IL23R Gene Research Articles

Interleukin-6 signalling, lipoprotein (a) lowering and cardiovascular disease: a mendelian randomisation study

Abstract Background Elevated lipoprotein(a) (Lp[a]) levels and chronic low-grade inflammation play causal roles in cardiovascular disease (CVD) development, representing promising targets for managing residual risk. CVD prevention trials are currently assessing the efficacy of IL-6 pathway inhibition in ameliorating chronic pro-atherogenic inflammation. Lp(a) increases in response to interleukin 6 (IL-6) and acute inflammatory states, and Lp(a) itself induces an inflammatory response that accelerates atherosclerosis. Recent studies indicate that IL-6-receptor inhibitors may lower Lp(a) levels and reduce inflammation, potentially decreasing CVD risk in an additive manner. Purpose This drug-target Mendelian Randomisation (MR) study aims to elucidate the on-target effects of pharmacological IL-6R and LPA inhibition on CVD and explore the relationship between downregulated IL6R signalling and Lp(a) levels. Methods Independent genetic variants associated with C-reactive protein levels from around the IL6R gene locus, and Lp(a) lowering variants from around the LPA gene locus were utilised to assess the effect of genetically proxied IL6R and LPA inhibition on CVD risk in large genomic consortia. Two-step cis-MR was then employed to estimate the effect of lower genetically predicted IL6R signalling on CVD, after adjusting for its influence on Lp(a) levels. Results Genetically proxied LPA inhibition was associated with reduced odds of coronary artery disease (CAD) (OR 0.88, 95% CI 0.86-0.89), ischaemic stroke (IS) (OR 0.98, 95% CI 0.96-1.00), cardioembolic stroke (OR 0.95, 95% CI 0.92-0.97), heart failure (HF) (OR 0.96, 95% CI 0.92-1.00), and aortic stenosis (OR 0.88, 95% CI 0.85-0.91). IL6R inhibition was associated with reduced odds of CAD (OR 0.76, 95% CI 0.68-0.86), IS (OR 0.89, 95% CI 0.80-0.98), small vessel stroke (SVS) (OR 0.72, 95% CI 0.59-0.89), large artery stroke (LAS) (0.61, 95% CI 0.48-0.78) and atrial fibrillation (OR 0.73, 95% CI 0.65-0.83). Furthermore, downregulated IL6R signalling was associated with lower Lp(a) levels (SD change -0.04, 95% CI -0.08,-0.01). In two-step cis-MR, Lp(a) levels partially mediated the total effect of IL6R inhibition on CAD (proportion-mediated = -11.33%, 95% CI -11.35, -11.31%) and LAS (proportion mediated = -4.19%, 95% CI -4.21, -4.17%), but had little effect on IS (proportion-mediated = -1.78%, 95% CI -1.80, -1.76%), SVS (proportion-mediated = -2.50%, 95% CI -2.52, -2.48%), or atrial fibrillation (proportion-mediated = -0.20%, 95% CI -0.22, -0.18%). Conclusion IL6R and Lp(a) inhibition are independently associated with reduced risk of CVD. Furthermore, IL6R inhibition is associated with lower Lp(a) and its effect on CVD is independent of its Lp(a)-lowering effects. Targeting the IL6 signalling pathway offers a promising approach to mitigate residual CVD risk in individuals with elevated Lp(a) levels. Future trials should investigate the additive effects of combined IL-6 inhibition and Lp(a) lowering therapies.

The Possible Association of IL-6R Gene Polymorphisms in the Development of Diabetic Nephropathy.

Diabetic nephropathy (DN) is a common complication of type 2 diabetes (T2D). Chronic inflammation and a combination of environmental and genetic factors are involved in the pathogenesis and development of DN. This case-control study aimed to determine the relationship between rs7529229 and rs2228145 polymorphisms of the IL-6R gene with the incidence of nephropathy among T2D patients. Fifty-six diabetic patients with nephropathy and 57 T2D patients without nephropathy were included based on inclusion criteria, along with 150 healthy individuals. The frequencies of AC and CC genotype distributions of the rs2228145 polymorphism in DN patients were significantly higher than in healthy individuals (24.1 and 9.3% versus 10.7 and 6.7%, respectively, P= 0.02). Moreover, the frequency of allele C was higher in DN patients compared to healthy controls (21.30% versus 12%, P=0.025). However, genotype distribution and allele frequencies of the rs7529229 IL-6R polymorphism in DN patients were not statistically significant in comparison with diabetic patients and healthy individuals (P> 0.05). The results showed that the allele and genotype distribution frequencies of rs2228145 IL-6R gene polymorphism in patients with DN were significantly higher than in healthy individuals. Therefore, the presence of this polymorphism may be involved in the development of diabetic nephropathy in this population.

IL6 receptor inhibitors: exploring the therapeutic potential across multiple diseases through drug target Mendelian randomization.

High interleukin-6 levels correlate with diseases like cancer, autoimmune disorders, and infections. IL-6 receptor inhibitors (IL-6Ri), used for rheumatoid arthritis and COVID-19, may have wider uses. We apply drug-target Mendelian Randomization (MR) to study IL-6Ri's effects. To simulate the effects of genetically blocking the IL-6R, we selected single nucleotide polymorphisms (SNPs) within or near the IL6R gene that show significant genome-wide associations with C-reactive protein. Using rheumatoid arthritis and COVID-19 as positive controls, our primary research outcomes included the risk of asthma, asthmatic pneumonia, cor pulmonale, non-small cell lung cancer, small cell lung cancer, Parkinson's disease, Alzheimer's disease, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, type 1 diabetes, and type 2 diabetes. The Inverse Variance Weighted (IVW) method served as our principal analytical approach, with the hypotheses of MR being evaluated through sensitivity and colocalization analyses. Additionally, we conducted Bayesian Mendelian Randomization analyses to minimize confounding and reverse causation biases to the greatest extent possible. IL-6 inhibitors significantly reduced the risk of idiopathic pulmonary fibrosis (OR= 0.278, 95% [CI], 0.138-0.558; P <0.001), Parkinson's disease (OR = 0.354, 95% CI, 0.215-0.582; P <0.001), and positively influenced the causal relationship with Type 2 diabetes (OR = 0.759, 95% CI, 0.637-0.905; P = 0.002). However, these inhibitors increased the risk for asthma (OR = 1.327, 95% CI, 1.118-1.576; P = 0.001) and asthmatic pneumonia (OR = 1.823, 95% CI, 1.246-2.666; P = 0.002). The causal effect estimates obtained via the BWMR method are consistent with those based on the IVW approach. Similarly, sIL-6R also exerts a significant influence on these diseases.Diseases such as Alzheimer's disease, Crohn's disease, pulmonary heart disease, systemic lupus erythematosus, Type 1 diabetes, Non-small cell lung cancer and ulcerative colitis showed non-significant associations (p > 0.05) and were excluded from further analysis. Similarly, Small cell lung cancer were excluded due to inconsistent results. Notably, the colocalization evidence for asthmatic pneumonia (coloc.abf-PPH4 = 0.811) robustly supports its association with CRP. The colocalization evidence for Parkinson's disease (coloc.abf-PPH4 = 0.725) moderately supports its association with CRP. IL-6Ri may represent a promising therapeutic avenue for idiopathic pulmonary fibrosis, Parkinson's disease, and Type 2 diabetes.

Induction of Thymus Atrophy and Disruption of Thymocyte Development by Fipronil through Dysregulation of IL-7-Associated Genes.

The susceptibility of the immune system to immunotoxic chemicals is evident, particularly in the thymus, a vital primary immune organ prone to atrophy due to exposure to toxicants. Fipronil (FPN), a widely used insecticide, is of concern due to its potential neurotoxicity, hepatotoxicity, and immunotoxicity. Our previous study showed that FPN disturbed the antigen-specific T-cell functionality in vivo. As T-cell lineage commitment and thymopoiesis are closely interconnected with the normal function of the T-cell-mediated immune responses, this study aims to further examine the toxic effects of FPN on thymocyte development. In this study, 4-week-old BALB/c mice received seven doses of FPN (1, 5, 10 mg/kg) by gavage. Thymus size, medulla/cortex ratio, total thymocyte counts, double-positive thymocyte population, and IL-7-positive cells decreased dose-dependently. IL-7 aids the differentiation of early T-cell precursors into mature T cells, and several essential genes contribute to the maturation of T cells in the thymus. Foxn1 ensures that the thymic microenvironment is suitable for the maturation of T-cell precursors. Lyl1 is involved in specifying lymphoid cells and maintaining T-cell development in the thymus. The c-Kit/SCF collaboration fosters a supportive thymic milieu to promote the formation of functional T cells. The expression of IL-7, IL-7R, c-Kit, SCF, Foxn1, and Lyl1 genes in the thymus was significantly diminished in FPN-treated groups with the concordance with the reduction of IL-7 signaling proteins (IL-7, IL-7R, c-KIT, SCF, LYL1, FOXO3A, and GABPA), suggesting that the dysregulation of T-cell lineage-related genes may contribute to the thymic atrophy induced by FPN. In addition, FPN disturbed the functionality of thymocytes with an increase of IL-4 and IFN-γ production and a decrease of IL-2 secretion after T-cell mitogen stimulation ex vivo. Collectively, FPN significantly deregulated genes related to T-cell progenitor differentiation, survival, and expansion, potentially leading to impaired thymopoiesis.

Hyper IgE Syndromes.

The Hyper IgE Syndromes are rare primary immunodeficiencies characterized by eczema, recurrent skin and respiratory infections and elevated serum IgE levels. Nowadays a geneticmolecular characterization is possible and allows the distinction in various monogenic pathologies, which share some clinical characteristics but also important differences. In addition to long-known STAT3 and DOCK8 gene mutations, in fact, also ZNF341, CARD11, ERBB2IP, IL6R and IL6ST genes mutations can cause the disease. The main clinical manifestations are represented by newborn rash, eczema similar to atopic dermatitis, bacterial and viral skin infections, cold abscesses, respiratory infections with possible pulmonary complications, allergies, gastrointestinal manifestations, malignancies and connective tissue abnormalities. Diagnosis is still a challenge because, especially in the early stages of life, it is difficult to distinguish from other pathologies characterized by eczema and high IgE, such as atopic dermatitis. Several scores and diagnostic pathways have been developed, but it is essential to seek a genetic diagnosis. Treatment is based on prevention and early treatment of infections, meticulous skincare, intravenous immunoglobulins and HSCT, which, in some HIES subtypes, can modify the prognosis. Prognosis is related to the affected gene, but also to early diagnosis, timely treatment of infections and early HSCT.

Genetic variations of IL10 and IL6R genes in acute anterior uveitis in Han Chinese

BackgroundSeveral autoimmune disorders have been linked to polymorphisms in IL10 and IL6R genes. This research aimed to study whether single nucleotide polymorphisms (SNPs) in the genes of IL10 and IL6R were associated with acute anterior uveitis (AAU) in Han Chinese.MethodsGenotyping was carried out by the iPLEX Gold Genotyping Assay. Our study comprised 420 patients with AAU and 918 healthy subjects from Han Chinese. Using the chi-square (χ2) test, alleles and genotypes were analyzed between AAU subjects and healthy controls.ResultsAll ten SNPs were successfully genotyped and four SNPs (IL10/rs1800871, IL10/rs3021094, IL10/rs2222202, IL6R/rs4845618) exhibited weak associations with AAU, as indicated by their Puncorr values. However, upon applying the Bonferroni correction, there was no significant association between AAU and the control subjects. Additionally, the haplotype analysis of the ten SNPs revealed no association with AAU.ConclusionOur findings suggested that polymorphisms of the tested ten SNPs on the IL10 and IL6R genes did not show any association with the risk of developing AAU among the Han Chinese population.

Modifiable risk factors and inflammation-related proteins in polymyalgia rheumatica: genome-wide meta-analysis and Mendelian randomisation.

Polymyalgia rheumatica (PMR) is an age-related inflammatory disease of unknown cause. We aimed to identify potentially modifiable risk factors and therapeutic targets for preventing or treating PMR. We meta-analysed genetic association data from 8,156 cases of PMR (defined using diagnostic codes and self-report) and 416,495 controls of European ancestry from the UK Biobank and FinnGen. We then performed Mendelian randomization analyses to estimate the association between eight modifiable risk factors (using data from up to 1.2 million individuals) and 65 inflammation-related circulating proteins (up to 55,792 individuals), using the inverse variance weighted and pleiotropy robust methods. We identified three novel genome-wide significant loci in the IL1R1, NEK6 and CCDC88B genes and confirmation of previously described associations with HLA-DRB1 and ANKRD55. Genetically predicted smoking intensity (OR 1.32; 95%CI 1.08-1.60; p = 0.006) and visceral adiposity (OR 1.22; 95%CI 1.10-1.37; p = 3.10x10-4) were associated with PMR susceptibility. Multiple circulating proteins related to IL-1 family signaling were associated with PMR. IL-1 receptor-like 2, also known as IL-36 receptor (OR 1.25; p = 1.89x10-32), serum amyloid A2 (OR 1.06, 9.91x10-10) and CXCL6 (OR 1.09, p = 4.85x10-7) retained significance after correction for multiple testing. Reducing smoking and visceral adiposity at a population level might reduce incidence of PMR. We identified proteins that may play causal roles in PMR, potentially suggesting new therapeutic opportunities. Further research is needed before these findings are applied to clinical practice.

Dietary mercury intake, the IL23R rs10889677 polymorphism, and the risk of gastric cancer in a Korean population: a hospital-based case-control study.

Mercury can stimulate immune responses through T helper 17 (Th17). The gene IL23R is a key factor in Th17 function, which may also contribute to digestive tract diseases. The aim of this study was to identify the associations between dietary mercury and gastric cancer (GC) and to investigate whether the IL23R rs10889677 polymorphism modifies those associations. This case-control study included 377 patients with GC and 756 healthy controls. Dietary mercury intake (total mercury and methylmercury) was assessed using a dietary heavy metal database incorporated into the food frequency questionnaire. IL23R genetic polymorphism rs10889677 (A>C) was genotyped. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression models with adjustments for potential confounders. A higher dietary methylmercury intake was associated with an elevated risk of GC (OR for the highest vs. lowest tertile [T3 vs. T1], 2.02; 95% CI, 1.41 to 2.91; p for trend <0.001). The IL23R rs10889677 reduced the risk of GC in individuals who carried at least 1 minor allele (OR, 0.62; 95% CI, 0.46 to 0.83; p=0.001; AC/CC vs. AA). Individuals with a C allele exhibited a lower susceptibility to GC through methylmercury intake than those with the AA genotype (OR for the T3 of methylmercury and AA carriers, 2.93; 95% CI, 1.77 to 4.87; and OR for the T3 of methylmercury and AC/CC genotype, 1.30; 95% CI, 0.76 to 2.21; p-interaction=0.013). Our findings suggest that a genetic polymorphism, rs10889677 in IL23R, plays a role in modifying the association between dietary methylmercury intake and the risk of GC.

Insights into Therapeutic Response Prediction for Ustekinumab in Ulcerative Colitis Using an Ensemble Bioinformatics Approach.

Optimizing treatment with biological agents is an ideal goal for patients with ulcerative colitis (UC). Recent data suggest that mucosal inflammation patterns and serum cytokine profiles differ between patients who respond and those who do not. Ustekinumab, a monoclonal antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23, has shown promise, but predicting treatment response remains a challenge. We aimed to identify prognostic markers of response to ustekinumab in patients with active UC, utilizing information from their mucosal transcriptome. We performed a prospective observational study of 36 UC patients initiating treatment with ustekinumab. Colonic mucosal biopsies were obtained before treatment initiation for a gene expression analysis using a microarray panel of 84 inflammatory genes. A differential gene expression analysis (DGEA), correlation analysis, and network centrality analysis on co-expression networks were performed to identify potential biomarkers. Additionally, machine learning (ML) models were employed to predict treatment response based on gene expression data. Seven genes, including BCL6, CXCL5, and FASLG, were significantly upregulated, while IL23A and IL23R were downregulated in non-responders compared to responders. The co-expression analysis revealed distinct patterns between responders and non-responders, with key genes like BCL6 and CRP highlighted in responders and CCL11 and CCL22 in non-responders. The ML algorithms demonstrated a high predictive power, emphasizing the significance of the IL23R, IL23A, and BCL6 genes. Our study identifies potential biomarkers associated with ustekinumab response in UC patients, shedding light on its underlying mechanisms and variability in treatment outcomes. Integrating transcriptomic approaches, including gene expression analyses and ML, offers valuable insights for personalized treatment strategies and highlights avenues for further research to enhance therapeutic outcomes for patients with UC.

No Association of Polymorphisms in the Genes Encoding Interleukin-6 and Interleukin-6 Receptor Subunit Alpha with the Risk of Keloids in Polish Patients.

A keloid is a benign fibroproliferative hypertrophy of scar tissue that extends outside the original wound and invades adjacent healthy skin. Keloid formation is thought to be a complex process including overactivity of the interleukin-6 signaling pathway and genetic susceptibility. The aim of the study was to investigate possible associations between rs1800797, rs1800796, and rs1800795 polymorphisms in the promoter of the IL6 gene encoding interleukin-6 and the rs2228145 polymorphism in the IL6R gene encoding the interleukin-6 receptor subunit alpha with the predisposition to keloids in Polish patients. The genetic polymorphisms were identified either using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) or sequencing of samples of genomic DNA extracted from blood leukocytes of 86 adult patients with keloids and 100 newborns comprising a control group. No significant differences in the distributions of IL6 or IL6R alleles or genotypes were found between keloid patients and newborn controls. There were also no significant differences between both groups in the distribution of IL6 haplotypes. The IL6 rs1800797, rs1800796 and rs1800795 and IL6R rs2228145 polymorphisms were not found to predispose individuals in the study group to keloids. IL6 promoter haplotypes were not found to be associated with a higher risk of keloids in the studied group.

IL1R2 is a Novel Prognostic Biomarker for Lung Adenocarcinoma.

The aim of this study is to figure out the role of IL1R2 in LUAD (lung adenocarcinoma). IL1R2, a special member of IL-1 receptor family, binds to IL-1 and plays an important role in inhibiting IL-1 pathway, which seems to be involved in tumorigenesis. Emerging studies demonstrated higher IL1R2 expression levels in several malignancies. In the present study, we assessed the expression of IL1R2 in LUAD tissues with immunohistochemistry and explored various databases to determine whether it could be a potential prognostic biomarker and therapeutic target. The expression level of IL1R2 in lung adenocarcinoma was analyzed by Immunohistochemistry and UALCAN database. The correlation between IL1R2 expression and the patient prognosis was identified by Kaplan-Meier plotter. The correlation of IL1R2 expression with immune infiltrates was clarified by TIMER database. The protein-protein interaction network and gene functional enrichment analysis were constructed and performed by STRING and Metascape database. Immunohistochemistry showed that the expression of IL1R2 was higher in tumor tissues of LUAD patients and that patients with lower IL1R2 level have a better prognosis than their counterparts. We validated our findings in several online databases and found that IL1R2 gene was also positively correlated with B cells and neutrophils and biomarkers of CD8+T cells and exhausted T cells. PPI network and gene enrichment analyses showed that expression of IL1R2 was also associated with complex functionspecific networks involving IL-1 signal, NF-KappaB transcription factors. According to these findings, we demonstrated that IL1R2 was involved in the progression and prognosis of LUAD and the underlying mechanism needs further investigation.

Genetically proxied IL-6 receptor inhibition is associated with increased risk of atopic dermatitis

BackgroundDermatitis has been reported after initiation of IL-6 receptor inhibitors (IL-6Ri), while genetic association studies of atopic dermatitis (AD) have implicated IL-6R pathway signalling. However, causality remains unclear. As indications for IL-6Ri expand, so do the clinical importance of determining whether there is mechanistic evidence linking it to AD. ObjectiveTo examine the association between IL-6Ri and risk of AD. MethodsTo genetically mimic IL-6Ri, we selected single nucleotide polymorphisms within or near the IL6R gene associated with C-reactive protein (CRP) at genome-wide significance among 343,524 individuals. Genetic data for AD were obtained from 10,788 cases and 30,047 controls of European ancestry. We used the inverse-variance weighted and pleiotropy-robust methods and examined genetic confounding using colocalization. Analyses were replicated using 13,473 AD Finnish cases and 2,385 East Asian cases. Results from three independent analyses were pooled by meta-analysis. ResultsGenetically proxied IL-6Ri was associated with increased risk of AD (OR 1.78 per 4.4 mg/l reduction in CRP; 95%CI 1.28, 2.48; p=6.5x10-4). Results were replicated using Finnish outcome data (OR 2.07; 95%CI 1.58, 2.72; p=1.57x10-7), and Eastern Asian datasets (OR 1.68; 95%CI 1.12, 2.54; p=0.013). Meta-analysis of three independent populations (OR 1.89; 95%CI 1.57, 2.28; p=2.68x10-11) showed no statistical evidence of heterogeneity (p=0.65). We found no statistical evidence for pleiotropy or genetic confounding. ConclusionThis genetic investigation provides consistent evidence, across independent multi-ancestry populations, that IL-6R signalling is causally implicated in AD susceptibility. Clinicians should remain vigilant for adverse effects resembling AD when using IL-6R inhibitors for immune-mediated inflammatory diseases.

Pathological variations and immune response in Channa argus infected with pathogenic Nocardia seriolae strain

Nocardia seriolae pathogen causes chronic granulomatous disease, reportedly affecting over 40 species of marine and freshwater cultured fish. Hence, research is required to address and eliminate this significant threat to the aquaculture industry. In this respect, a reliable and reproducible infection model needs to be established to better understand the biology of this pathogen and its interactions with the host during infection, as well as to develop new vaccines or other effective treatment methods. In this study, we examined the pathogenicity of the pathogen and the immune response of snakehead (Channa argus) juvenile to N. seriolae using a range of methods and analyses, including pathogen isolation and identification, histopathology, Kaplan-Meier survival curve analysis, and determination of the median lethal dose (LD50) and cytokine expression. We have preliminarily established a N. seriolae - C. argus model. According to our morphological and phylogenetic analysis data, the isolated strain was identified as N. seriolae and named NSE01. Eighteen days post-infection of healthy juvenile C. argus with N. seriolae NSE01, the mortality rate in all four experimental groups (intraperitoneally injected with 1 × 105 CFU/mL – 1 × 108 CFU/mL of bacterial suspension) (n = 120) was 100 %. The LD50 of N. seriolae NSE01 for juvenile C. argus was determined to be 1.13 × 106 CFU/fish. Infected juvenile C. argus had significant pathological changes, including visceral tissue swelling, hemorrhage, and the presence of numerous nodules of varying sizes in multiple tissues. Further histopathological examination revealed typical systemic granuloma formation. Additionally, following infection with N. seriolae NSE01, the gene expression of important cytokines, such as Toll-like receptor genes TLR2, TLR13, interleukin-1 receptor genes IL1R1, IL1R2, and interferon regulatory factor IRF2 were significantly upregulated in different tissues, indicating their potential involvement in the host immune response and regulation against N. seriolae. In conclusion, juvenile C. argus can serve as a suitable model for N. seriolae infection. The establishment of this animal model will facilitate the study of the pathogenesis of nocardiosis and the development of vaccines.

IL1R2 Gene Expression Is Downregulated in Obesity- Associated Asthma.

IL1R2 Gene Expression Is Downregulated in Obesity- Associated Asthma.

Novel Synonymous Variant in IL7R Causes Preferential Expression of the Soluble Isoform

PurposeThe interleukin-7 receptor (IL-7R) is primarily expressed on lymphoid cells and plays a crucial role in the development, proliferation, and survival of T cells. Autosomal recessive mutations that disrupt IL-7Rα chain expression give rise to a severe combined immunodeficiency (SCID), which is characterized by lymphopenia and a T−B+NK+ phenotype. The objective here was to diagnose two siblings displaying the T−B+NK+ SCID phenotype as initial clinical genetic testing did not detect any variants in known SCID genes.MethodsWhole genome sequencing (WGS) was utilized to identify potential variants causing the SCID phenotype. Splicing prediction tools were employed to assess the deleterious impact of the mutation. Polymerase Chain Reaction (PCR), Sanger sequencing, flow cytometry, and ELISA were then used to validate the pathogenicity of the detected mutation.ResultsWe discovered a novel homozygous synonymous mutation in the IL7R gene. Our functional studies indicate that this variant is pathogenic, causing exon 6, which encodes the transmembrane domain, to be preferentially spliced out.ConclusionIn this study, we identified a novel rare synonymous mutation causing a loss of IL-7Rα expression at the cellular membrane. This case demonstrates the value of reanalyzing genetic data based on the clinical phenotype and highlights the significance of functional studies in determining the pathogenicity of genetic variants.

Prevalence of Selected Polymorphisms of Il7R, CD226, CAPSL, and CLEC16A Genes in Children and Adolescents with Autoimmune Thyroid Diseases.

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are common autoimmune endocrine disorders in children. Studies indicate that apart from environmental factors, genetic background significantly contributes to the development of these diseases. This study aimed to assess the prevalence of selected single-nucleotide polymorphisms (SNPs) of Il7R, CD226, CAPSL, and CLEC16A genes in children with autoimmune thyroid diseases. We analyzed SNPs at the locus rs3194051, rs6897932 of IL7R, rs763361 of CD226, rs1010601 of CAPSL, and rs725613 of CLEC16A gene in 56 HT patients, 124 GD patients, and 156 healthy children. We observed significant differences in alleles IL7R (rs6897932) between HT males and the control group (C > T, p = 0.028) and between all GD patients and healthy children (C > T, p = 0.035) as well as GD females and controls (C > T, p = 0.018). Moreover, the C/T genotype was less frequent in GD patients at rs6897932 locus and in HT males at rs1010601 locus. The presence of the T allele in the IL7R (rs6897932) locus appears to have a protective effect against HT in males and GD in all children. Similarly, the presence of the T allele in the CAPSL locus (rs1010601) seems to reduce the risk of HT development in all patients.

Interleukin gene polymorphisms and alopecia areata: A systematic review and meta-analysis.

Alopecia areata (AA) is an autoimmune disease which results in non-scarring hair loss on the scalp or any surface with hair. Several genetic polymorphisms of the interleukin genes have been linked with this disease but the results are inconsistent. This systematic review and meta-analysis were done to find the association between rs3118470, rs2275913, rs3212227, and rs10889677 of the IL2RA, IL17A, IL12B, and IL23R genes, respectively, of the interleukin family with alopecia areata. A comprehensive search for relevant research articles was conducted in Pubmed, Google Scholar, and Embase databases. Our search yielded 8 relevant articles with 1940 cases and 1788 controls. The odds ratio with 95% confidence intervals was calculated using fixed effect and random effect models. Heterogeneity was determined using the Q-test and I2 test. Publication bias was determined and funnel plots were used to adjust the odds ratio. We found a significant risk effect for rs3118470 of the IL2RA gene with alopecia areata in the dominant model (CC + CT vs TT; OR = 1.54, 95% confidence interval = 1.05-2.26, P < .05, I2 = 69.03%) and homozygous model (CC vs TT; OR = 2.00, 95% confidence interval = 1.07-3.71, P < .05, I2 = 72.84%). For the other single nucleotide polymorphisms, we could not find any statistically significant association with the disease. Our analysis showed that mutation of rs3118470 of IL2RA gene possesses a significant risk effect for alopecia areata. Future studies with larger sample sizes and ethnic backgrounds are warranted to confirm our findings.

Evidence for the Involvement of Gene Regulation of Inflammatory Molecules in the Accumulation of Intracellular Cholesterol: The Mechanism of Foam Cell Formation in Atherosclerosis.

The relationship between the cellular pro-inflammatory response and intracellular lipid accumulation in atherosclerosis is not sufficiently studied. Transcriptomic analysis is one way to establish such a relationship. Previously, we identified 10 potential key genes (IL-15, CXCL8, PERK, IL-7, IL-7R, DUSP1, TIGIT, F2RL1, TSPYL2, and ANXA1) involved in cholesterol accumulation in macrophages. It should be noted that all these genes do not directly participate in cholesterol metabolism, but encode molecules related to inflammation. In this study, we conducted a knock-down of the 10 identified key genes using siRNA to determine their possible role in cholesterol accumulation in macrophages. To assess cholesterol accumulation, human monocyte-derived macrophages (MDM) were incubated with atherogenic LDL from patients with atherosclerosis. Cholesterol content was assessed by the enzymatic method. Differentially expressed genes were identified with DESeq2 analysis. Master genes were determined by the functional analysis. We found that only 5 out of 10 genes (IL-15, PERK, IL-7, IL-7R, ANXA1) can affect intracellular lipid accumulation. Knock-down of the IL-15, PERK, and ANXA1 genes prevented lipid accumulation, while knock-down of the IL-7 and IL-7R genes led to increased intracellular lipid accumulation during incubation of MDM with atherogenic LDL. Seventeen overexpressed genes and 189 underexpressed genes were obtained in the DGE analysis, which allowed us to discover 20 upregulated and 86 downregulated metabolic pathways, a number of which are associated with chronic inflammation and insulin signaling. We also elucidated 13 master regulators of cholesterol accumulation that are immune response-associated genes. Thus, it was discovered that 5 inflammation-related master regulators may be involved in lipid accumulation in macrophages. Therefore, the pro-inflammatory response of macrophages may trigger foam cell formation rather than the other way around, where intracellular lipid accumulation causes an inflammatory response, as previously assumed.

Coculture of bacterial levans and evaluation of its anti-cancer activity against hepatocellular carcinoma cell lines

This research represents a novel study to assess how coculture affects levan yield, structure, bioactivities, and molecular weight. Among the 16 honey isolates, four bacterial strains recorded the highest levan yield. The Plackett–Burman design showed that the coculture (M) of isolates G2 and K2 had the maximum levan yield (52 g/L) and the effective factors were sucrose, incubation time, and sugarcane bagasse. The CCD showed that the most proper concentrations for maximum levan yield (81 g/L): were 130 g/L of sucrose and 6 g/f of sugarcane bagasse. Levan’s backbone was characterized, and the molecular weight was determined. G2 and K2 isolates were identified based on 16 sRNA as Bacillus megaterium strain YM1C10 and Rhizobium sp. G6-1. M levan had promising antioxidant activity (99.66%), slowed the migration activity to a great extent, and recorded 70.70% inhibition against the hepatoblastoma cell line (HepG2) at 1000 µg/mL. Gene expression analysis in liver cancer cell lines (HePG2) revealed that M levan decreased the expression of CCL20), 2GRB2, and CCR6) genes and was superior to Doxo. While increasing the expression of the IL4R and IL-10 genes. The DNA damage values were significantly increased (P < 0.01) in treated liver cancer cell lines with levan M and Doxo. The results referred to the importance of each of the hydroxyl and carboxyl groups and the molecular weight in levans bioactivities.

Association of Interleukin 23 Receptor Polymorphisms with Predisposition to Rheumatoid Arthritis: An Updated Meta and Trial Sequential Analysis.

The etiology of Rheumatoid Arthritis (RA) development remained unclear, and several factors, such as environmental, genetic, and immune system dysfunction, have been attributed to the susceptibility. Interleukin 23 (IL23) induces expansion of the Th17 cells through the IL-23 receptor (IL-23R) and believes in playing a major role in RA pathogenesis. Various genetic mutants in the IL23R gene (rs10489629, rs1343151, rs2201841, rs7517847, rs1004819, rs10889677, rs11209026, rs7530511) have been associated with the susceptibility RA, but results are contradictories. We performed a meta-analysis to establish the association of IL23R polymorphisms with susceptibility RA. For the meta-analysis, a detailed search of databases like Google Scholar, PubMed, Scopus, Web of Science, and Science Direct was conducted, and data were extracted from the included reports. The meta-analysis was performed by the Comprehensive Meta-Analysis v3 software. A significant association of IL-23R rs11209026 (AA vs. GG: Odds ratio = 2.250, p-value = 0.01; AA vs. GG+GA: Odds ratio = 2.271, p-value = 0.01), rs1343151 (A vs. G: Odds ratio = 1.091, p-value = 0.001; AA vs. GG: Odds ratio = 1.209, p-value = 0.001; GA vs. GG: Odds ratio = 1.116, p-value = 0.004; AA+GA vs. GG: Odds ratio = 1.135, p-value = 0.000; AA vs. GG+GA: Odds ratio = 1.144, p-value = 0.012) and rs10889677 (CA vs. CC: Odds ratio = 1.375, p-value = 0.041) polymorphisms were observed with increased susceptibility for the development of RA. In contrast, IL-23R rs10489629 (G vs. A: odds ratio = 0.901, p-value = 0.047, GG vs. AA: Odds ratio = 0.763, p-value = 0.022, GG vs. AA+AG: Odds ratio = 0.852, p-value = 0.00) and IL23R rs2201841 (CC vs. TT+TC: Odds ratio = 0.826, p-value = 0.026) variants were linked with protection against the development of RA. In addition, the trial sequential analysis revealed the inclusion of a sufficient number of studies in the present meta-analysis, and no further additional studies are required. IL-23R variants are associated with genetic susceptibility or resistance against the development of RA.