IL23R Gene Research Articles

Psoriasis and Cardiometabolic Diseases: Shared Genetic and Molecular Pathways.

A convincing deal of evidence supports the fact that severe psoriasis is associated with cardiovascular diseases. However, the precise underlying mechanisms linking psoriasis and cardiovascular diseases are not well defined. Psoriasis shares common pathophysiologic mechanisms with atherosclerosis and cardiovascular (CV) risk factors. In particular, polymorphism in the IL-23R and IL-23 genes, as well as other genes involved in lipid and fatty-acid metabolism, renin–angiotensin system and endothelial function, have been described in patients with psoriasis and with cardiovascular risk factors. Moreover, systemic inflammation in patients with psoriasis, including elevated serum proinflammatory cytokines (e.g., TNF-α, IL-17, and IL-23) may contribute to an increased risk of atherosclerosis, hypertension, alteration of serum lipid composition, and insulin resistance. The nonlinear and intricate interplay among various factors, impacting the molecular pathways in different cell types, probably contributes to the development of psoriasis and cardiovascular disease (CVD). Future research should, therefore, aim to fully unravel shared and differential molecular pathways underpinning the association between psoriasis and CVD.

Associations of genetically predicted IL-6 signaling with cardiovascular disease risk across population subgroups

BackgroundInterleukin 6 (IL-6) signaling is being investigated as a therapeutic target for atherosclerotic cardiovascular disease (CVD). While changes in circulating high-sensitivity C-reactive protein (hsCRP) are used as a marker of IL-6 signaling, it is not known whether there is effect heterogeneity in relation to baseline hsCRP levels or other cardiovascular risk factors. The aim of this study was to explore the association of genetically predicted IL-6 signaling with CVD risk across populations stratified by baseline hsCRP levels and cardiovascular risk factors.MethodsAmong 397,060 White British UK Biobank participants without known CVD at baseline, we calculated a genetic risk score for IL-6 receptor (IL-6R)-mediated signaling, composed of 26 variants at the IL6R gene locus. We then applied linear and non-linear Mendelian randomization analyses exploring associations with a combined endpoint of incident coronary artery disease, ischemic stroke, peripheral artery disease, aortic aneurysm, and cardiovascular death stratifying by baseline hsCRP levels and cardiovascular risk factors.ResultsThe study participants (median age 59 years, 53.9% females) were followed-up for a median of 8.8 years, over which time a total of 46,033 incident cardiovascular events occurred. Genetically predicted IL-6R-mediated signaling activity was associated with higher CVD risk (hazard ratio per 1-mg/dL increment in absolute hsCRP levels: 1.11, 95% CI: 1.06–1.17). The increase in CVD risk was linearly related to baseline absolute hsCRP levels. There was no evidence of heterogeneity in the association of genetically predicted IL-6R-mediated signaling with CVD risk when stratifying the population by sex, age, body mass index, estimated glomerular filtration rate, or systolic blood pressure, but there was evidence of greater associations in individuals with low-density lipoprotein cholesterol ≥ 160 mg/dL.ConclusionsAny benefit of inhibiting IL-6 signaling for CVD risk reduction is likely to be proportional to absolute reductions in hsCRP levels. Therapeutic inhibition of IL-6 signaling for CVD risk reduction should therefore prioritize those individuals with the highest baseline levels of hsCRP.

Primary myoblasts from intrauterine growth-restricted fetal sheep exhibit intrinsic dysfunction of proliferation and differentiation that coincides with enrichment of inflammatory cytokine signaling pathways.

Intrauterine growth restriction (IUGR) is linked to lifelong reductions in muscle mass due to intrinsic functional deficits in myoblasts, but the mechanisms underlying these deficits are not known. Our objective was to determine if the deficits were associated with changes in inflammatory and adrenergic regulation of IUGR myoblasts, as was previously observed in IUGR muscle. Primary myoblasts were isolated from IUGR fetal sheep produced by hyperthermia-induced placental insufficiency (PI-IUGR; n = 9) and their controls (n = 9) and from IUGR fetal sheep produced by maternofetal inflammation (MI-IUGR; n = 6) and their controls (n = 7). Proliferation rates were less (P < 0.05) for PI-IUGR myoblasts than their controls and were not affected by incubation with IL-6, TNF-α, norepinephrine, or insulin. IκB kinase inhibition reduced (P < 0.05) proliferation of control myoblasts modestly in basal media but substantially in TNF-α-added media and reduced (P < 0.05) PI-IUGR myoblast proliferation substantially in basal and TNF-α-added media. Proliferation was greater (P < 0.05) for MI-IUGR myoblasts than their controls and was not affected by incubation with TNF-α. Insulin increased (P < 0.05) proliferation in both MI-IUGR and control myoblasts. After 72-h differentiation, fewer (P < 0.05) PI-IUGR myoblasts were myogenin+ than controls in basal and IL-6 added media but not TNF-α-added media. Fewer (P < 0.05) PI-IUGR myoblasts were desmin+ than controls in basal media only. Incubation with norepinephrine did not affect myogenin+ or desmin+ percentages, but insulin increased (P < 0.05) both markers in control and PI-IUGR myoblasts. After 96-h differentiation, fewer (P < 0.05) MI-IUGR myoblasts were myogenin+ and desmin+ than controls regardless of media, although TNF-α reduced (P < 0.05) desmin+ myoblasts for both groups. Differentiated PI-IUGR myoblasts had greater (P < 0.05) TNFR1, ULK2, and TNF-α-stimulated TLR4 gene expression, and PI-IUGR semitendinosus muscle had greater (P < 0.05) TNFR1 and IL6 gene expression, greater (P < 0.05) c-Fos protein, and less (P < 0.05) IκBα protein. Differentiated MI-IUGR myoblasts had greater (P < 0.05) TNFR1 and IL6R gene expression, tended to have greater (P = 0.07) ULK2 gene expression, and had greater (P < 0.05) β-catenin protein and TNF-α-stimulated phosphorylation of NFκB. We conclude that these enriched components of TNF-α/TNFR1/NFκB and other inflammatory pathways in IUGR myoblasts contribute to their dysfunction and help explain impaired muscle growth in the IUGR fetus.

IL-7/IL7R axis dysfunction in adults with severe community-acquired pneumonia (CAP): a cross-sectional study

Community-acquired pneumonia (CAP) is a worldwide leading cause of death. Recognized risk factors in some severe cases have not been identified. Lymphocytopenia has been frequently described in CAP. Since IL-7, membrane-bound receptor (IL7Rα;CD127) and soluble IL7Rα (sIL7R) are critical in lymphocytes homeostasis, in this work we aimed to evaluate the involvement of the IL-7/IL7Rα axis in the severity of adult CAP, since it has not been explored. The IL7Rα SNPs rs6897932, rs987106, and rs3194051 SNPs in IL7α were genotyped, the systemic expression of the IL7R gene, sIL7R, IL-7, and levels of peripheral IL7Rα+ T lymphocytes were quantified in 202 hospitalized CAP cases. rs3194051GG was more frequent in non-survivors than in survivors; rs987106TT was more frequent and rs3194051AA less frequent in patients at intensive care unit (ICU) than in those not admitted to ICU. IL7Rα gene expression was lower in non-survivors than in survivors, and in severe than in mild cases. CD3+CD127+ lymphocytes were lower in severe than in mild cases; in non-survivors than in survivors and in ICU than in non- ICU admitted cases. sIL7Rα plasmatic levels were higher in non-survivors than in survivors, and in severe than in mild cases. rs6897932CC, rs987106AA and rs3194051GG carriers showed the highest while rs6897932TT showed the lowest sIL7Rα levels. The AUC of sIL7Rα levels predicting 30-day mortality was 0.71. Plasma IL-7 levels were lower in ICU-admitted than in not ICU-admitted and in non-survivors than in survivors. No additional association was detected. In conclusion, rs3194051GG and rs987106TT IL7R genotypes were associated with a poorer prognosis. A significant association between sIL7R levels and SNPs of the IL7R gene is described for the first time in adult CAP. Increased plasmatic sIL7R could contribute to identifying adult CAP cases at risk of death.

Genetic Biomarkers as Predictors of Response to Tocilizumab in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis.

Rheumatoid arthritis (RA) is a lifelong, debilitating disease which incredibly impacts a patient’s quality of life if not treated to the optimal target. The clinical response of tocilizumab, an interleukin-6 (IL-6) inhibitor, is associated with several gene polymorphisms, particularly targeting the IL-6 pathway. This systematic review and meta-analysis seeks to investigate genetic biomarkers that predict the treatment outcome of tocilizumab therapy in RA patients. After evaluating the quality of retrieved records, five studies were chosen to carry out a quantitative synthesis involving 591 participants. We analysed genetic markers of IL-6R single nucleotide polymorphism (SNP)s rs12083537, rs2228145 and rs4329505, FCGR3A, CD69, GALNT18 and FCGR2A. A plausible finding based on meta-analysis revealed that RA patients with homozygous AA genotype for rs12083537 polymorphism of the IL-6R gene demonstrate a better response to TCZ treatment as opposed to homozygous and heterozygous patients with the G allele. Nonetheless, limitations in evaluating the available studies by meta-analysis include a lack of studies with dissimilarities in study design and outcome definitions, small sample sizes with low statistical power and heterogeneity of cohorts, a restricted the number of tested SNPs and small effects for the selected variants. Inconsistent finding remains as a great challenge to forge ahead towards personalised medicine for RA management.

Diyabetik Periferik Polinöropatili Hastalarda İnterlökin-23R Gen Polimofizmleri

Objective: Proinflammatory and neurovascular changes are blamed in the pathogenesis of diabetic neuropathy. Although it is accepted that diabetes is a trigger for vascular inflammation, it has been suggested that inflammation itself may trigger diabetes. Interleukin-23 (IL-23) is a pro-inflammatory cytokine secreted by activated macrophages and dendritic cells. Interleukin-23R is known to have a critical role in chronic inflammatory diseases. The aim of this study is to determine the relationship between IL-23R polymorphism and diabetic peripheral neuropathy.&#x0D; Method: 50 diabetic peripheral neuropathy patients who applied to Neurology outpatient clinic, and 52 healthy controls compatible with the patient group in terms of age and gender were included. Electromyography was performed on all of the volunteers, who agreed to participate in the study, and 2 ml of blood samples were taken into tubes with EDTA, and the IL-23R gene polymorphism was analyzed using the pyrosequencing method.&#x0D; Results: IL-23R gene variants rs2201841, rs199542433, rs201052419, rs11209026 were analyzed in diabetic peripheral neuropathy (DPN) patients and control group. While we investigate IL23R polymorphisms we didn’t find any significant differences between patient and control groups. But when we use odds ratios, rs2201841 seems to have a protective role, and rs199542433 in both dominant and recessive models and rs11209026 only recessive model seem to be related 10 fold higher risks for DPN.&#x0D; Conclusion: IL-23R gene polymorphism has been shown to be associated with many autoimmune and inflammatory diseases. It is known that inflammation has an important effect on diabetes. The frequency of IL-23R gene polymorphism was not significant in diabetic peripheral neuropathy. Our study is the only and first study investigating the role of IL-23R gene polymorphism in diabetic peripheral neuropathy. Ethnicity is very important in genetic studies, and it will give us more clear information for the future to carry out this study in patients with other ethnic origins and to recruit larger study groups.

Association between IL-23R rs11209026 Gene polymorphism and soluble interleukin 23 receptor (△9) in Iraqi patients with and without lupus nephritis

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by the uncontrolled formation of antibodies, overproduction of pro-inflammatory cytokines with a genetic background that is poorly understood. This case-control study comprised 80 SLE patients, SLE patients who met the American College of Rheumatology (ACR) criteria (40 SLE and 40 LN groups), and 40 healthy controls. All participants' serum IL-23R levels were determined using an enzyme-linked immunosorbent assay (ELISA). 40 patients (20 SLE and 20 LN groups) and 12 age- and sex-matched healthy controls were genotyped for IL-23R gene polymorphisms (rs11209026 G&gt;A) by direct DNA sequencing. As for sIL-23R levels, the results showed non-significant differences between the groups of the patients (0.18(0.11-7.50) vs 0.17(0.12- 3.73) (P= 0.751) in SLE and LN, respectively) and the control group (0.17 (0.12-2.69) (P=0.713) vs (P=0.934) in SLE and LN, respectively). Analysis of the rs11209026 sequencing results showed that most patients and the control group share the same genotype, which is GG, and that the A allele is underrepresented in the studied groups, as the AA genotype did not appear in the results. Our results suggest that rs11209026 affects the production of the soluble form of IL-23R.

Abstract 1641: Evaluating in vivo efficacy of bi-functional fusion protein anti-PD-1-IL21 in humanized B-hIL21R mice and B-hPD-1/hIL21R mice

Abstract Interleukin 21 (IL21) binding to its receptor IL21R, results in downstream activation of multiple signaling molecules, including JAK1, JAK3, STAT1, and STAT3. Intriguingly, IL21 has been implicated in both positively and negatively regulating immune responses in a cell-type specific manner, suggesting drug candidates that target IL21/IL21R signaling has therapeutic potential. Specifically, recent reports suggest that antibodies targeting PD-1 fused to IL-21 has a synergistic anti-tumor effect. To generate a suitable animal model for in vivo assessment of a human anti-PD-1-IL21 fusion protein, Biocytogen developed humanized PD-1 and IL21R mice (B-hIL21R mice and B-hPD-1/hIL21R mice) by replacing the murine Il21r and PD-1 gene with the human IL21R and PD-1 counterparts via homologous recombination. Our data shows that human IL21R was detectable in sorted cells from homozygous B-hIL21R and B-hPD-1/hIL21R mice, while human PD-1 was detectable in B-hPD-1/hIL21R mice compared to wild type mice. Furthermore, STAT3 phosphorylation in splenocytes was successfully induced with mouse IL21 or human IL21 in homozygous B-hIL21R mice. In addition, percentages of T cells, B cells, NK cells, DCs, granulocytes, monocytes, macrophages, CD8+ T cells, CD4+ T cells and Tregs in homozygous B-hIL21R mice and B-hPD-1/hIL21R mice were similar to those in wild type mice, demonstrating that introduction of human IL21R and PD-1 genes in place of its mouse counterpart does not change the overall development, differentiation or distribution of these cell types. To evaluate in vivo efficacy of anti-mPD-1-hIL21 and anti-hPD-1-hIL21 fusion proteins, mouse colon adenocarcinoma MC38 cells were subcutaneously implanted into homozygous B-hIL21R mice (female, 6-7-week-old, n=6) or B-hPD-1/hIL21R mice (female, 6-7-week-old, n=6). Mice were grouped and treated when tumor volume reached approximately 100 mm3. Results showed that anti-PD-1-hIL21 fusion proteins were efficient at inhibiting tumor growth in B-hIL21R and B-hPD-1/hIL21R mice. Altogether, B-hIL21R and B-hPD-1/hIL21R mice are promising humanized mouse models for preclinical in vivo studies to assess novel drug candidates. Keywords: IL21/IL21R, humanized mice, fusion protein Citation Format: Ruili Lyu, Zhixia Li, Leila Kokabee, Jiawei Yao, Yanhui Nie, Chaoshe Guo. Evaluating in vivo efficacy of bi-functional fusion protein anti-PD-1-IL21 in humanized B-hIL21R mice and B-hPD-1/hIL21R mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1641.

Precise CRISPR-Cas-mediated gene repair with minimal off-target and unintended on-target mutations in human hematopoietic stem cells.

While CRISPR-Cas9 is key for the development of gene therapy, its potential off-target mutations are still a major concern. Here, we establish a “spacer-nick” gene correction approach that combines the Cas9D10A nickase with a pair of PAM-out sgRNAs at a distance of 200 to 350 bp. In combination with adeno-associated virus (AAV) serotype 6 template delivery, our approach led to efficient HDR in human hematopoietic stem and progenitor cells (HSPCs including long-term HSCs) and T cells, with minimal NHEJ-mediated on-target mutations. Using spacer-nick, we developed an approach to repair disease-causing mutations occurring in the HBB, ELANE, IL7R, and PRF1 genes. We achieved gene correction efficiencies of 20 to 50% with minimal NHEJ-mediated on-target mutations. On the basis of in-depth off-target assessment, frequent unintended genetic alterations induced by classical CRISPR-Cas9 were significantly reduced or absent in the HSPCs treated with spacer-nick. Thus, the spacer-nick gene correction approach provides improved safety and suitability for gene therapy.

Associations between IL-23R gene polymorphism (rs10889677 A/C) and ankylosing spondylitis and rheumatoid arthritis susceptibility: A meta-analysis with trial sequential analysis

Objectives Autoimmune diseases are a kind of chronic diseases for which the immune system loses tolerance to autoantigens. This meta-analysis’ purpose is to determine whether there exists a correlation between IL-23R polymorphism and common autoimmune diseases like ankylosing spondylitis (AS) and rheumatoid arthritis (RA). Methods We searched the relevant literatures up to September 2021 and used different effect models for meta-analysis. 95% confidence interval (95% CI) and odds ratio (OR) were used to determine the relationship between rs10889677 (A/C) polymorphism and AS as well as RA. Finally, to promote the reliability of results, the trial sequential analysis (TSA) has also been applied and we searched the data related to autoimmune diseases (AS, RA) on genome-wide association studies (GWAS). Results Generally, 31 studies were included. Rs10889677 (A/C) was significantly correlated with the susceptibility to AS and RA among the general individuals (p < .05). Moreover, there existed a relevance between allele A and AS as well as RA in Caucasians (p < .05). AA genotype increased the risk of autoimmune diseases in Mongolians. As a result, the robustness of meta-analysis has further been proved by TSA. Conclusion IL-23R (rs10889677 A/C) A allele was a risk gene for AS and RA in the general population, especially in Caucasians. AA genotype increased the risk of AS and RA in Mongolians.

Single nucleotide polymorphisms located in TNFA, IL1RN, IL6R, and IL6 genes are associated with COVID-19 risk and severity in an Iranian population.

Cytokines play pivotal functions in coronavirus disease 2019 (COVID‐19) pathogenesis. However, little is known about the rationale and importance of genetic variations associated with immune system responses, so‐called “immunogenetic profiling.” We studied whether polymorphisms of IL6, IL6R, TNFA, and IL1RN affect the disorder severity and outcome in patients infected with COVID19. We recruited 317 hospitalized patients with laboratory‐confirmed COVID‐19 from Bu‐Ali hospital and 317 high‐risk participants who had high exposure to COVID‐19 patients but with a negative real‐time‐polymerase chain reaction (PCR) test. Multiple regression analyses were applied. We indicated that participants carrying the A allele in TNFA‐rs361525, G>A (p < .004), the C allele in IL1RN‐rs419598 T>C (p < .004), the A allele in IL6R‐rs2228145, A>C (p = .047) are more susceptible to develop COVID‐19. In contrast, those who carry the G allele of IL6‐rs2069827, G>T (p = .01), are more protected from COVID‐19. Also, we compared the various genotypes regarding the disorder severity and poor prognosis; we found that the AA genotype in TNFA is related to more aggressive illness and bad prognostic in contrast to the other inflammatory cytokines' genotypes. In addition, a high level of inflammatory indications, such as neutrophil‐to‐lymphocyte ratio and systemic immune‐inflammation index, was observed in deceased patients compared with the survived subjects (p < .0001). We advised considering inflammatory cytokines polymorphisms as the main item to realize the therapeutic response against the acute respiratory distress syndrome induced by the SARS‐CoV‐2 virus.

Construction of a Joint Prediction Model for the Occurrence of Ischemic Stroke and Acute Myocardial Infarction Based on Bioinformatic Analysis.

Ischemic stroke (IS) has imposed significant threat to both middle-aged and elderly people worldwide. Acute myocardial infarction (AMI) is a rare but serious complication following IS, which can further increase patient disability and mortality rates. With the development of intravenous thrombolysis and endovascular treatment, the prognosis of IS has been greatly improved. However, the pathogenesis of IS complicated with AMI is still unclear. To fill this gap, this work uses bioinformatic analysis, where IS and AMI datasets were combined for differential gene analysis, and then, a ROC prediction model for target gene analysis was constructed. It is found that OSM gene has the highest prediction accuracy (AUC = 0.793), followed by IL6ST, IL6, JAK1, IL6R, and JAK2 genes. Joint prediction model showed higher accuracy in predicting the outcome of control and case (AUC = 0.918). The etiology of ischemic stroke and acute myocardial infarction is complicated. Their cooccurring pathological mechanisms and the conversion between the two diseases could not be explained by a single gene. Therefore, the joint prediction model in this work can provide a better prediction accuracy for research purpose.

Clinical and Genetic Characteristics of IKZF1 Mutation in Chinese Children With B-Cell Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is a malignancy associated with altered lymphoid precursor hyperplasia and accompanied with different genetic mutations. Few studies have been reported on the association between gene mutations and clinical features of IKZF1 mutation in children with B-cell ALL (B-ALL). We investigated clinical and genetic characteristics in 200 newly diagnosed pediatric B-ALL through multiplex ligation-dependent probe amplification (MLPA) and targeted next-generation sequencing (NGS) method. We found that IKZF1 mutations, including large segment deletions, small insertions or deletions (InDels) and single nucleotide variations (SNVs), were detected in 22 patients with a positive mutation rate of 11.0%. IKZF1 mutation was significantly associated with higher WBC count (19.38 × 109/L vs. 5.80 × 109/L, p = 0.002). Compared with IKZF1 wild-type cases, a higher frequency of IL7R gene mutation was discovered in IKZF1 mutant cases (9.1% vs. 0.0%, p = 0.012). Patients with IKZF1 mutation were less sensitive to glucocorticoid induction than patients without IKZF1 mutation (63.6% vs. 9.0%, p < 0.001). On the 15th day of induction, minimal residual disease (MRD) > 10−3 level were higher in IKZF1 mutant patients than wild-type patients (45.5% vs. 22.3%, p = 0.018). In conclusion, our study reveals the association between genetic mutations and clinical features in Chinese children with B-ALL, which might contribute to molecular classification, risk stratification and prognosis evaluation, and provide new ideas for targeted therapy in ALL.

Association of the IL-6R gene polymorphic variant rs2228145(C>A) with IL-6 gene polymorphisms in a healthy cohort of Turkish population.

The main aim of this study was to investigate the relationship of the carriership of rs2228145 allelic variations of IL-6R with two other allelic variations in IL-6 gene at rs1800795 and rs1800796 loci and with the laboratory data of a healthy cohort of the Turkish population. The data of 121 healthy Turkish subjects (aged 12–84 years) including the past diseases, comorbidities were collected. The laboratory parameters were compared by the frequency of alleles of rs2228145 (C>A). The possible association of polymorphism at rs2228145 locus with the age, gender, and body mass index (BMI) and the frequencies of alleles of rs1800795 and rs1800796 polymorphisms were evaluated. The majority of the subjects had allele A at rs2228145 locus and allele G at rs1800796 locus. The number of white blood cells, platelets, neutrophils and monocytes were significantly higher in the subjects with allele C than those with allele A at rs2228145 locus (P < 0.05). The concentrations of total and direct bilirubin, iron, Sex Hormone Binding Globulin (SHBG) and folic acid of the subjects with allele C were significantly lower than those with allele A (P < 0.05). The uric acid and fasting insulin levels were higher in the subjects with allele C compared with those allele A (P = 0.04). The diversities of the hematological parameters, laboratory findings of liver function tests and renal panel and hormone levels may be explained by the variants of rs2228145 locus at IL-6R gene among healthy Turkish individuals.

Polymorphisms and Gene-Gene Interaction in AGER/IL6 Pathway Might Be Associated with Diabetic Ischemic Heart Disease.

Background: Although the genetic susceptibility to diabetes and ischemic heart disease (IHD) has been well demonstrated, studies aimed at exploring gene variations associated with diabetic IHD are still limited; Methods: Our study included 204 IHD cases who had been diagnosed with diabetes before the diagnosis of IHD and 882 healthy controls. Logistic regression was used to find the association of candidate SNPs and polygenic risk score (PRS) with diabetic IHD. The diagnostic accuracy was represented with AUC. Generalized multifactor dimensionality reduction (GMDR) was used to illustrate gene-gene interactions; Results: For IL6R rs4845625, the CT and TT genotypes were associated with a lower risk of diabetic IHD than the CC genotype (OR = 0.619, p = 0.033; OR = 0.542, p = 0.025, respectively). Haplotypes in the AGER gene (rs184003-rs1035798-rs2070600-rs1800624) and IL6R gene (rs7529229-rs4845625-rs4129267-rs7514452-rs4072391) were both significantly associated with diabetic IHD. PRS was associated with the disease (OR = 1.100, p = 0.005) after adjusting for covariates, and the AUC were 0.763 (p < 0.001). The GMDR analysis suggested that rs184003 and rs4845625 were the best interaction model after permutation testing (p = 0.001) with a cross-validation consistency of 10/10; Conclusions: SNPs and haplotypes in the AGER and IL6R genes and the interaction of rs184003 and rs4845625 were significantly associated with diabetic IHD.

ATF7ip Targets Transposable Elements for H3K9me3 Deposition to Modify CD8+ T Cell Effector and Memory Responses.

CD8+ T cells are critical for the immune response to pathogens and tumors, and CD8+ T cell memory protects against repeat infections. In this study, we identify the activating transcription factor 7 interacting protein (ATF7ip) as a critical regulator of CD8+ T cell immune responses. Mice with a T cell-specific deletion of ATF7ip have a CD8+ T cell-intrinsic enhancement of Il7r expression and Il2 expression leading to enhanced effector and memory responses. Chromatin immunoprecipitation sequencing studies identified ATF7ip as a repressor of Il7r and Il2 gene expression through the deposition of the repressive histone mark H3K9me3 at the Il7r gene and Il2-Il21 intergenic region. Interestingly, ATF7ip targeted transposable elements for H3K9me3 deposition at both the IL7r locus and the Il2-Il21 intergenic region, indicating that ATF7ip silencing of transposable elements is important for regulating CD8+ T cell function. These results demonstrate a new epigenetic pathway by which IL-7R and IL-2 production are constrained in CD8+ T cells, and this may open up new avenues for modulating their production.

Local genetic variation of inflammatory bowel disease in Basque population and its effect in risk prediction

Inflammatory bowel disease (IBD) is characterised by chronic inflammation of the gastrointestinal tract. Although its aetiology remains unknown, environmental and genetic factors are involved in its development. Regarding genetics, more than 200 loci have been associated with IBD but the transferability of those signals to the Basque population living in Northern Spain, a population with distinctive genetic background, remains unknown. We have analysed 5,411,568 SNPs in 498 IBD cases and 935 controls from the Basque population. We found 33 suggestive loci (p < 5 × 10−6) in IBD and its subtypes, namely Crohn’s Disease (CD) and Ulcerative Colitis (UC), detecting a genome-wide significant locus located in HLA region in patients with UC. Those loci contain previously associated genes with IBD (IL23R, JAK2 or HLA genes) and new genes that could be involved in its development (AGT, BZW2 or FSTL1). The overall genetic correlation between European populations and Basque population was high in IBD and CD, while in UC was lower. Finally, the use of genetic risk scores based on previous GWAS findings reached area under the curves > 0.68. In conclusion, we report on the genetic architecture of IBD in the Basque population, and explore the performance of European-descent genetic risk scores in this population.

MicroRNA-103 and microRNA-190 negatively regulate NF-κB-mediated immune responses by targeting IL-1R1 in Miichthys miiuy

Accumulating evidence has demonstrated that microRNAs (miRNAs) regulate various physiological and pathological processes at the transcriptional level, thus called novel regulators in immune response. In this study, we used bioinformatics and functional experiments to determine the role of miR-103 and miR-190 in the regulation of IL-1R1 gene involved in the immune and inflammatory responses in miiuy croakers. First, we predicted the target genes of miR-103 and miR-190 through bioinformatics and found that IL-1R1 is a direct target gene of miR-103 and miR-190. This was further confirmed by the dual-luciferase reporter assay that the over-expression of miR-103, miR-190 mimics and the pre-miR-103, pre-miR-190 plasmids inhibit the luciferase levels of the wild-type of IL-1R1 3′UTR. miR-103 and miR-190 inhibitors increase the luciferase levels of IL-1R1-3′UTR. Additionally, we found that miR-103 and miR-190 could negatively regulate the mRNA expression of IL-1R1. Importantly, we demonstrated that miR-103 and miR-190 significantly inhibit the NF-κB signaling pathway by targeting IL-1R1 upon LPS stimulation. Collectively, these results provide strong evidence for an important regulatory mechanism of miR-103 and miR-190 targeting the IL-1R1 gene, thereby preventing excessive inflammatory immune responses from causing autoimmunity.

Association of interleukin-6 level and DNA polymorphism in type 2 diabetic patients in Kirkuk city

The basic inflammatory factor interleukin-6 plays an important role in the inflammatory response. It has been shown that IL-6 has a role in insulin resistance and T2DM. The IL-6 gene is found on chromosome 7p15-p21 in humans, it works via a receptor composed of two components, the IL-6 receptor, and gp130. Single nucleotide polymorphisms in the regulatory areas of IL-6R genes influence their expression levels and are linked to a higher risk of T2DM. There were 80 T2DM patients and 80 healthy people enrolled in the present work. Fasting blood glucose levels, HbA1C, and IL-6 concentrations were estimated in both groups. The allelic frequencies of 2 single nucleotide polymorphisms (rs2229238, rs4845625) were identified by PCR-SSP. In this study, we found that the fasting blood sugar levels, HbA1c, and IL-6 levels were statistically highly significant in patients in comparison with controls. In regarding the association of genotypic (CC, CT, TT) and allelic frequencies of rs2229238, and rs4845625 polymorphism of the gene IL6R, and prevalence of diabetes mellitus. The results of PCR-SPP products of rs2229238 (C/T) of the IL6R gene indicated the significant correlation the rs4845625 IL6R polymorphism with T2DM, where no significant association was observed between these genotypes (CC, CT, TT) and allelic (T) frequencies of rs2229238 as a risk factor and T2D.

Non-additive QTL mapping of lactation traits in 124,000 cattle reveals novel recessive loci

BackgroundDeleterious recessive conditions have been primarily studied in the context of Mendelian diseases. Recently, several deleterious recessive mutations with large effects were discovered via non-additive genome-wide association studies (GWAS) of quantitative growth and developmental traits in cattle, which showed that quantitative traits can be used as proxies of genetic disorders when such traits are indicative of whole-animal health status. We reasoned that lactation traits in cattle might also reflect genetic disorders, given the increased energy demands of lactation and the substantial stresses imposed on the animal. In this study, we screened more than 124,000 cows for recessive effects based on lactation traits.ResultsWe discovered five novel quantitative trait loci (QTL) that are associated with large recessive impacts on three milk yield traits, with these loci presenting missense variants in the DOCK8, IL4R, KIAA0556, and SLC25A4 genes or premature stop variants in the ITGAL, LRCH4, and RBM34 genes, as candidate causal mutations. For two milk composition traits, we identified several previously reported additive QTL that display small dominance effects. By contrasting results from milk yield and milk composition phenotypes, we note differing genetic architectures. Compared to milk composition phenotypes, milk yield phenotypes had lower heritabilities and were associated with fewer additive QTL but had a higher non-additive genetic variance and were associated with a higher proportion of loci exhibiting dominance.ConclusionsWe identified large-effect recessive QTL which are segregating at surprisingly high frequencies in cattle. We speculate that the differences in genetic architecture between milk yield and milk composition phenotypes derive from underlying dissimilarities in the cellular and molecular representation of these traits, with yield phenotypes acting as a better proxy of underlying biological disorders through presentation of a larger number of major recessive impacts.