Chromosome X-wide association study in case control studies of pathologically confirmed Alzheimer's disease in a European population.

Although there are several genome-wide association studies available which highlight genetic variants associated with Alzheimer's disease (AD), often the X chromosome is excluded from the analysis. We conducted an X-chromosome-wide association study (XWAS) in three independent studies with a pathologically confirmed phenotype (total 1970 cases and 1113 controls). The XWAS was performed in males and females separately, and these results were then meta-analysed. Four suggestively associated genes were identified which may be of potential interest for further study in AD, these are DDX53 (rs12006935, OR = 0.52, p = 6.9e-05), IL1RAPL1 (rs6628450, OR = 0.36, p = 4.2e-05; rs137983810, OR = 0.52, p = 0.0003), TBX22 (rs5913102, OR = 0.74, p = 0.0003) and SH3BGRL (rs186553004, OR = 0.35, p = 0.0005; rs113157993, OR = 0.52, p = 0.0003), which replicate across at least two studies. The SNP rs5913102 in TBX22 achieves chromosome-wide significance in meta-analysed data. DDX53 shows highest expression in astrocytes, IL1RAPL1 is most highly expressed in oligodendrocytes and neurons and SH3BGRL is most highly expressed in microglia. We have also identified SNPs in the NXF5 gene at chromosome-wide significance in females (rs5944989, OR = 0.62, p = 1.1e-05) but not in males (p = 0.83). The discovery of relevant AD associated genes on the X chromosome may identify AD risk differences and similarities based on sex and lead to the development of sex-stratified therapeutics.

Interleukin-1 receptor accessory protein blockade limits the development of atherosclerosis and reduces plaque inflammation.

AIMS: The interleukin-1 receptor accessory protein (IL1RAP) is a co-receptor required for signalling through the IL-1, IL-33, and IL-36 receptors. Using a novel anti-IL1RAP-blocking antibody, we investigated the role of IL1RAP in atherosclerosis. METHODS AND RESULTS: Single-cell RNA sequencing data from human atherosclerotic plaques revealed the expression of IL1RAP and several IL1RAP-related cytokines and receptors, including IL1B and IL33. Histological analysis showed the presence of IL1RAP in both the plaque and adventitia, and flow cytometry of murine atherosclerotic aortas revealed IL1RAP expression on plaque leucocytes, including neutrophils and macrophages. High-cholesterol diet fed apolipoprotein E-deficient (Apoe-/-) mice were treated with a novel non-depleting IL1RAP-blocking antibody or isotype control for the last 6 weeks of diet. IL1RAP blockade in mice resulted in a 20% reduction in subvalvular plaque size and limited the accumulation of neutrophils and monocytes/macrophages in plaques and of T cells in adventitia, compared with control mice. Indicative of reduced plaque inflammation, the expression of several genes related to leucocyte recruitment, including Cxcl1 and Cxcl2, was reduced in brachiocephalic arteries of anti-IL1RAP-treated mice, and the expression of these chemokines in human plaques was mainly restricted to CD68+ myeloid cells. Furthermore, in vitro studies demonstrated that IL-1, IL-33, and IL-36 induced CXCL1 release from both macrophages and fibroblasts, which could be mitigated by IL1RAP blockade. CONCLUSION: Limiting IL1RAP-dependent cytokine signalling pathways in atherosclerotic mice reduces plaque burden and plaque inflammation, potentially by limiting plaque chemokine production.

Different Gene Expression Patterns of IL-1 Family Members in Parkinson's Disease: Results from Bayesian Regression Model.

Parkinson's disease, the second most prevalent neurodegenerative disorder lacking a recognized etiology, is influenced by oxidative stress and alterations in inflammatory cytokine levels. This study aimed to investigate the expression levels of Interleukin(IL)1 receptor accessory protein (IL-1RAcP), IL1ß, IL1α, IL33, and IL36 genes in blood cells and serum IL-1ß levels in Parkinson's disease patients compared to healthy controls (HCs).I n this case-control study, 44 Parkinson's disease patients and 44 age- and sex-matched HCs were included. Gene expression levels were assessed using Quantitative Real-time PCR, and serum IL-1ß levels were measured via enzyme-linked immunosorbent assay. Advanced statistical analyses using the Bayesian regression model in R software were employed. Parkinson's disease patients exhibited elevated expression levels of IL-1RAcP and IL1ß genes  but decreased levels of IL1α, IL33, and IL36 compared to HCs. Age-based differences were not significant. Regarding gender, IL33 transcript levels were significantly higher in males, and serum IL-1ß levels were increased in patients. Subgroup analysis by gender indicated alterations in IL1ß and IL-1RAcP expression in both genders, while IL1α, IL33, and IL36 showed reduced expression only in males. Remarkably, only female patients displayed significantly higher serum IL-1ß levels than female HCs. These findings suggest that dysregulation of immune-related factors plays a crucial role in Parkinson's disease.

RGS3 and IL1RAPL1 missense variants implicate defective neurotransmission in early-onset inherited schizophrenias.

BACKGROUND: Schizophrenia is characterized by hallucinations, delusions and disorganized behaviour. Recessive or X-linked transmissions are rarely described for common psychiatric disorders. We examined the genetics of psychosis to identify rare large-effect variants in patients with extreme schizophrenia. METHODS: We recruited 2 consanguineous families, each with patients affected by early-onset, severe, treatment-resistant schizophrenia. We performed exome sequencing for all participants. We checked variant rarity in public databases and with ethnically matched controls. We performed in silico analyses to assess the effects of the variants on proteins. RESULTS: Structured clinical evaluations supported diagnoses of schizophrenia in all patients and phenotypic absence in the unaffected individuals. Data analyses identified multiple variants. Only 1 variant per family was predicted as pathogenic by prediction tools. A homozygous c.649C > T:p.(Arg217Cys) variant in RGS3 and a hemizygous c.700A > G:p.(Thr234Ala) variant in IL1RAPL1 affected evolutionary conserved amino acid residues and were the most likely causes of phenotype in the patients of each family. Variants were ultra-rare in publicly available databases and absent from the DNA of 400 ethnically matched controls. RGS3 is implicated in modulating sensory behaviour in Caenorhabditis elegans. Variants of IL1RAPL1 are known to cause nonsyndromic X-linked intellectual disability with or without human behavioural dysfunction. LIMITATIONS: Each variant is unique to a particular family's patients, and findings may not be replicated. CONCLUSION: Our work suggests that some rare variants may be involved in causing inherited psychosis or schizophrenia. Variant-specific functional studies will elucidate the pathophysiology relevant to schizophrenias and motivate translation to personalized therapeutics.

Novel IL1RAP mutation associated with schizophrenia interferes with neuronal growth and related NF-κB signal pathways.

Schizophrenia is a complex, severe psychiatric disorder with a high heritability that affects approximately 1% of the world's population. Numerous schizophrenia-related risk genes have been reported in large-scale studies, but the role of most genetic abnormalities in the pathogenesis of the disease is still obscure. In this study, using whole-exome sequencing, we identified a novel nonsense mutation c.1324C > T in the Interleukin 1 receptor accessory protein (IL1RAP) gene in four affected individuals with schizophrenia of a Chinese family. IL1RAP was found involved in initiating the immune responses and regulating synaptic formation. Considering that schizophrenia has been hypothesized to be neurodevelopment disorder for decades, we further explored the influence of altered expression of IL1RAP gene on neuronal growth, and assessed whether this mutation affects the function of IL1RAP protein in IL-1 signaling pathway. We used lentivirus-mediated shRNA to knockdown the IL1RAP gene expression, which suppressed the axon and dendrites growth of cultured mouse cortical neurons. These defects can be recovered by human IL1RAP wild type construct, but not the R442* mutant construct. Furthermore, this mutant even inhibited neuronal growth and IL-1ß-induced JNK phosphorylation when overexpressed in cortical neurons. Although overexpression of this mutant in HePG2 cells did not change IL1RAP protein expression, it partially prohibited the IL-1ß-induced nuclear translocation of transcript factor NF-κB, indicating that IL1RAP c.1324C > T is a loss-of-function mutation. Our findings show that IL1RAP plays an important role in early stages of neurodevelopment, and the mutation c.1324C > T may contribute to the pathogenesis of schizophrenia.

Circ_0037078 promotes trophoblast cell proliferation, migration, invasion and angiogenesis by miR-576-5p/IL1RAP axis.

BACKGROUND: Preeclampsia (PE) is a common hypertensive disorder of pregnancy. Recent studies have suggested that circular RNAs (circRNAs) play a pathological role in PE. Herein, this study aimed to investigate the action and mechanism of circ_0037078 in PE process. METHODS: The quantitative real-time PCR (qRT-PCR) and Western blot were used to determine the expression levels of RNAs and genes. Cell proliferation, migration, invasion and angiogenesis were evaluated by using cell counting kit-8 (CCK-8), colony formation, transwell, and tube formation assays, respectively. The target relation between miR-576-5p and IL1RAP (Interleukin-1 receptor accessory protein) and circ_0037078 was predicted by bioinformatics analysis and verified by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. RESULTS: Circ_0037078 expression was higher in placental tissues of patients with PE than that of normal control. Knockdown of circ_0037078 led to an enhancement of the proliferation, migration, invasion, and angiogenesis in trophoblast cells. Mechanistically, circ_0037078 acted as a sponge for miR-576-5p, thus elevating the expression of IL1RAP, which was targeted by IL1RAP. Further rescue experiments suggested that miR-576-5p inhibition reversed the effects of circ_0037078 knockdown on above behaviors of trophoblast cells. Moreover, miR-576-5p overexpression enhanced the proliferative, migratory, invasive, angiogenic phenotypes of trophoblast cells, which were attenuated by IL1RAP up-regulation. CONCLUSION: Circ_0037078 knockdown promotes trophoblast cell proliferation, migration, invasion, and angiogenesis in vitro by miR-576-5p/IL1RAP axis, providing a novel insight into the etiology of PE.

Risk Variants in Three Alzheimer's Disease Genes Show Association with EEG Endophenotypes.

BACKGROUND: Dementia due to Alzheimer's disease (AD) is a complex neurodegenerative disorder, which much of heritability remains unexplained. At the clinical level, one of the most common physiological alterations is the slowing of oscillatory brain activity, measurable by electroencephalography (EEG). Relative power (RP) at the conventional frequency bands (i.e., delta, theta, alpha, beta-1, and beta-2) can be considered as AD endophenotypes. OBJECTIVE: The aim of this work is to analyze the association between sixteen genes previously related with AD: APOE, PICALM, CLU, BCHE, CETP, CR1, SLC6A3, GRIN2 ß, SORL1, TOMM40, GSK3 ß, UNC5C, OPRD1, NAV2, HOMER2, and IL1RAP, and the slowing of the brain activity, assessed by means of RP at the aforementioned frequency bands. METHODS: An Iberian cohort of 45 elderly controls, 45 individuals with mild cognitive impairment, and 109 AD patients in the three stages of the disease was considered. Genomic information and brain activity of each subject were analyzed. RESULTS: The slowing of brain activity was observed in carriers of risk alleles in IL1RAP (rs10212109, rs9823517, rs4687150), UNC5C (rs17024131), and NAV2 (rs1425227, rs862785) genes, regardless of the disease status and situation towards the strongest risk factors: age, sex, and APOE ɛ4 presence. CONCLUSION: Endophenotypes reduce the complexity of the general phenotype and genetic variants with a major effect on those specific traits may be then identified. The found associations in this work are novel and may contribute to the comprehension of AD pathogenesis, each with a different biological role, and influencing multiple factors involved in brain physiology.

The Potential Role of IL1RAP on Tumor Microenvironment-Related Inflammatory Factors in Stomach Adenocarcinoma.

This study was performed to investigate the role of interleukin-1 receptor accessory protein (IL1RAP) in stomach carcinoma in vitro and in vivo, determine whether IL1RAP knockdown could regulate the development of stomach carcinoma, and elucidate the relationship between IL1RAP knockdown and inflammation by tumor microenvironment-related inflammatory factors in stomach carcinoma. We first used TCGA and GEPIA systems to predict the potential function of IL1RAP. Second, western blot and RT-PCR were used to analyze the expression, or mRNA level, of IL1RAP at different tissue or cell lines. Third, the occurrence and development of stomach carcinoma in vitro and in vivo were observed by using IL1RAP knockdown lentivirus. Finally, the inflammation of stomach carcinoma in vitro and in vivo was observed. Results show that in GEPIA and TCGA systems, IL1RAP expression in STAD tumor tissue was higher than normal, and high expression of IL1RAP in STAD patients had a worse prognostic outcome. Besides, GSEA shown IL1RAP was negative correlation of apopopsis, TLR4 and NF-κB signaling pathway. We also predicted that IL1RAP may related to IL-1 s, IL-33, and IL-36 s in STAD. The IL1RAP expression and mRNA level in tumor, or MGC803, cells were increased. Furthermore, IL1RAP knockdown by lentivirus could inhibit stomach carcinoma development in vitro and in vivo through weakening tumor cell proliferation, migration, invasion, therefore reducing tumor volume, weight, and biomarker levels, and increasing apoptotic level. Finally, we found IL1RAP knockdown could increase inflammation of tumor microenvironment-related inflammatory factors of stomach carcinoma, in vitro and in vivo. Our study demonstrates that IL1RAP is possibly able to regulate inflammation and apoptosis in stomach carcinoma. Furthermore, TLR4, NF-κB, IL-1 s, IL-33, and IL-36 s maybe the downstream target factor of IL1RAP in inflammation. These results may provide a new strategy for stomach carcinoma development by regulating inflammation.

Distinct Gene Expression Signatures Characterize Strong Clinical Responders Versus Nonresponders to Canakinumab in Children With Systemic Juvenile Idiopathic Arthritis.

OBJECTIVE: Canakinumab is a human anti-interleukin-1ß (anti-IL-1ß) blocking agent that effectively neutralizes IL-1ß-mediated signaling for treatment of systemic juvenile idiopathic arthritis (JIA). While many patients have dramatic clinical response to IL-1 blockade, approximately one-third fail to respond, but there are currently no validated clinical or immunologic predictors of response. We undertook this study to characterize distinct gene signatures for treatment response and nonresponse to canakinumab in systemic JIA patients. METHODS: We performed a secondary analysis of whole-blood gene expression microarrays using blood samples obtained from healthy controls and systemic JIA patients at baseline and on day 3 after canakinumab treatment (GEO accession no. GSE80060). Patients were considered strong clinical responders if they met the ACR90 response (exhibited ≥90% improvement in the American College of Rheumatology [ACR] JIA response criteria; nonresponders were those who met ACR30 [exhibiting ≤30% improvement in the ACR JIA response criteria]). A random-effects model with patient identity as the random variable was used for differential expression analysis. RESULTS: We identified a distinct gene expression signature in patients with a strong clinical response to canakinumab treatment as compared to nonresponders, mediated by up-regulation of neutrophil- and IL-1-associated genes and characterized by increasing divergence from control transcriptomes with increasing clinical response. We also identified a signature including up-regulated CD163 expression that was associated with canakinumab nonresponse. Intriguingly, canakinumab treatment induced either up- or down-regulation of type I interferon (IFN) genes, independent of clinical response. CONCLUSION: Here, we identify a gene signature in systemic JIA patients prior to receiving treatment that distinguishes strong responders to canakinumab from nonresponders. Further prospective studies are needed to assess the utility of these insights for treatment decisions in systemic JIA and to track the association of up-regulated type I IFN signatures with systemic JIA complications.

The Role of SNPs in IL1RL1 and IL1RAP Genes in Age-related Macular Degeneration Development and Treatment Efficacy.

BACKGROUND: Age-related macular degeneration (AMD) affects the central part of the retina and causes blindness. In developed countries, AMD occurs in people over 50 years old. Important factors for AMD pathogenesis are an immune response, inflammation, and genetic factors. This study aimed to determine the impact of IL1RL1 rs1041973 and IL1RAP rs4624606 single nucleotide polymorphisms (SNPs) on the occurrence of AMD and the outcome of treatment with aflibercept and bevacizumab. PATIENTS AND METHODS: 563 patients with AMD and 281 healthy candidates were evaluated. Patients with exudative AMD were treated with intravitreal bevacizumab and aflibercept and, after 6 months based on the changes in best-corrected visual acuity and central macular thickness, were classified as 'responders' or 'poor-responders'. Genotyping of IL1RL1 rs1041973 and IL1RAP rs4624606 was accomplished using real-time PCR. Age was compared using the Mann-Whitney U-test. Categorical data (gender, genotype, and allele distributions) compared between groups using the χ2 test or the Fisher's exact test. Associations of gene polymorphisms were calculated using logistic regression analysis with adjustment for age in exudative and atrophic AMD analysis. An adjusted significance threshold for multiple comparisons α=0.025 was applied. RESULTS: Statistically significant differences in the distribution of IL1RAP rs4624606 genotypes (TT, TA and AA) were found between males with atrophic AMD and controls: 50%, 42.9% and 7.1% vs. 69.7%, 30.3% and 0%, respectively, p=0.015. Moreover, we found that 'responders' had a significantly better best-corrected visual acuity than 'poor-responders' before treatment (p=0.032). The central macular thickness was significantly lower in exudative AMD patients with IL1RL1 rs1041973 AA genotype than in wild type and heterozygous (CC+CA) genotype carriers before treatment (p=0.017). CONCLUSION: IL1RAP rs4624606 may be associated with atrophic AMD in males while IL1RL1 rs1041973 may play a protective role against macular thickening in exudative AMD patients.

Epigenetic and transcriptomic consequences of excess X-chromosome material in 47,XXX syndrome-A comparison with Turner syndrome and 46,XX females.

47,XXX (triple X) and Turner syndrome (45,X) are sex chromosomal abnormalities with detrimental effects on health with increased mortality and morbidity. In karyotypical normal females, X-chromosome inactivation balances gene expression between sexes and upregulation of the X chromosome in both sexes maintain stoichiometry with the autosomes. In 47,XXX and Turner syndrome a gene dosage imbalance may ensue from increased or decreased expression from the genes that escape X inactivation, as well as from incomplete X chromosome inactivation in 47,XXX. We aim to study genome-wide DNA-methylation and RNA-expression changes can explain phenotypic traits in 47,XXX syndrome. We compare DNA-methylation and RNA-expression data derived from white blood cells of seven women with 47,XXX syndrome, with data from seven female controls, as well as with seven women with Turner syndrome (45,X). To address these questions, we explored genome-wide DNA-methylation and transcriptome data in blood from seven females with 47,XXX syndrome, seven females with Turner syndrome, and seven karyotypically normal females (46,XX). Based on promoter methylation, we describe a demethylation of six X-chromosomal genes (AMOT, HTR2C, IL1RAPL2, STAG2, TCEANC, ZNF673), increased methylation for GEMIN8, and four differentially methylated autosomal regions related to four genes (SPEG, MUC4, SP6, and ZNF492). We illustrate how these changes seem compensated at the transcriptome level although several genes show differential exon usage. In conclusion, our results suggest an impact of the supernumerary X chromosome in 47,XXX syndrome on the methylation status of selected genes despite an overall comparable expression profile.

Associations between IL1RAP rs4624606, IL1RL1 rs1041973, IL-6 rs1800795, and HTRA1 rs11200638 gene polymorphisms and development of optic neuritis with or without multiple sclerosis.

BACKGROUND: Optic neuritis (ON) and multiple sclerosis (MS) are complex diseases with multifactorial pathogenesis. The role of genetic factors in the development of these diseases is hypothesized, and specific biochemical components involved in the pathogenesis of ON and MS are yet to be determined. The aim of our study was to determine the associations between IL1RAP rs4624606, IL1RL1 rs1041973, IL-6 rs1800795, and HTRA1 rs11200638 gene polymorphisms and development of ON with or without MS. MATERIALS AND METHODS: The study subjects included 80 ON patients and 146 healthy controls (HCs). Genotyping of IL1RAP rs4624606, IL1RL1 rs1041973, IL-6 rs1800795, and HTRA1 rs11200638 was performed using real-time polymerase chain reaction. RESULTS: A/C genotype of IL1RL1 rs1041973 was more frequent in ON patients than in HC subjects (p = 0.026). The IL1RL1 rs1041973 A/C genotype was associated with increased odds of ON development under the overdominant (p = 0.041) model. CONCLUSIONS: Our study showed that IL1RAP rs4624606, IL-6 rs1800795, and HTRA1 rs11200638 are not associated with an increased risk of developing ON. However, the IL1RL1 rs1041973 A/C genotype might be associated with an increased risk of developing ON.

Associations of IL6 rs1800795, BLK rs13277113, TIMP3 rs9621532, IL1RL1 rs1041973 and IL1RAP rs4624606 single gene polymorphisms with laryngeal squamous cell carcinoma.

OBJECTIVE: Survival rate of laryngeal squamous cell carcinoma (LSCC) patients is not improving. To understand more complete biology of LSCC, studies focused on identification of new specific and prognostic markers are performed. The aim of current study was to evaluate the impact of five different single nucleotide polymorphisms (SNP) (IL6 rs1800795, BLK rs13277113, TIMP3 rs9621532, IL1RL1 rs1041973 and IL1RAP rs4624606) on LSCC development. MATERIAL AND METHODS: A total of 891 subjects (353 histologically verified LSCC patients and 538 healthy controls) were involved in this study. The genotyping was carried out using the real-time-PCR. RESULTS: Statistical analysis revealed statistically significant associations between TIMP3 rs96215332 variants and LSCC in the codominant (OR = 0.600; 95% CI: 0.390-0.922; p = 0.020), overdominant (OR = 0.599; 95% CI: 0.390-0.922; p = 0.020) and additive (OR = 0.675; 95% CI: 0.459-0.991; p = 0.045) models. Also, significant variants of IL1RAP rs4624606 were determined in the codominant (OR = 1.372; 95% CI: 1.031-1.827; p = 0.030), overdominant (OR = 1.353; 95% CI: 1.018-1.798; p = 0.037) and additive (OR = 1.337; 95% CI: 1.038-1.724; p = 0.025) models. CONCLUSION: Results of the current study indicate significant associations between TIMP3 rs9621532 and IL1RAP rs4624606 gene polymorphisms and LSCC development.

Splice-dependent trans-synaptic PTPδ-IL1RAPL1 interaction regulates synapse formation and non-REM sleep.

Alternative splicing regulates trans-synaptic adhesions and synapse development, but supporting in vivo evidence is limited. PTPδ, a receptor tyrosine phosphatase adhering to multiple synaptic adhesion molecules, is associated with various neuropsychiatric disorders; however, its in vivo functions remain unclear. Here, we show that PTPδ is mainly present at excitatory presynaptic sites by endogenous PTPδ tagging. Global PTPδ deletion in mice leads to input-specific decreases in excitatory synapse development and strength. This involves tyrosine dephosphorylation and synaptic loss of IL1RAPL1, a postsynaptic partner of PTPδ requiring the PTPδ-meA splice insert for binding. Importantly, PTPδ-mutant mice lacking the PTPδ-meA insert, and thus lacking the PTPδ interaction with IL1RAPL1 but not other postsynaptic partners, recapitulate biochemical and synaptic phenotypes of global PTPδ-mutant mice. Behaviorally, both global and meA-specific PTPδ-mutant mice display abnormal sleep behavior and non-REM rhythms. Therefore, alternative splicing in PTPδ regulates excitatory synapse development and sleep by modulating a specific trans-synaptic adhesion.

Associations of IL1RAP and IL1RL1 gene polymorphisms with obesity and inflammation mediators.

OBJECTIVES: Obesity is attributable to high free fatty acids, ER stress, oxidative stress and inflammation. The expression of IL-33, IL-1RL1 and IL-1RAP gene was observed in human visceral white fats, pre-adipocytes and adipocytes. The aim of this study was to determine whether IL1RAP and IL1RL1 gene variants were associated with obesity and inflammation mediators. METHODS: 3 SNPs of IL1RAP (rs9990107, rs3836449 and rs9290936) and 11 SNPs of IL1RL1 (rs3771180, rs13431828, rs3214363, rs1420101, rs12905, rs3771175, rs3821204, rs12712142, rs10204137, rs4988958, and rs10206753) were genotyped for 175 obesity (BMI ≥ 25) and 358 non-obesity (BMI < 25.0) subjects. The genotype of SNPs was determined by the Axiom Genome-Wide Human Assay. RESULTS: The allele and genotype frequencies of 2 SNPs in the IL1RAP gene (rs9990107 and rs3836449) and 11 SNPs in the IL1RL1 gene (rs3771180, rs13431828, rs3214363, rs1420101, rs12905, rs3771175, rs3821204, rs12712142, rs10204137, rs4988958 and rs10206753) were significantly associated between the obesity and non-obesity groups. The two haplotypes (GCTTATGAATT and TT-CGACCGCC) in block1 were associated with obesity. In the non-obesity group, genotype frequencies of rs3771180, rs13431828, rs3214363, rs10204137, rs4988958 and rs10206753 SNPs of IL1RL1 showed significant differences in the dominant models in lymphatic cell percentage. The genotype frequencies of rs1420101, rs21905, rs3821024 and rs12712142 SNPs of IL1RL1 showed significant differences in the dominant models in eosinophil percentage. CONCLUSIONS: Our results suggest that IL1RAP and IL1RL1 gene polymorphisms may be associated with obesity and inflammation mediators.

Biallelic variants/mutations of IL1RAP in patients with steroid-sensitive nephrotic syndrome.

Nephrotic syndrome (NS) is a renal disease characterized by severe proteinuria and hypoproteinemia. Although several single-gene mutations have been associated with steroid-resistant NS, causative genes for steroid-sensitive NS (SSNS) have not been clarified. While seeking to identify causative genes associated with SSNS by whole-exome sequencing, we found compound heterozygous variants/mutations (c.524T>C; p.I175T and c.662G>A; p.R221H) of the interleukin-1 receptor accessory protein (IL1RAP) gene in two siblings with SSNS. The siblings' parents are healthy, and each parent carries a different heterozygous IL1RAP variant/mutation. Since IL1RAP is a critical subunit of the functional interleukin-1 receptor (IL-1R), we investigated the effect of these variants on IL-1R subunit function. When stimulated with IL-1ß, peripheral blood mononuclear cells from the siblings with SSNS produced markedly lower levels of cytokines compared with cells from healthy family members. Moreover, IL-1R with a variant IL1RAP subunit, reconstituted on a hematopoietic cell line, had impaired binding ability and low reactivity to IL-1ß. Thus, the amino acid substitutions in IL1RAP found in these NS patients are dysfunctional variants/mutations. Furthermore, in the kidney of Il1rap-/- mice, the number of myeloid-derived suppressor cells, which require IL-1ß for their differentiation, was markedly reduced although these mice did not show significantly increased proteinuria in acute nephrotic injury with lipopolysaccharide treatment. Together, these results identify two IL1RAP variants/mutations in humans for the first time and suggest that IL1RAP might be a causative gene for familial NS.

IL-38 Ameliorates Skin Inflammation and Limits IL-17 Production from γδ T Cells.

Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptors remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. We report an investigation in cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38 knockout (IL-38 KO) mice show delayed disease resolution with exacerbated IL-17-mediated inflammation, which is reversed by the administration of mature IL-38 or γδ T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon γδ T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress γδ T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by γδ T cells. Our findings indicate a role for IL-38 in the regulation of γδ T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease.

Different attentional dysfunctions in eEF2K-/- , IL1RAPL1-/- and SHANK3Δ11-/- mice.

A common feature of several psychiatric disorders is the attentional impairment. eEF2K -/- , IL1RAPL1 -/- and SHANK3Δ11 -/- mice were used as animal models consistently linked to changes in synaptic plasticity, learning and memory. All knockout (KO) mice and their corresponding littermates were submitted to the novel object recognition (NOR) and visual object recognition (VOR) tasks. In the NOR, eEF2K-/- mice exhibited a normal performance in terms of mean discrimination index, while SHANK3Δ11-/- and IL1RAPL1 -/- mice were impaired when a delay of 2 and 24 hours was introduced. Surprisingly, when submitted to VOR, where the two objects were replaced with two shapes delivered from two iPods, all the mutant mice performed worse than those in the NOR. In VOR, the application of motion to different shapes, to increase attention, improved performance in eEF2K -/- and IL1RAPL1 -/- but not in SHANK3Δ11 -/- mice. In SHANK3Δ11 -/- mice, attentional deficit was also present even if different motions were applied to the same shapes or when these mice were repeatedly exposed for 5 days to the context. Behavioral analysis showed that eEF2K-/- and IL1RAPL1 -/- mice had a good flexibility tested in the T-maze. eEF2K-/- showed normal self-grooming. On the basis of previous literature data indicating that SHANK3Δ11 -/- showed impaired flexibility and reduced sociability, we identified in this genotype the most exhaustive model showing all the core symptoms of autism spectrum disorder including a heavy visual attention deficit. These findings show the importance of VOR to identify mouse models of autism.

Association of IL1RAP-related genetic variation with cerebrospinal fluid concentration of Alzheimer-associated tau protein.

A possible involvement of the gene IL1RAP (interleukin-1 receptor-associated protein) in the pathogenesis of Alzheimer's disease (AD) has been suggested in GWASs of cerebrospinal fluid (CSF) tau levels and longitudinal change in brain amyloid burden. The aim of this study was to examine previously implicated genetic markers in and near IL1RAP in relation to AD risk, CSF tau and Aß biomarkers, as well as cognitive decline, in a case (AD)-control study and an age homogenous population-based cohort. Genotyping of IL1RAP-related single nucleotide polymorphisms (SNPs), selected based on previous GWAS results, was performed. 3446 individuals (1154 AD cases and 2292 controls) were included in the analyses of AD risk, 1400 individuals (cognitively normal = 747, AD = 653) in the CSF biomarker analyses, and 861 individuals in the analyses of cognitive decline. We found no relation between IL1RAP-related SNPs and AD risk. However, CSF total-tau and phospho-tau were associated with the SNP rs9877502 (p = 6 × 10-3 and p = 5 × 10-4). Further, nominal associations (p = 0.03-0.05) were found between three other SNPs and CSF biomarker levels, or levels of cognitive performance and decline in a sub-sample from the general population. These results support previous studies suggesting an association of IL1RAP with disease intensity of AD.