Variants of the <i>IFI16</i> Gene Affecting the Levels of Expression of mRNA Are Associated with Susceptibility to Behçet Disease

Ortiz-Fernández, Lourdes; García‐Lozano, José‐Raúl; Montes-Cano, Marco-Antonio; Conde-Jaldón, Marta; Ortego-Centeno, Norbérto; García-Hernández, Francisco-José; Espinosa, Gerard; Gil, Jenaro Graña; Sánchez‐Bursón, Juan; Blanco, Ricardo; Barnosi-Marín, Ana-Celia; Solans, Roser; Fanlo, P.; Rodríguez-Carballeira, Mónica; Camps, Teresa; Castañeda, Santos; Núñez‐Roldán, Antonio; Martín, Javier; González-Escribano, Marı́a-Francisca

doi:10.3899/jrheum.140949

Cited by 20 publications

(17 citation statements)

References 36 publications

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“…These results are in support of the current data and the concept that changes in the innate immune functions can alter the host response and facilitate development of diseases. A recent study found that IFI16 rs6940 (also identified in this study) and AIM2 rs855873 (also upstream of AIM2 ) were associated with increased susceptibility to Behçet disease, a systemic immune‐mediated disease characterized by vasculitis and recurrent mucosal ulcerations 41 . The study shows rs6940 decreases expression of anti‐inflammatory IFI16 and increases susceptibility to an immune‐mediated disease 41 .…”

Section: Discussionsupporting

confidence: 71%

“…A recent study found that IFI16 rs6940 (also identified in this study) and AIM2 rs855873 (also upstream of AIM2 ) were associated with increased susceptibility to Behçet disease, a systemic immune‐mediated disease characterized by vasculitis and recurrent mucosal ulcerations 41 . The study shows rs6940 decreases expression of anti‐inflammatory IFI16 and increases susceptibility to an immune‐mediated disease 41 . The fact that Behçet is associated with epithelial ulceration and the present results show associations of these SNPs with BOP suggests that these variants may impair innate immune responses that maintain epithelial integrity at mucosal surfaces.…”

Section: Discussionsupporting

confidence: 64%

“…SNP rs6940 is predicted to alter only isoform 3, which is probably related to the different sizes of the isoforms. A previous study suggests that instead of protein function, SNP IFI16 rs6940 decreases expression of IFI16 41 . It is possible that additional SNPs in high linkage disequilibrium with rs6940 are leading to this effect.…”

Section: Discussionmentioning

confidence: 96%

“…It is possible that additional SNPs in high linkage disequilibrium with rs6940 are leading to this effect. However, no functional assays were performed in the study 41 . Because the SNP associated with AIM2 is not present in a missense region, predictions for potential alterations could not be performed.…”

Section: Discussionmentioning

confidence: 99%

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Common Polymorphisms in IFI16 and AIM2 Genes Are Associated With Periodontal Disease

Marchesan

Jiao

Moss

et al. 2017

Journal of Periodontology

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Background We investigated the single nucleotide polymorphism (SNP) context of a previously identified periodontitis-associated locus and examined its association with microbial, biological and periodontal disease clinical parameters. Methods We annotated a 200Kb-spanning region of 1q12 previously highlighted in a genome-wide association scan among 4,910 European American individuals (SNP rs1633266). Two haplotype blocks were selected. We examined the association of these polymorphisms with data on microbial plaque composition, gingival crevicular fluid (GCF)-interleukin (IL)-1β levels and clinical parameters of periodontal disease. Descriptive analysis of IFI16 and AIM2 protein expression in gingival tissues from healthy (n=2) and chronic periodontitis individuals (n=2) was done via immunohistochemistry. Results The highlighted locus is a 100Kb region containing the interferon gamma-inducible protein 16 (IFI16) and absent in melanoma 2 (AIM2) genes. Two haplotype blocks rs6940 and rs1057028 were significantly associated with increased extent bleeding on probing and levels of microorganisms Porphyromonas gingivalis, Tannerella forsythia and Campylobacter rectus (p≤0.05). Haplotype block rs1057028 was also significantly associated with pathogens Fusobacterium nucleatum and Aggregatibacter actinomycetemcomitans, increased GCF-IL-1β levels and extent of probing depth≥4mm (p≤0.05). Prevalence of severe periodontitis (biofilm-gingival interface-P3 classification) was positively associated with haplotype block rs1057028. Similar trends were observed for haplotype block rs1057028. IFI16 and AIM2 protein expression was observed in multiple cell types of gingival tissues, including inflammatory cells. Conclusion This study found IFI16 and AIM2 SNPs associated with higher levels periodontal microorganisms and increased percentage of periodontal disease clinical parameters, suggesting the need for functional studies and additional fine-mapping of variants in the 1q12-locus.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Common Polymorphisms in IFI16 and AIM2 Genes Are Associated With Periodontal Disease

Marchesan

Jiao

Moss

et al. 2017

Journal of Periodontology

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“…In one study conducted with 371 patients with BD, an association was found between the disease and the IFI16 single nucleotide polymorphism, a mediator of the AIM2-inflammasome pathway. 64 Four mutations of the NLRP3/cryopyrin gene were identified in a study conducted with 50 cases of BD. 65 However, another study was unable to demonstrate a greater activation of caspase-1 through the inflammasome pathway in dendritic cells and neutrophils of sick patients, as compared to the controls.…”

Section: Dermatological Diseases Associated With Inflammasomesmentioning

confidence: 99%

Inflammasomes and dermatology

Sá

Neto

2016

An. Bras. Dermatol.

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Inflammasomes are intracellular multiprotein complexes that comprise part of the innate immune response. Since their definition, inflammasome disorders have been linked to an increasing number of diseases. Autoinflammatory diseases refer to disorders in which local factors lead to the activation of innate immune cells, causing tissue damage when in the absence of autoantigens and autoantibodies. Skin symptoms include the main features of monogenic inflammasomopathies, such as Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF), Schnitzler Syndrome, Hyper-IgD Syndrome (HIDS), PAPA Syndrome, and Deficiency of IL-1 Receptor Antagonist (DIRA). Concepts from other pathologies have also been reviewed in recent years, such as psoriasis, after the recognition of a combined contribution of innate and adaptive immunity in its pathogenesis. Inflammasomes are also involved in the response to various infections, malignancies, such as melanoma, autoimmune diseases, including vitiligo and lupus erythematosus, atopic and contact dermatitis, acne, hidradenitis suppurativa, among others. Inhibition of the inflammasome pathway may be a target for future therapies, as already occurs in the handling of CAPS, through the introduction of IL-1 inhibitors. This study presents a literature review focusing on the participation of inflammasomes in skin diseases.

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Innate immune inflammatory cell death: PANoptosis and PANoptosomes in host defense and disease

et al. 2023

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Regulated cell death (RCD) triggered by innate immune activation is an important strategy for host survival during pathogen invasion and perturbations of cellular homeostasis. There are two main categories of RCD, including nonlytic and lytic pathways. Apoptosis is the most well‐characterized nonlytic RCD, and the inflammatory pyroptosis and necroptosis pathways are among the best known lytic forms. While these were historically viewed as independent RCD pathways, extensive evidence of cross‐talk among their molecular components created a knowledge gap in our mechanistic understanding of RCD and innate immune pathway components, which led to the identification of PANoptosis. PANoptosis is a unique innate immune inflammatory RCD pathway that is regulated by PANoptosome complexes upon sensing pathogens, pathogen‐associated molecular patterns (PAMPs), damage‐associated molecular patterns (DAMPs) or the cytokines produced downstream. Cytosolic innate immune sensors and regulators, such as ZBP1, AIM2 and RIPK1, promote the assembly of PANoptosomes to drive PANoptosis. In this review, we discuss the molecular components of the known PANoptosomes and highlight the mechanisms of PANoptosome assembly, activation and regulation identified to date. We also discuss how PANoptosomes and mutations in PANoptosome components are linked to diseases. Given the impact of RCD, and PANoptosis specifically, across the disease spectrum, improved understanding of PANoptosomes and their regulation will be critical for identifying new therapeutic targets and strategies.

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Variants of the IFI16 Gene Affecting the Levels of Expression of mRNA Are Associated with Susceptibility to Behçet Disease

Abstract: Our findings suggest association of IFI16, a cytosolic sensor of dsDNA and mediator of the AIM2 inflammasome-dependent pathway, in susceptibility to BD. Differences genetically determined in the levels of this molecule could be the cause of this association.

Cited by 20 publications

References 36 publications

Common Polymorphisms in IFI16 and AIM2 Genes Are Associated With Periodontal Disease

Common Polymorphisms in IFI16 and AIM2 Genes Are Associated With Periodontal Disease

Inflammasomes and dermatology

Innate immune inflammatory cell death: PANoptosis and PANoptosomes in host defense and disease

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