human immune aging stems from CD8+ T cells.

Aging is linked to deficiencies in immune responses and increased systemic inflammation. To unravel the regulatory programs behind these changes, we applied systems immunology approaches and profiled chromatin accessibility and the transcriptome in PBMCs and purified monocytes, B cells, and T cells. Analysis of samples from 77 young and elderly donors revealed a novel and robust aging signature in PBMCs, with simultaneous systematic chromatin closing at promoters and enhancers associated with T cell signaling and a potentially stochastic chromatin opening mostly found at quiescent and repressed sites. Combined analyses of chromatin accessibility and the transcriptome uncovered immune molecules activated/inactivated with aging and identified the silencing of the IL7R gene and the IL-7 signaling pathway genes as potential biomarkers. This signature is borne by memory CD8+ T cells, which exhibited an aging-related loss in binding of NF-κB and STAT factors. Thus, our study provides a unique and comprehensive approach to identifying candidate biomarkers and provides mechanistic insights into aging-associated immunodeficiency.

Neuropathological and behavioral sequelae in IL-1R1 and IL-1Ra gene knockout mice after soman (GD) exposure

Soman (GD) exposure results in status epilepticus (SE) that leads to neurodegeneration, neuroinflammation, and behavioral consequences including learning and memory deficits. The neuroinflammatory response is characterized by the upregulation of the pro-inflammatory cytokine, interleukin-1 (IL-1), which mediates the expression of other neurotoxic cytokines induced after GD exposure. However, the specific role of IL-1 signaling has not been defined in terms of the consequences of GD-induced SE. Therefore, the purpose of this study was to regulate IL-1 signaling and study the behavioral deficits and neurodegeneration that occur after convulsion onset. Wild type (WT), IL-1 receptor (IL-1R1) knockout (KO), and IL-1 receptor antagonist (IL-1Ra) KO mice were exposed to a convulsive dose of GD, and behavior was evaluated up to 18days later. Activity was studied using the Open Field, anxiety was assessed in the Zero Maze, and spatial learning and memory were evaluated with the Barnes Maze. The animals were euthanized at 24hours and 18days to determine neuropathology in the piriform cortex, amygdala, thalamus, and CA1, CA2/3, and CA4 regions of the hippocampus. Unlike the IL-1Ra KO, the IL-1R1 KO showed less neuropathology compared to WT at 24hours, but moderate to severe injury was found in all strains at 18days. Compared to their saline controls, the exposed WT mice were significantly more active in the Open Field, and the IL-1R1 KO strain showed reduced anxiety in the Zero Maze Test. Compared to WT mice, IL-1R1 and IL-1Ra KO mice had spatial learning and memory impairments in the Barnes Maze. Therefore, the IL-1 signaling pathway affects neurodegeneration and behavior after GD-induced convulsions.

IL-23R and IL-17A polymorphisms correlate with susceptibility of ankylosing spondylitis in a Southwest Chinese population.

The association between the IL-23R and IL-17A polymorphisms and ankylosing spondylitis (AS) in the Southwest Chinese Population is still unclear. The purpose of this study is to detect the association between IL-23R and IL-17A polymorphisms and AS. A case–control study consisting of 486 AS patients and 480 healthy controls was performed. We used the high-resolution melting methods (HRM) to genotype five selected single nucleotide polymorphisms (SNPs), rs6693831, rs7517847, rs1884444, rs10889677 in the IL-23R gene and rs2275913 in the IL-17A gene. Meanwhile, the laboratory indexes were recorded. In this study, patients with genotype CC (p = 8.574E-8) and allele C (p = 3.206E-31) on SNP rs6693831 (IL-23R) showed decreased risk of AS. The genotype TT (p = 4.551E-6) and allele T (p = 0.02) on SNP rs1884444 (IL-23R) showed significant lower risk of AS. Individuals carrying the allele A of rs2275913 showed higher morbidity of AS (p = 0.04). We first detected that rs6693831 and rs1884444 in IL-23R gene and rs2275913 in IL-17A gene have genetic association with AS.

A comprehensive review and update on Crohn's disease

The term inflammatory bowel disease (IBD) refers principally to two major categories of chronic relapsing inflammatory intestinal disorders: Crohn's disease (CD) and ulcerative colitis (UC). In the United States, it is currently estimated that about 1.5 million people suffer from IBD, causing considerable suffering, mortality and economic loss every year. Yet the cause of IBD is unknown, and until we understand more, prevention or cure will not be possible. There is a lot of variation in the incidence and prevalence of CD based on geographic region, environment, immigrant population, and ethnic groups. The annual incidence of CD in North America is reported to be 3.1–20.2 per 100,000 with a prevalence of 201 per 100,000 population. Based on the epidemiological, genetic and immunological data, CD is considered to be a heterogeneous disorder with multifactorial etiology in which genetics and environment interact to manifest the disease. Several genes have been studied so for with respect to CD, but thus far the strong and replicated associations have been identified with NOD2, IL23R and ATG16L1 genes. The risk factors implicated with CD include smoking, low fiber- high carbohydrate diet, altered microbiome and medications such as non-steroidal anti-inflammatory drugs.CD is typically characterized by transmural inflammation of the intestine and could affect any part of the gastrointestinal tract from mouth to perianal area. In terms of distribution of the disease 25% of the patients have colitis only, 25% is ileitis only and 50% have ileocolitis. The Montreal classification is based on the age at diagnosis (<16, 17–40, > 40), disease location (Ileal, colonic, Ileocolonic) and the disease behavior (nonstricturing/nonpenetrating, stricturing, penetrating). The key features for diagnosing CD comprises a combination of radiographic, endoscopic and pathological findings demonstrating focal, asymmetric, transmural or granulomatous features. Abdominal Computed tomography (CT) enterography is the most preferred first-line radiologic study used in the assessment of small bowel CD. The diagnostic accuracy of magnetic resonance enterography/enteroclysis is similar to that of CT scans and also prevents exposure to ionizing radiation. Endoscopic scores are considered to be the gold standard tool to measure the activity of CD and they are used more commonly in the clinical trials to measure the efficacy of various drugs on inducing and maintaining mucosal healing. The most common scoring systems used to measure clinical disease activity include Crohn's Disease Activity Index (CDAI), HBI- Harvey-Bradshaw index (HBI), short inflammatory bowel disease questionnaire (SIBDQ) and Lehmann score.Management of Crohn's disease has been seen as an evolving challenge owing to its widely heterogeneous manifestations, overlapping characteristics with other inflammatory disorders, often elusive extraintestinal manifestations and uncertain etiology. Therapeutic interventions are tailored to address symptomatic response and subsequent tolerance of the intervention. Chronology of treatment should favor treatment dose acute disease or “induction therapy”, followed by maintenance of adequate response or remission, i.e. “maintenance therapy”. The medications which are highly effective in inducing remission include steroids and Tumor Necrosis Factor (TNF) inhibitors. Medications used to maintain remission include 5-aminosalicyclic acid products, immunomodulators (Azathioprine, 6-mercaptopurine, methotrexate) and TNF inhibitors (infliximab, adalimumab, certolizumab and golimumab). Surgical interventions like bowel resection, stricturoplasty or drainage of abscess is required in up to two thirds of CD patients during their lifetime. The most common indications for surgical resection are medically refractory disease, perforation, persisting or recurrent obstruction, abscess not amenable to percutaneous drainage, intractable hemorrhage, dysplasia or cancer. Endoscopic recurrence in postoperative CD patients, as defined by Rutgeers score i2-i4 occur in 30–90% of the patients at the neoterminal ileum within 12 months of surgery and almost universally by 5 years. Treating CD requires a comprehensive care team including the patient, primary care provider, and gastroenterologist. In summary CD is a chronic inflammatory condition with a remitting and relapsing course primarily affecting relatively younger population with significant socioeconomic effects.

Mutations in TP53 and JAK2 are independent prognostic biomarkers in B-cell precursor acute lymphoblastic leukaemia

Background:In B-cell precursor acute lymphoblastic leukaemia (B-ALL), the identification of additional genetic alterations associated with poor prognosis is still of importance. We determined the frequency and prognostic impact of somatic mutations in children and adult cases with B-ALL treated with Spanish PETHEMA and SEHOP protocols.Methods:Mutational status of hotspot regions of TP53, JAK2, PAX5, LEF1, CRLF2 and IL7R genes was determined by next-generation deep sequencing in 340 B-ALL patients (211 children and 129 adults). The associations between mutation status and clinicopathological features at the time of diagnosis, treatment outcome and survival were assessed. Univariate and multivariate survival analyses were performed to identify independent prognostic factors associated with overall survival (OS), event-free survival (EFS) and relapse rate (RR).Results:A mutation rate of 12.4% was identified. The frequency of adult mutations was higher (20.2% vs 7.6%, P=0.001). TP53 was the most frequently mutated gene (4.1%), followed by JAK2 (3.8%), CRLF2 (2.9%), PAX5 (2.4%), LEF1 (0.6%) and IL7R (0.3%). All mutations were observed in B-ALL without ETV6-RUNX1 (P=0.047) or BCR-ABL1 fusions (P<0.0001). In children, TP53mut was associated with lower OS (5-year OS: 50% vs 86%, P=0.002) and EFS rates (5-year EFS: 50% vs 78.3%, P=0.009) and higher RR (5-year RR: 33.3% vs 18.6% P=0.037), and was independently associated with higher RR (hazard ratio (HR)=4.5; P=0.04). In adults, TP53mut was associated with a lower OS (5-year OS: 0% vs 43.3%, P=0.019) and a higher RR (5-year RR: 100% vs 61.4%, P=0.029), whereas JAK2mut was associated with a lower EFS (5-year EFS: 0% vs 30.6%, P=0.035) and a higher RR (5-year RR: 100% vs 60.4%, P=0.002). TP53mut was an independent risk factor for shorter OS (HR=2.3; P=0.035) and, together with JAK2mut, also were independent markers of poor prognosis for RR (TP53mut: HR=5.9; P=0.027 and JAK2mut: HR=5.6; P=0.036).Conclusions:TP53mut and JAK2mut are potential biomarkers associated with poor prognosis in B-ALL patients.

GENE POLYMORPHISM OF PROINFLAMMATORY CYTOKINES (TNF, IL6) AND THEIR RECEPTORS (TNFRSF1A, TNFRSF1B, IL6R): IMPLICATIONS FOR NON-ALCOHOLIC FATTY LIVER DISEASE

Proinflammatory cytokines (tumor necrosis factor alpha (TNFα) and interleukin 6 (IL6)) play an important role in the etiology and pathogenesis of non-alcoholic fatty liver disease (NAFLD), since they can promote inflammation and regulate apoptosis and necrosis of liver cells, induce fibrosis. Cytokines perform their functions through interaction with membrane-bound and soluble receptors on the cell surface, and the soluble forms of receptors may act as antagonists or as enhancers of their biological effects. Differences in the level of cytokines and soluble and membrane-bound cytokine receptors may be due to the presence of mutations in different regions of the corresponding genes. This may influence the formation of the signaling pathway that determines the fate of cells (i. e., survival, apoptosis or necrosis) and, accordingly, the development and progress of NAFLD, some forms of which, in particular steatohepatitis and cirrhosis, involve intensified hepatic cell death. However, the question of whether the polymorphism of TNF , IL6 genes and their receptors affects NAFLD development and progress currently remains largely uninvestigated. This paper presents current data from the literature investigating the relationship between TNF, IL6, TNFRSF1A, TNFRSF1B, IL6R gene polymorphism and the development of non-alcoholic fatty liver disease.

Association of UGT2B7, UGT1A9, ABCG2, and IL23R polymorphisms with rejection risk in kidney transplant patients

ABSTRACTDespite advances in testing compatibility between donor and recipient, graft rejection remains a current concern. Single-nucleotide polymorphisms (SNPs) that codify altered enzymes of metabolism, drug transport, and the immune system may contribute to graft rejection in transplant patients. This study examined the association between SNPs present in genes of these processes and occurrence of graft rejection episodes in 246 kidney transplant patients, 35% of which were diagnosed with rejection. Genotype–gene expression associations were also assessed. Peripheral blood samples were used for genotyping of 24 SNPs on the following genes: CYP3A4, CYP3A5, CYP2E1, POR, UGT2B7, UGT1A9, ABCB1, ABCC2, ABCG2, SLCO1B1, TNF, IL2, IRF5, TGFB1, NFKBIA, IL10, IL23R, NFAT, and CCR5 by real-time PCR. The analysis of gene expression was performed by RT-qPCR. The association between graft rejection episodes and polymorphic variants was assessed using odds ratios. Polymorphisms rs7662029 (UGT2B7) and rs6714486 (UGT1A9) were associated with occurrence of graft rejection episodes, rs7662029 (UGT2B7) exhibited a protective effect (1.85-fold), and rs6714486 (UGT1A9) an increased 1.6-fold increased risk of graft rejection. Among drug transporter genes, only rs2231142 (ABCG2) demonstrated an association with a 1.92-fold decrease in the risk of graft rejection. The immunological SNP rs10889677 (IL23R) was associated with a 1.9-fold enhanced risk of graft rejection. Association between genotypes and gene expression was not detected. Therefore, SNPs of UGT2B7, UGT1A9, ABCG2, and IL23R genes may be useful as candidate markers for screening of risk graft rejection in renal transplant patients. These markers may improve medical decisions, avoiding adverse effects.

Dynamic cytokine gene expression characterized by increased IL-1 and IL-27 but decreased IL-8 occurs during development of bovine neonatal immunity.

Abstract We analyzed 18 RNA-seq libraries from 3 bovine calves at day 0, 7, 14 and 28, together with their dams (day 0 and 7) for cytokine gene expression. Expression of IL7, required for B- and T-cell development, significantly increases from day 0 to day 28 post-birth (LogFC 1.98, FDR 0.0054). By contrast IL7R gene expression significantly declined from day 0 to day 7 (LogFC −1.22, FDR 6.1E-08). The IL21 was expressed at low levels but IL21R gene expression increased day 0 vs day 7 (LogFC 1.17, FDR 0.000140). IL12B expression, a subunit of IL-12, increased from day 0 vs day 7 (LogFC1.14, FDR 0.016) and then declined. In parallel, IL12RB1 expression increased from day 0 to day 7 to achieve adult levels (LogFC1.31, FDR 5.5E-10). By contrast, IL12RB2 declined significantly within 7 days post-birth (LogFC −1.46, FDR 3.1E-05). Both IL12RB1 and IL12RB2 constitute IL12 receptor complex involved in T cell differentiation. The IL27 was expressed at low levels at birth but reached adult levels by day 7 (LogFC 1,66, FDR 0.006). The IL1B expression increased post-birth by day 7 (LogFC 1.44, FDR 0.0083) whereas IL1R2 gene was highly expressed at birth but declined by day 7 (LogFC −3.22, FDR 5.9E-34). Expression of chemokine IL8 that encodes CXCL8 declined day 0 vs day 7 post-birth (LogFC −1.13, FDR 0.00015). The pro-inflammatory cytokine TNFα gene expression increased by day 14 (LogFC 1.04, FDR 0.015). While various cytokines are expressed in a dynamic manner, an increase in IL-1B, IL-7, IL-12B and a decrease in IL-8 appears to be of functional significance in the development of neonatal immunity. These observations are in contrast to other species such as humans. [Supported by NSERC Discovery Grant]

Association of genetic polymorphisms in IL-1R1 and IL-1R2 genes with IgA nephropathy in the Han Chinese population.

AimIgA nephropathy (IgAN) is the major cause of end-stage renal disease(ESRD) in Asia and its pathogenesis is influenced by both genetic and environmental factors. Single nucleotide polymorphisms (SNPs) in IL1R1 and IL-1R2 may be associated with susceptibility to IgAN. In this study, we study the association between genetic variants of IL-1R1 and IL-1R2 and IgA nephropathy risk in the Chinese Han population.ResultIn the allelic model analysis, the rs10490571 and rs3917225 were associated with a 1.40-fold, and 1.31-fold increased risk of IgA nephropathy, respectively. In the genetic model analysis, the rs10490571 in IL1R1 was associated with a 1.46-fold increased risk of IgAN in the dominant model and 1.36-fold increased risk in the Log-additive model, respectively. However, the rs3218977 in IL1R2 was associated with a 0.71-fold decrease risk of IgAN in the dominant model and a 0.71–fold decrease risk in the over-dominant model, respectively. We found four SNPs (rs11674595, rs4851521, rs719250, and rs3218896) constructed four haplotypes in the IL1R2 gene and none of the haplotype was significantly associated with risk of IgAN.Materials and MethodsA case-control study was conducted including 426 nephropathy patients and 463 healthy controls. Chi-squared tests and genetic model were used to evaluate associations.>ConclusionsThese findings suggested that IL-1R1 and IL-1R2 polymorphisms may contribute to the development of IgAN.

Genetic Characterization and Influence on Inflammatory Bowel Disease Expression in a Diverse Hispanic South Florida Cohort.

Objectives:Hispanics represent an understudied inflammatory bowel disease (IBD) population. Prior studies examining genetic predisposition to IBD in Hispanics are limited. In this study, we examined whether European-derived IBD variants confer risk in Hispanics and their influence on IBD phenotype in Hispanics compared to non-Hispanic whites (NHW).Methods:Self-identified Hispanics and NHWs with IBD were included. Hispanic controls were included for our genetic analyses. We performed single-variant testing at previously identified Crohn's disease (CD) and ulcerative colitis (UC) IBD variants in Hispanic cases and controls. These risk variants were used to compute individual genetic risk scores. Genetic risk scores and phenotype associations were compared between Hispanic and NHW.Results:A total of 1,115 participants were included: 698 controls and 417 IBD patients (230 Hispanics). We found evidence of association within our Hispanic cohort at 22 IBD risk loci, with ~76% of the risk loci demonstrating over-representation of the European risk allele; these included loci corresponding to IL23R and NOD2 genes. CD genetic risk score for Hispanics (199.67) was similar to the score for NHW (200.33), P=0.51; the same was true in UC. Genetic risk scores did not predict IBD phenotype or complications in Hispanics or NHW except for a younger age of CD onset in Hispanics (P=0.04).Conclusions:This study highlights the fundamental importance of these loci in IBD pathogenesis including in our diverse Hispanic population. Future studies looking at non-genetic mechanisms of disease are needed to explain differences in age of presentation and phenotype between Hispanics and NHW.

Polymorphisms in Inflammatory Mediator Genes and Risk of Preeclampsia in Taiyuan, China.

Excessive maternal inflammatory response is involved in the pathogenesis of preeclampsia. Few epidemiologic studies have investigated the associations between genetic variations in the inflammatory mediator genes and preeclampsia risk, and these studies have reached inconsistent results. We examined 31 single-nucleotide polymorphisms in IL-1A, IL-1B, IL-1R1, IL-2RA, IL-5RA, IL-6, IL-6R, TNFSF11, TNFRSF11A, IL-28RA, IRAK4, and KIT genes and the risk of preeclampsia and its clinical subtypes in a nested case-control study including 203 preeclampsia cases and 233 controls. We found that IL-1R1, IL-5RA, IL-6R, and TNFSF11 were associated with the risk of preeclampsia. Although the significant associations observed for preeclampsia overall were mainly seen for late-onset preeclampsia and severe preeclampsia, IL-6R (rs2229238) and TNFSF11 (rs9525643) polymorphisms were associated with the risk of early-onset preeclampsia. TNFSF11 (rs2200287 and rs2148072) polymorphisms were associated with risk of mild preeclampsia. Our study provided the first evidence that genetic variations in inflammatory mediator genes IL-1R1, IL-6R, TNFSF11, and IL-5RA were associated with preeclampsia risk, and the risk varied by preeclampsia subtypes.

An interleukin 12 B single nucleotide polymorphism increases IL-12p40 production and is associated with increased disease susceptibility in patients with relapsing-remitting multiple sclerosis

Background: Through mounting genetic investigations, it has been established that IL12B and IL23R gene single nucleotide polymorphisms have significant associations with autoimmune diseases including inflammatory bowel disease, psoriasis, and ankylosing spondylitis. IL-12/IL-23 pathway plays a pivotal role in etiopathogenesis of multiple sclerosis (MS), suggested by studies both in patients and animal models.Methods: In a case-control study, 145 MS patients and 200 healthy subjects were genotyped for polymorphisms in IL12B and IL23R genes using Real-Time PCR allelic discrimination approach. Additionally, quantitative analysis of mRNA expression of IL12B in Peripheral Blood Mononuclear Cells from patients and controls was conducted through Real-Time PCR using the TaqMan Gene Expression Assay.Results: The rs6887695 single-nucleotide polymorphism (SNP) in IL12B gene showed an association with susceptibility to MS. GG genotype of this variation was more frequent in patients. mRNA expression of IL12B was upregulated in patients. Expression of IL12B mRNA in both MS patients collectively and those with GG genotype for rs6887695 SNP correlated negatively with onset age of MS patients.Conclusions: The GG genotype of rs6887695 SNP in IL12B gene plays a role in etiopathogenesis of MS.

Association of IL23R gene rs10489630 single nucleotide polymorphism with EV71 hand foot and mouth disease

目的 探讨IL23R基因rs10489630单核苷酸多态性(single nucleotide polymorphisms，SNP)与肠道病毒71型(enterovirus 71，EV71)手足口病(hand，foot and mouth disease，HFMD)易感性及严重程度的相关性。 方法 应用TaqMan探针基因分型技术，对125例健康志愿者、252例EV71 HFMD(125例重症EV71和127例轻症EV71)患者，进行rs10489630位点基因分型，比较不同人群等位基因频率差异，探讨rs10489630 SNP与EV71 HFMD易感性以及严重程度的相关性。 结果 EV71 HFMD患者中rs10489630 C等位基因的频率稍高于健康志愿者(36.9%比34.4%)，差异不具有统计学意义(P>0.05)。与轻症EV71相比，重症EV71患者中rs10489630 C等位基因的频率明显升高(44.0%比29.9%)，差异具有统计学意义(P＝0.0011)。 结论 在深圳汉族人群中，IL23R基因rs10489630 SNP与EV71 HFMD的严重程度相关。

Role of gene polymorphism of IL-4 and IL-17 in recurrent miscarriage, came in art cycles

Most researchers suggest that more than 50% of pregnant women after use of assisted reproductive technologies (ART) are faced with the problem of miscarriage, especially in the first trimester. The aim of the study was to investigate the frequency of genotypes and allelic variants of the IL-4 (S589T and S33T), IL-4R (Q576R), IL-17A (G197A) and IL-17F (488T/C) genes, depending on the reproductive status and assessment of their association with recurrent miscarriage, which occurred in ART cycles. Peripheral blood of 240 patients – the eastern Slav with habitual miscarriage, came in ART cycles, and 100 apparently healthy fertile women in the control group with a history of at least one term delivery and lack of spontaneous abortion episodes was studied. The groups were representative of age. DNA for molecular genetic studies of nuclei isolated from peripheral blood lymphocytes. The method is based on the destruction of lymphocytes using lysis buffer without affecting the integrity of the membranes of lymphocytes nuclei. For typing single nucleotide polymorphisms of IL-4 immune response, IL-4R, IL-17A and IL-17F using polymerase chain reaction product with the melting reaction in the presence of “adjacent” oligonucleotides. It was found that the genotype CT-33 (OR 3.99; 95% CI 2,42–6,57) and CT-589 (OR 3.99; 95% CI 2,42–6,57) gene IL-4; genotype GG576 (OR 5.95; 95% CI 1,39–25,58) gene IL-4R and TT488 genotype (OR 2.33; 95% CI 1,39–3,91) and CC488 (OR 2.27; 95% CI 0,76–6,84) IL-17F gene were associated with a significant increase in the risk of miscarriage. On the other hand, no significant differences were found between the control group and the basic frequency of polymorphisms IL-17A-G197A (rs227593). The results of the molecular-genetic typing it possible to identify in the Eastern Slavic population of residents of Odesa region of Ukraine immunogenetic markers of susceptibility/ resistance to the development of recurrent miscarriage. It is shown that cytokine gene typing can be used as a method of early diagnosis and pregravid prognosis of immune forms of reproductive loss in women.

The expression of lnc-IL-7R long non-coding RNA dramatically correlated with soluble and membrane-bound isoforms of IL-7Ra gene in multiple sclerosis patients

Background and purposeMultiple sclerosis (MS) is a neurological disease of the central nervous system (CNS) that causes physical and cognitive impairments. IL-7Ra is a key non-MHC gene associated with MS. IL-7Ra is a likely functional candidate for this complex disease because it is involved in the development, maturation, and homeostasis of T and B cells. Our aim was to evaluate the expression level and controlling role of lnc-IL-7R in the expression of two variants of IL-7Ra in MS patients versus healthy controls and their correlation with certain clinical features. MethodsUsing the real-time PCR method, we analyzed the expression levels of membrane-bound (IL-7RB) and soluble (IL-7RS) isoforms of IL-7R gene and lnc-IL-7R in 36 MS patients versus 30 healthy controls. ResultsOur results revealed no significant difference between the expression levels of IL-7RB and IL-7RS isoforms of IL-7R gene and lnc-IL-7R in MS patients versus healthy controls (p=0.7, p=0.6 and p=0.8, respectively). Moreover, we found a significant correlation between the expression levels of IL-7RB with lnc-IL-7R, IL-7RS with lnc-IL-7R and IL-7RB with IL-7RS in both patient and control groups. ConclusionsWe have probably uncovered new evidence for the controlling role of long non-coding RNAs in the expression level of genes and their roles in MS.