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Multi-tissue eQTL analyses for rs2205986 and IRF6 from the GTEx Project m values represent the posterior probability for an eQTL effect (PLoS Genet. 8, e1002555, 2012), and tissues with values > 0.9 (i.e., cerebellum, tibial nerve, aorta, cerebellar hemisphere, whole blood and frontal cortex) are predicted to be eQTLs.
Source publication
Multiple sclerosis (MS) is a disease of the central nervous system treated with disease-modifying therapies, including the biologic, interferon-β (IFN-β). Up to 60% of IFN-β-exposed MS patients develop abnormal biochemical liver test results1,2, and 1 in 50 experiences drug-induced liver injury3. Since genomic variation contributes to other forms o...
Citations
... Analyses were performed for pediatric and adult patients separately and combined. A threshold of P < 5 × 10 −8 was considered statistically significant, and P < 1 × 10 −6 was considered suggestive of significance, as previously described (48). The R package ggplot2 (version 3.2.0) ...
Objective
Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) is a rare, life‐threatening inflammation of blood vessels that can affect both adults and children. Compared to adult‐onset disease, AAV is especially rare in children, with an annual prevalence of 0.5–6.4 cases per million children. The etiology of AAV remains largely unknown, and both environmental and genetic factors are likely involved. The present study was undertaken to explore the genetic susceptibility factors recently identified in adult patients, including HLA–DP and HLA–DQ, in pediatric patients.
Methods
We performed a genome‐wide association study of pediatric AAV in patients of European ancestry (n = 63 AAV cases, n = 315 population‐matched controls).
Results
We identified a significant genetic association between pediatric AAV and the HLA–DPB1*04:01 allele (P = 1.5 × 10⁻⁸, odds ratio [OR] 3.5), with a stronger association observed in children with proteinase 3–ANCA positivity than in children with myeloperoxidase−ANCA positivity. Among the HLA alleles, the HLA–DPB1*04:01 allele was the most highly associated with AAV, although not significantly, in a follow‐up adult AAV cohort (P = 2.6 × 10⁻⁴, OR 0.4). T cell receptor and interferon signaling pathways were also shown to be enriched in the pediatric AAV cohort.
Conclusion
The HLA–DPB1 locus showed an association with pediatric AAV, as similarly shown previously in adult AAV. Despite the difference in the age of onset, these findings suggest that childhood‐ and adult‐onset vasculitis share a common genetic predisposition. The identification of genetic variants contributing to AAV is an important step to improved classification tools and treatment strategies.
... Notably, the gene most significantly overexpressed in the adipose tissue NEB group (log2FC = −10.4) is IRF6, which belongs to the interferon regulatory transcription factor (IRF) [82]. It is linked to liver damage [83] and obesity-related metabolic and immunological homeostasis [84,85]. In addition, increased expression of IRF6 in adipose and liver may be related to the inflammatory tissue damage caused by severe NEB [81]. ...
Negative energy balance (NEB) during the perinatal period leads to metabolic and immunological disorders in dairy cows, resulting in systemic responses and inflammation. The innate immune system is crucial for the host’s protection and inflammatory response. However, systematic research is still lacking on how NEB affects the innate immune system to alter the ’host defense capability and inflammatory response. In this investigation, raw transcriptome data of adipose, blood, endometrial, hypothalamus, and liver tissues were downloaded from a public database, cleaned, aligned, quantified, and batch-corrected. The innate immune gene list was retrieved from innateDB, followed by the expression matrix of innate immune genes in various tissues for differential expression analysis, principle component analysis (PCA), and gene set enrichment analysis (GSEA). Under the effect of NEB, adipose tissue had the most differentially expressed genes, which were predominantly up-regulated, whereas blood GSEA had the most enriched biological processes, which were predominantly down-regulated. The gene sets shared by different tissues, which are predominantly involved in biological processes associated with defense responses and inflammation, were dramatically down-regulated in endometrial tissues and highly up-regulated in other tissues. Under the impact of NEB, LBP, PTX3, S100A12, and LCN2 play essential roles in metabolism and immunological control. In conclusion, NEB can downregulate the defensive response of innate immune genes in endometrial, upregulate the immune and inflammatory response of other tissues, activate the host defense response, and increase the systemic inflammatory response. The analysis of the effects of NEB on innate immune genes from the multiple tissues analysis provides new insights into the crosstalk between metabolism and immunity and also provides potential molecular targets for disease diagnosis and disease resistance breeding in dairy cows.
... As suggested recently, a combined Note: Based on >15 cases available for study but no detectable significant signal in HLA region. 7,11,12,16 Abbreviation: DILI, drug-induced liver injury. polygenic risk score involving the two HLA alleles associated with amoxicillin-clavulanate DILI together with the PTPN22 and ERAP2 variants may be a useful predictor of susceptibility to this adverse reaction or at least useful as a diagnostic tool. ...
... polygenic risk score involving the two HLA alleles associated with amoxicillin-clavulanate DILI together with the PTPN22 and ERAP2 variants may be a useful predictor of susceptibility to this adverse reaction or at least useful as a diagnostic tool. 10 In a separate GWAS concerned entirely with DILI induced by interferon beta, a genomewide significant signal was detected for an apparently functionally significant polymorphism close to the gene IRF6 (interferon regulatory factor 6). 11 This association has not been observed for DILI induced by other drugs and it seems likely to be specific for interferon in view of the direct biological association. ...
Idiosyncratic drug‐induced liver injury (DILI) remains an important clinical problem, both during drug development and the prescription of a range of licensed drugs. Although rare, the consequences are serious. Ongoing studies on genetic risk factors for DILI, especially genomewide association studies, have resulted in the identification of a number of genetic risk factors, including particular HLA alleles and a few non‐HLA genes, both immune‐related and metabolic. Some non‐HLA associations, such as N‐acetyltransferase 2 in isoniazid DILI and interferon regulatory factor 6 in interferon‐beta DILI are likely to be drug‐specific due to the role of the associated gene, but there is also evidence for polygenic susceptibility involving pathways such as oxidative and endoplasmic reticulum stress and mitochondrial function for DILI induced by multiple drugs. Increased knowledge of genetic risk factors should assist in better understanding underlying DILI mechanisms and help improve methods for identifying hepatotoxic drugs early in development. HLA allele‐specific T cell proliferation together with in silico prediction of drug binding to specific HLA proteins have confirmed genetic findings for certain common causes of DILI. However, studies in hepatocytes exposed to high drug concentrations suggest toxicity that is not dependent on genotype also occurs. It seems likely that susceptibility to DILI involves several genetic risk factors combining with other factors that affect drug levels. Despite recent progress in detecting genetic risk factors for DILI, low positive predictive values mean that general implementation of genotyping prior to prescription of potentially hepatotoxic drugs is not useful currently.
... Several IRF members e.g. IRF-1, IRF-6, IRF-7 and IRF-8 are able to increase the expression of some pro-inflammatory cytokines and chemokines, and closely related to inflammatory diseases [38][39][40][41][42][43][44][45]. For example, upregulated IRF-1 promotes liver ischemia/reperfusion injury after transplant, and the mechanism involves in elevating IL-15/IL-15Rα production in hepatocytes and accumulation of NK, NKT, and CD8 + T cells in liver tissues [43]. ...
Mesangioproliferative glomerulonephritis (MsPGN) is a common human kidney disease. Rat Thy-1 nephritis (Thy-1N) is an animal model widely used for the study of MsPGN. Thy-1N is not only sublytic C5b-9-dependent, but also related to pro-inflammatory cytokine production and macrophage (Mφ) accumulation in rat renal tissues. In this study, we found that the expression or phosphorylation of chemokine CCL3/4, CD68 (Mφ marker), IRF-8, PKC-α and NF-κB-p65 (p65) were all up-regulated both in the renal tissues of Thy-1N rats (in vivo) and in the glomerular mesangial cells (GMCs) upon sublytic C5b-9 stimulation (in vitro). Further experiments in vitro revealed that the phosphorylated PKC-α (p-PKC-α) could promote p65 phosphorylation, and then p-p65 enhanced IRF-8 expression through binding to IRF-8 promotor (-591 ~ -582 nt and -299 ~ -290 nt). Additionally, up-regulation or silencing of IRF-8 gene promoted or reduced CCL3/4 production, and then regulated Mφ chemotaxis. The underlying mechanism involved in IRF-8 binding to CCL3 promoter (-249 ~ -236 nt), which resulted in CCL3 gene transcription. The experiments in vivo showed that knockdown of renal PKC-α, p65, IRF-8 and CCL3/4 genes could inhibit CCL3/4 production, Mφ accumulation, GMC proliferation and proteinuria of Thy-1N rats. Furthermore, p-PKC-α, p-p65, IRF-8, CCL3/4 expression and Mφ accumulation were also increased in the renal tissues of MsPGN patients. Collectively, these findings indicate that sublytic C5b-9 induces CCL3/4 production and Mφ accumulation via PKC-α/p65/IRF-8 axis, and finally aggravates the pathological changes of MsPGN.
... The rs2205986 variant near IRF6 was associated with IFN-β-induced liver injury in patients with multiple sclerosis [88]. IRF7 was downregulated in patients with cytomegalovirus (CMV) infection and late-stage liver fibrosis, compared with that in CMVnegative patients [89]. ...
Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease with many metabolic comorbidities, such as obesity, diabetes, and cardiovascular diseases. Non-alcoholic steatohepatitis (NASH), an advanced form of NAFLD, accompanies the progression of hepatic steatosis, inflammation, cell death, and varying degree of liver fibrosis. Interferons (IFNs) have been shown to play important roles in the pathogenesis of NAFLD and NASH. Their regulating transcriptional factors such as interferon regulatory factors (IRFs) can regulate IFN expression, as well as genes involved in macrophage polarization, which are implicated in the pathogenesis of NAFLD and advanced liver disease. In this review, the roles of IRF-involved signaling pathways in hepatic inflammation, insulin resistance, and immune cell activation are reviewed. IRFs such as IRF1 and IRF4 are also involved in the polarization of macrophages that contribute to critical roles in NAFLD or NASH pathogenesis. In addition, IRFs have been shown to be regulated by treatments including microRNAs, PPAR modulators, anti-inflammatory agents, and TLR agonists or antagonists. Modulating IRF-mediated factors through these treatments in chronic liver disease can ameliorate the progression of NAFLD to NASH. Furthermore, adenoviruses and CRISPR activation plasmids can also be applied to regulate IRF-mediated effects in chronic liver disease. Pre-clinical and clinical trials for evaluating IRF regulators in NAFLD treatment are essential in the future direction.
... Apart from monitoring liver enzymes during treatment, pharmacogenomic testing might prevent drug-induced liver injury in at-risk patients. In fact, Kowalec et al. have identified an association between rs2205986 and IFN-β-induced liver injury (Kowalec, et al., 2018). rs2205986 is an intronic synaptotagmin-14 (SYT14) variant as well as an expression quantitative trait locus (eQTL) for the interferon regulatory factor 6 (IRF6) gene (Kowalec, et al., 2018). ...
... In fact, Kowalec et al. have identified an association between rs2205986 and IFN-β-induced liver injury (Kowalec, et al., 2018). rs2205986 is an intronic synaptotagmin-14 (SYT14) variant as well as an expression quantitative trait locus (eQTL) for the interferon regulatory factor 6 (IRF6) gene (Kowalec, et al., 2018). ...
... These numbers are of a significant lower order of magnitude than in the discovery phase of the latest IMSGC susceptibility GWAS, i.e. 14,802 MS cases and 26,703 controls (International Multiple Sclerosis Genetics Consortium, 2019), and highlight the need for large (longitudinal) cohorts with deep phenotyping. (Mero, et al., 2013) Discovery (Buck, et al., 2013) Discovery: (Gasperi, et al., 2020) Nonresponse to IFN-β treatment (Esposito, et al., 2015b) Discovery (Kowalec, et al., 2018 Disease severity: structural retinal thinning using optical coherence tomography (Fitzgerald, et al., 2019) Discovery: 374 MS Replication: 376 MS SNP rs2497800*T near SLC39A12 associated with faster rates of GCIP atrophy Additive difference in rate of GCIP: -0.08 (95% CI = -0.11, -0.06), P = 2.65 × 10 -8 in discovery cohort Disease severity: sustained loss of 5-letters in low-contrast letter acuity (Fitzgerald, et al., 2019) Discovery: 582 MS Replication: 253 MS SNP rs72830848*T in MSI2 associated with risk of LCLA changes: HR = 2.25 (95% CI = 1.78-2.85), ...
... While IRF4 competes with IRF5 to downregulate the expression of proinflammatory cytokines rather than IFNs in macrophages (19), it still displays a weak binding affinity to ISRE/IRF-E motifs (12). Recent studies have linked IRF6 to IFNb-induced liver injury (20) and its inhibitory role in poly(I:C)-triggered IFN promoter activation. ...
Interferon regulatory factors (IRFs) constitute a family of transcription factors that synchronize interferon (IFN) antiviral response through translocating to nucleus and binding to the promoters of IFN and IFN-stimulated genes (ISGs). Fish contain 11 IRF members; however, whether or how fish IRF family genes function in IFN response remains limited. Herein, we determine the regulatory roles of 11 zebrafish IRF family members in IFN response relevant to their subcellular localization and promoter binding. Zebrafish IRF family members display three patterns of constitutive localization, only in nucleus (IRF1/2/9/11), only in cytoplasm (IRF3/5/7), and largely in nucleus with small amounts in cytoplasm (IRF4b/6/8/10). DNA pull-down assays confirm that all zebrafish IRF proteins are capable to bind fish IFN promoters, albeit to various degrees, thus regulating IFN gene transcription as activators (IRF1/3/5/6/7/8/9/11) or repressors (IRF2/4b/10). Further characterization of distinct IFN gene activation reveals that IRF1/3/5/6/7/8/9/11 efficiently stimulate zebrafish IFNφ1 expression, and IRF1/7/11 are responsible for zebrafish IFNφ3 expression. Two conserved basic residues within the helix α3 of DNA binding domains (DBDs) contribute to constitutive or inducible nuclear import for all zebrafish IRF family members and DNA binding for most members, thereby enabling them to function as transcription factors. Our results reveal a conserved and general mechanism that specifies zebrafish IRF family proteins to nuclear import and DNA binding, thereby regulating fish IFN response.
... p = 2.3 × 10 -8 ). The results were subsequently confirmed in an independent cohort study of patients with multiple sclerosis in which liver injury was proved with significantly increased aspartate aminotransferase and alkaline phosphatase concentrations for those who carried IRF6 genetic variants (Kowalec et al., 2018;Takahashi et al., 2020). , 2016, 2018). ...
Many drugs are being administered to tackle coronavirus disease 2019 (COVID-19) pandemic situations without establishing clinical effectiveness or tailoring safety. A repurposing strategy might be more effective and successful if pharmacogenetic interventions are being considered in future clinical studies/trials. Although it is very unlikely that there are almost no pharmacogenetic data for COVID-19 drugs, however, from inferring the pharmacokinetic (PK)/pharmacodynamic(PD) properties and some pharmacogenetic evidence in other diseases/clinical conditions, it is highly likely that pharmacogenetic associations are also feasible in at least some COVID-19 drugs. We strongly mandate to undertake a pharmacogenetic assessment for at least these drug–gene pairs (atazanavir– UGT1A1 , ABCB1 , SLCO1B1 , APOA5 ; efavirenz– CYP2B6 ; nevirapine– HLA , CYP2B6 , ABCB1 ; lopinavir– SLCO1B3 , ABCC2 ; ribavirin– SLC28A2 ; tocilizumab– FCGR3A ; ivermectin– ABCB1 ; oseltamivir– CES1 , ABCB1 ; clopidogrel– CYP2C19 , ABCB1 , warfarin– CYP2C9 , VKORC1 ; non-steroidal anti-inflammatory drugs (NSAIDs)– CYP2C9 ) in COVID-19 patients for advancing precision medicine. Molecular docking and computational studies are promising to achieve new therapeutics against SARS-CoV-2 infection. The current situation in the discovery of anti-SARS-CoV-2 agents at four important targets from in silico studies has been described and summarized in this review. Although natural occurring compounds from different herbs against SARS-CoV-2 infection are favorable, however, accurate experimental investigation of these compounds is warranted to provide insightful information. Moreover, clinical considerations of drug–drug interactions (DDIs) and drug–herb interactions (DHIs) of the existing repurposed drugs along with pharmacogenetic (e.g., efavirenz and CYP2B6 ) and herbogenetic (e.g., andrographolide and CYP2C9 ) interventions, collectively called multifactorial drug–gene interactions (DGIs), may further accelerate the development of precision COVID-19 therapies in the real-world clinical settings.
... Most genetic associations with the risk of IDILI development have been related to HLA polymorphisms (Kaliyaperumal et al., 2018). In some cases, other associations have been found, such as an association with an IL-10-low producing phenotype that correlated with an absence of peripheral eosinophilia and more severe liver injury (Pachkoria et al., 2008), an association between increased risk of IDILI with a genetic variant linked to differential expression of interferon regulatory factor-6 in the context of interferon (IFN)-b treatment in multiple sclerosis (Kowalec et al., 2018), and an association between increased risk of IDILI and a missense variant of the gene encoding protein tyrosine phosphatase, nonreceptor type 22 gene (Cirulli et al., 2019). ...
Idiosyncratic drug reactions (IDRs) range from relatively common, mild reactions to rarer, potentially life-threatening adverse effects that pose significant risks to both human health and successful drug discovery. Most frequently, IDRs target the liver, skin, and blood or bone marrow. Clinical data indicate that most IDRs are mediated by an adaptive immune response against drug-modified proteins, formed when chemically reactive species of a drug bind to self-proteins, making them appear foreign to the immune system. Although much emphasis has been placed on characterizing the clinical presentation of IDRs and noting implicated drugs, limited research has focused on the mechanisms preceding the manifestations of these severe responses. Therefore, we propose that to address the knowledge gap between drug administration and onset of a severe IDR, more research is required to understand IDR-initiating mechanisms; namely, the role of the innate immune response. In this review, we outline the immune processes involved from neoantigen formation to the result of the formation of the immunologic synapse and suggest that this framework be applied to IDR research. Using four drugs associated with severe IDRs as examples (amoxicillin, amodiaquine, clozapine, and nevirapine), we also summarize clinical and animal model data that are supportive of an early innate immune response. Finally, we discuss how understanding the early steps in innate immune activation in the development of an adaptive IDR will be fundamental in risk assessment during drug development. SIGNIFICANCE STATEMENT: Although there is some understanding that certain adaptive immune mechanisms are involved in the development of idiosyncratic drug reactions, the early phase of these immune responses remains largely uncharacterized. The presented framework refocuses the investigation of IDR pathogenesis from severe clinical manifestations to the initiating innate immune mechanisms that, in contrast, may be quite mild or clinically silent. A comprehensive understanding of these early influences on IDR onset is crucial for accurate risk prediction, IDR prevention, and therapeutic intervention.
... IRF6 related disorders span a spectrum from cleft lip and Van der Woude syndrome (VWS) to popliteal pterygium syndrome (PPS) at the more severe end [55]. Although bioinformatic analysis revealed that IRF6 is a potential biomarker for SLE and variation near IRF6 gene is associated with IFN-β induced liver injury in multiple sclerosis [56,57], the exact biological meaning of IRF6 and its role in IBD is largely elusive. ...
Inflammatory bowel disease (IBD) is an autoimmune disease characterized by unresolved colitis and epithelial injury. Intestinal microbiota and its interaction with immune system are critical etiologic factors. In response to gut virome and bacteria derived nucleic acid, interferon regulatory factors (IRFs) are activated to promote the production of cytokines, including type I interferons (IFN-Is), to help maintain intestinal homeostasis under both physiological and pathophysiological conditions. However, derailed IRF/IFN-I pathway other-wisely contributes to the progression of IBD with distinct IRF member exerting differential regulatory effect. Here, we summarize the recent advances regarding the role of IRF/IFN-I pathway in the development of IBD. We emphasize that IFN-I is a double-edged sword in IBD pathogenesis, as IFN-Is are protective in acute colitis while becoming pro-inflammatory during the chronic recovery phase. Besides, the functional outcome of IRFs is diverse and complex, which hinges on the cell types affected and the presence of other immune mediators. All in all, IRF/IFN-I pathway serves as a versatile regulator in IBD pathogenesis and holds the potential for therapeutic interventions.
