Causal associations between estradiol and mouth ulcers: A Mendelian randomization study.

People have difficulty in eating and speaking when they are suffering from mouth ulcers. Some studies suggest that estradiol is associated with the development and treatment of mouth ulcers, while some do not. To clarify the effect of estradiol on mouth ulcers, we performed 2-sample Mendelian randomization and multivariable Mendelian randomization (MVMR) analysis to evaluate their relationship. Data were obtained from the IEU OpenGWAS project and UK biobank, including male estradiol dataset (case/controls = 13,367/134,323), female estradiol dataset (case/controls = 37,461/126,524), mouth ulcers dataset (case/controls = 47,102/414,011). The causal associations were estimated by MR-Egger, weighted median, inverse-variance weighted (IVW) method, simple mode, and weighted mode. Cochran Q test, MR-Egger intercept test, MR-PRESSO tests, and leave-one-out analysis were used to examine sensitivity analyses. The MVMR controlling for depression, anxiety or panic attacks, severe stress and adjustment disorders was used to assess the effect of estradiol on mouth ulcers. Through screening, 13 single nucleotide polymorphisms (SNPs) of males and 2 SNPs of females in estradiol were used for harmonizing and MR analysis. The 2-sample MR analysis showed no causal association between estradiol of males and mouth ulcers (IVW, OR: 0.998, 95% confidence interval [95% CI]: 0.995-1.001, P = .18). Similar results were obtained between estradiol of females and mouth ulcers (IVW, OR: 1.000, 95% CI: 0.988-1.012, P = .97). No pleiotropy and heterogeneity were found and the results were robust (P > .05). After adjusting for the potential effects of confounders, estradiol of males and mouth ulcers still showed no causal association through MVMR analysis (P = .081). While MVMR analysis showed that the causal relationship between estradiol and mouth ulcers in women could not be statistical for the small number of SNPs. There was no evidence of a causal relationship between estradiol and mouth ulcers. The strategy of treating mouth ulcers with estradiol still needs to be confirmed by more studies.

Identification of the causal relationship between sleep quality, insomnia, and oral ulcers.

BACKGROUND: Multiple epidemiological studies have posited a potential association between sleep quality and the risk of oral diseases, yet the resulting conclusions have remained contentious, and the presence of a causal link remains equivocal. In this study, we aimed to investigate the causal relationship between sleep duration, insomnia, and common oral diseases. METHODS: We utilized genetic correlation and two-sample Mendelian randomization analyses based on summary statistics from genome-wide association studies of sleep duration (N = 460,099), insomnia (N = 462,341), mouth ulcer (N = 385,026), oral cavity cancer (N = 4,151), and periodontal disease (N = 527,652). RESULTS: Our results revealed a negative genetic correlation between sleep duration and mouth ulcer (genetic correlation: -0.09, P = 0.007), while a positive genetic correlation between insomnia and mouth ulcer was observed (genetic correlation: 0.18, P = 2.51E-06). Furthermore, we demonstrated that longer sleep duration is significantly associated with a reduced risk of mouth ulcers (OR: 0.67, 95% CI: 0.54-0.83, P = 2.84E-04), whereas insomnia is nominally associated with an increased risk of mouth ulcers (OR: 1.40, 95% CI: 1.01-1.95, P = 0.044). In contrast, no significant association was detected between sleep quality and periodontal disease or oral cavity cancer. CONCLUSIONS: This work provides robust evidence to support the notion that enhanced sleep quality may confer a decreased risk of oral ulcers, thereby bearing considerable clinical relevance.

Integrating GWAS and proteome data to identify novel drug targets for MU.

Mouth ulcers have been associated with numerous loci in genome wide association studies (GWAS). Nonetheless, it remains unclear what mechanisms are involved in the pathogenesis of mouth ulcers at these loci, as well as what the most effective ulcer drugs are. Thus, we aimed to screen hub genes responsible for mouth ulcer pathogenesis. We conducted an imputed/in-silico proteome-wide association study to discover candidate genes that impact the development of mouth ulcers and affect the expression and concentration of associated proteins in the bloodstream. The integrative analysis revealed that 35 genes play a significant role in the development of mouth ulcers, both in terms of their protein and transcriptional levels. Following this analysis, the researchers identified 6 key genes, namely BTN3A3, IL12B, BPI, FAM213A, PLXNB2, and IL22RA2, which were related to the onset of mouth ulcers. By combining with multidimensional data, six genes were found to correlate with mouth ulcer pathogenesis, which can be useful for further biological and therapeutic research.

A genome-wide association analysis: m6A-SNP related to the onset of oral ulcers.

Oral ulcers are one of the most common inflammatory diseases on oral mucosa that have obvious impacts on patients. Studies have shown that N6-methyladenosine (m6A) RNA transcription modification may be involved in the development of various inflammatory responses, and whether the pathogenesis of oral ulcers is related to m6A is unclear. This study aims to identify how m6A-related single nucleotide polymorphisms (m6A-SNPs) may affect oral ulcers. The UKBB dataset containing 10,599,054 SNPs was obtained from the GWAS database using the keyword "oral ulcer" and compared with the M6AVar database containing 13,703 m6A-SNPs.With 7,490 m6A-SNPs associated with oral ulcers identified, HaploReg and RegulomeDB were used for further functional validation and differential gene analysis was performed using the GEO database dataset GSE37265. A total of 7490 m6A-SNPs were detected in this study, 11 of which were related to oral ulcers (p<5E-08), and all of these SNPs showed eQTL signals. The SNP rs11266744 (p=2.00E-27) may regulate the expression of the local gene CCRL2, thereby participating in the pathogenesis of oral ulcers. In summary, by analyzing genome-wide association studies, this study showed that m6A modification may be involved in the pathogenesis of oral ulcers and CCRL2 may be the targeted gene.

A Novel RELA Truncating Mutation in a Familial Behçet's Disease-like Mucocutaneous Ulcerative Condition.

OBJECTIVE: Monogenic Behçet's disease (BD)-like conditions are increasingly recognized and to date have been found to predominantly involve loss-of-function variants in TNFAIP3. This study was undertaken to identify genetic and pathobiologic mechanisms associated with a BD-like mucocutaneous ulcerative syndrome and neuromyelitis optica (NMO) occurring in 3 generations of an Irish family (n = 5 cases and 5 familial controls). METHODS: Whole-exome sequencing was used to identify potential pathogenic variants in affected family members and determine segregation between affected and unaffected individuals. Relative v-rel reticuloendotheliosis viral oncogene homolog A (RELA) expression in peripheral blood mononuclear cells was compared by Western blotting. Human epithelial and RelA-/- mouse fibroblast experimental systems were used to determine the molecular impact of the RELA truncation in response to tumor necrosis factor (TNF). NF-κB signaling, transcriptional activation, apoptosis, and cytokine production were compared between wild-type and truncated RELA in experimental systems and patient samples. RESULTS: A heterozygous cytosine deletion at position c.1459 in RELA was detected in affected family members. This mutation resulted in a frameshift p.His487ThrfsTer7, producing a truncated protein disrupting 2 transactivation domains. The truncated RELA protein lacks a full transactivation domain. The RELA protein variants were expressed at equal levels in peripheral mononuclear cells. RelA-/- mouse embryonic fibroblasts (MEFs) expressing recombinant human RELAp.His487ThrfsTer7 were compared to those expressing wild-type RELA; however, there was no difference in RELA nuclear translocation. In RelA-/- MEFs, expression of RELAp.His487ThrfsTer7 resulted in a 1.98-fold higher ratio of cleaved caspase 3 to caspase 3 induced by TNF compared to wild-type RELA (P = 0.036). CONCLUSION: Our data indicate that RELA loss-of-function mutations cause BD-like autoinflammation and NMO via impaired NF-κB signaling and increased apoptosis.

Association of Clinical Phenotypes in Haploinsufficiency A20 (HA20) With Disrupted Domains of A20.

Background: Haploinsufficiency A20 (HA20) is a newly described monogenic disease characterized by a wide spectrum of manifestations and caused by heterozygous mutations in TNFAIP3 which encodes A20 protein. TNFAIP3 mutation leads to disruption of the A20 ovarian tumor (OTU) domain and/or the zinc finger (ZnF) domain. This study aims at exploring the association between the various manifestations of HA20 and different domains disruption of A20. Methods: We reviewed the HA20 cases in previous literature and summarized the clinical features, TNFAIP3 mutation loci and the disrupted domains caused by different sites and patterns of mutations. Patients were classified into three groups according to the A20 domains disruption. Results: A total of 89 patients from 39 families with a genetic diagnosis of HA20 were included. Overall, the age at onset of HA20 was early (median:5.92, IQR:1-10). Patients in the ZnF group showed the earliest onset (median:2.5, IQR:0.6-5), followed by patients in the OTU+ZnF group (median:6, IQR:1-10) and patients in the OTU group (median:10, IQR:8-14). The main manifestations of HA20 patients were recurrent oral ulcers (70%), recurrent fever (42%), gastrointestinal ulcers (40%), skin lesion (38%), genital ulcers (36%), and musculoskeletal disorders (34%). The percentage of patients with musculoskeletal disorders was significantly different among the three groups (p = 0.005). Patients in the OTU+ZnF group and ZnF group were more likely to develop musculoskeletal disorders than patients in the OTU group (p = 0.002 and p = 0.035, respectively). Besides, forty-three percent of HA20 patients were initially diagnosed as Behcet's disease (BD). Compared to the ZnF group, the OTU+ZnF group and OTU group had a higher percentage of patients initially diagnosed as BD (p = 0.006 and p < 0.001, respectively). Conclusion: HA20 is characterized by early-onset and the most common symptoms of HA20 are recurrent oral ulcers, fever and gastrointestinal ulcers. The onset of HA20 in patients with the ZnF domain disruption is earlier than patients with the OTU domain disruption. Compared to the OTU domain, the ZnF domain may be more closely related to musculoskeletal disorders.

Gene mapping and functional annotation of GWAS of oral ulcers using FUMA software.

Oral ulcers not only influence the physical health of patients, but they also interfere with their quality of life. However, the exact etiology of oral ulcers is not clear. To explore the roles of genetic factors in oral ulcers, a genome-wide association study of the condition in European individuals was re-evaluated by the FUMA v1.3.5e online tool. A total of 380 independent significant single nucleotide polymorphisms (SNPs) and 89 lead SNPs were identified in 34 genomic risk loci. Out of these identified genomic risk loci, 280 possible causal genes were pinpointed by positional mapping and expression quantitative trait locus mapping. Among these genes, 216 novel genes were identified. Furthermore, some genomic loci were mapped to a single gene. Functional annotation of these prioritized genes revealed that the immune response pathway was implicated in the onset of oral ulcers. Overall, our findings revealed novel possible causal genes and demonstrated that the immune response has a crucial role in the occurrence of oral ulcers.

Clinicopathological analysis of 34 Japanese patients with EBV-positive mucocutaneous ulcer.

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) is a unifocal mucosal or cutaneous ulcer that is histologically characterized by proliferating EBV-positive atypical B cells. While EBVMCU demonstrates a histology similar to that of EBV-positive diffuse large B-cell lymphoma (DLBCL), their clinical behavior differs. Thus, characterizing distinguishing features of EBVMCU and EBV-positive DLBCL is critical. To identify unique characteristics between EBVMCU and lymphoma, we analyzed the clinicopathological and genetic features of 34 Japanese patients with EBVMCU and compared them to those of 24 EBV-positive DLBCL patients and 25 EBV-negative DLBCL patients. All patients with EBVMCU had localized ulcerative lesions, and 31 patients (91%) were using immunosuppressants, such as methotrexate (MTX) or hydroxycarbamide. All patients that were followed up with exhibited good prognosis following immunosuppressant reduction or chemotherapy. In addition, 17 EBV-positive DLBCL patients, and 15 EBV-negative DLBCL patients, received chemotherapy (P < 0.001, P < 0.001, respectively). Our data showed that EBVMCU did not increase indicators associated with lymphoma prognosis, such as soluble interleukin 2 receptor (sIL-2R) and lactate dehydrogenase (LDH) compared to those in the EBV-positive DLBCL or EBV-negative DLBCL groups (sIL-2R, P < 0.001, P = 0.025; LDH, P = 0.018, P = 0.038, respectively). However, histologically, EBVMCU exhibited EBV-positive, variable-sized, atypical B-cell proliferation. Thus, EBVMCU was histologically classified as: (1) polymorphous; (2) large cell-rich; (3) classic Hodgkin lymphoma-like; and (4) mucosa-associated lymphoid tissue lymphoma-like. Moreover, genetic analysis showed that immunoglobin heavy chain (IGH) gene rearrangement did not differ significantly between EBVMCU and EBV-positive DLBCL (44% vs. 32%; P = 0.377), or between EBVMCU and EBV-negative DLBCL (44% vs. 58%; P = 0.280). Therefore, it is difficult to distinguish EBVMCU from EBV-positive DLBCL using only pathological and genetic findings, suggesting that clinical information is important in accurately distinguishing between EBVMCU and EBV-positive DLBCL.

Mosaic Small Supernumerary Marker Chromosome Derived from Five Discontinuous Regions of Chromosome 8 in a Patient with Neutropenia and Oral Aphthous Ulcer.

Small supernumerary marker chromosomes (sSMCs) are characterized as additional centric chromosome fragments which are too small to be classified by cytogenetic banding alone and smaller than or equal to the size of chromosome 20 of the same metaphase spread. Here, we report a patient who presented with slight neutropenia and oral aphthous ulcers. A mosaic de novo sSMC, which originated from 5 discontinuous regions of chromosome 8, was detected in the patient. Formation of the sSMC(8) can probably be explained by a multi-step process beginning with maternal meiotic nondisjunction, followed by post-zygotic anaphase lag, and resulting in chromothripsis. Chromothripsis is a chromosomal rearrangement which occurs by breakage of one or more chromosomes leading to a fusion of surviving chromosome pieces. This case is a good example for emphasizing the importance of conventional karyotyping from PHA-induced peripheral blood lymphocytes and examining tissues other than bone marrow in patients with inconsistent genotype and phenotype.

Traumatic Ulcerative Granuloma with Stromal Eosinophilia: CD30 analysis and clonality for T cell receptor gene re-arrangement.

INTRODUCTION: Traumatic Ulcerative Granuloma with Stromal Eosinophilia (TUGSE) is a rare oral ulcerated lesion of uncertain etiology, showing eosinophil-rich granulation tissue, with occasional large atypical CD30 positive mononuclear cells. It had been suggested that it may represent an oral counterpart of cutaneous lymphomatoid papulosis, with a potential to evolve into CD30 + T cell lymphoma OBJECTIVES: To compare TUGSE and non-specific oral ulcers (NSU) clinically, histopathologically and by clonality analysis for T-cell receptor re-arrangement, aiming to determine whether TGUSE with atypical cells is a lymphomatous premalignant condition, and whether therapeutic approach should be radical or conservative. MATERIALS AND METHODS: Retrospective archival analysis included 17 TUGSE and 8 NSU cases. Histopathological parameters included mean eosinophil number per high power field (HPF), presence of infiltration of deep soft tissues and presence of atypical cells. Immuno-morphometry comprised of the mean number of CD30+ atypical cells per HPF. T-cell receptor (TCR) gene rearrangement by polymerase chain reaction (PCR) was performed in all cases showing atypical cells. Clinical and follow up data were retrieved from files. RESULTS: TUGSE showed a significantly higher mean eosinophil number/HPF in comparison to NSU (7.0 + 4.2 cells and 2.3 + 1.72, respectively; p < 0.001). Atypical cells were found in 9 (53%) cases of TUGSE and in only 1 (11%) case of NSU. CD30+ atypical cells were found in 7 (41%) cases of TUGSE and only in 1 (11%) case of NSU. Mean number of CD30+ cells/HPF was 0.23 + 0.19 (range 0 - 0.54 cells/HPF) for TUGSE. In the only NSU case with CD30+ cells, their density was 0.52/HPF. All lesions with atypical cells were polyclonal for TCR. All cases were self-limiting, with no recurrences, after 3-9 years (mean 4.6 years) follow up. CONCLUSIONS: Analysis found no support to the suggestion that TUGSE with atypical cells represents the oral counterpart of lymphomatoid papulosis or predisposes the lesions for a hematolymphoid malignancy. Suggestions for radical therapeutic approach and long-term follow-up are probably unjustified, with no recurrences or malignancy recorded following conservative treatment alone for a period of up to 9 years of follow-up. Staining for CD30 and PCR for TCR gene rearrangement should be reserved only for rare cases with abundant large atypical cells and/or unusual clinical behavior.

Genome wide analysis for mouth ulcers identifies associations at immune regulatory loci.

Mouth ulcers are the most common ulcerative condition and encompass several clinical diagnoses, including recurrent aphthous stomatitis (RAS). Despite previous evidence for heritability, it is not clear which specific genetic loci are implicated in RAS. In this genome-wide association study (n = 461,106) heritability is estimated at 8.2% (95% CI: 6.4%, 9.9%). This study finds 97 variants which alter the odds of developing non-specific mouth ulcers and replicate these in an independent cohort (n = 355,744) (lead variant after meta-analysis: rs76830965, near IL12A, OR 0.72 (95% CI: 0.71, 0.73); P = 4.4e-483). Additional effect estimates from three independent cohorts with more specific phenotyping and specific study characteristics support many of these findings. In silico functional analyses provide evidence for a role of T cell regulation in the aetiology of mouth ulcers. These results provide novel insight into the pathogenesis of a common, important condition.

Genetic modification to induce CXCR2 overexpression in mesenchymal stem cells enhances treatment benefits in radiation-induced oral mucositis.

Radiation-induced oral mucositis affects patient quality of life and reduces tolerance to cancer therapy. Unfortunately, traditional treatments are insufficient for the treatment of mucositis and might elicit severe side effects. Due to their immunomodulatory and anti-inflammatory properties, the transplantation of mesenchymal stem cells (MSCs) is a potential therapeutic strategy for mucositis. However, systemically infused MSCs rarely reach inflamed sites, impacting their clinical efficacy. Previous studies have demonstrated that chemokine axes play an important role in MSC targeting. By systematically evaluating the expression patterns of chemokines in radiation/chemical-induced oral mucositis, we found that CXCL2 was highly expressed, whereas cultured MSCs negligibly express the CXCL2 receptor CXCR2. Thus, we explored the potential therapeutic benefits of the transplantation of CXCR2-overexpressing MSCs (MSCsCXCR2) for mucositis treatment. Indeed, MSCsCXCR2 exhibited enhanced targeting ability to the inflamed mucosa in radiation/chemical-induced oral mucositis mouse models. Furthermore, we found that MSCCXCR2 transplantation accelerated ulcer healing by suppressing the production of pro-inflammatory chemokines and radiogenic reactive oxygen species (ROS). Altogether, these findings indicate that CXCR2 overexpression in MSCs accelerates ulcer healing, providing new insights into cell-based therapy for radiation/chemical-induced oral mucositis.

[Association between IL-10-1082G/A gene polymorphism and susceptibility of recurrent oral ulcer: meta analysis].

PURPOSE: To systematically review the association between interleukin-10 (IL-10) -1082G/A gene polymorphism and susceptibility of recurrent oral ulcer (ROU) by meta analysis. METHODS: Databases of PubMed, Embase, Web of Science, CNKI, CBM, WanFang, and VIP were electronically searched to collect studies published up to August 2017 about the association between IL-10-1082G/A gene polymorphism and ROU susceptibility. According to the inclusion and exclusion criteria, two reviewers independently screened literature and extracted data, the methodological quality assessment and heterogeneity test of included studies were performed. Meta analysis was performed with RevMan5.3 software. RESULTS: A total of 6 case-control studies were included, which involved 668 ROU patients in case group and 769 healthy individuals in control group. In the general population, the results of meta analysis showed that, under 3 genetic models including allele model (G vs A), recessive model (GG+GA vs AA) and heterozygous model (GA vs AA), there was significant association between IL-10-1082G/A gene polymorphism and ROU susceptibility (G vs A: OR=1.31, 95%CI 1.03 to 1.66, P=0.03; GG+GA vs AA: OR=1.45, 95%CI 1.16 to 1.82, P=0.001; GA vs AA: OR= 1.33, 95%CI 1.04 to 1.70, P=0.02). In the Asian population, meta analysis result was consistent with the general population. CONCLUSIONS: IL-10-1082G/A gene polymorphism is associated with ROU susceptibility. Individuals with G allele and GA genotype have a higher risk of ROU. Future more well-designed, large sample and multicenter studies are greatly needed to verify our conclusion.

The prevalence of Behçet's disease in the north of Jordan: a hospital-based epidemiological survey.

OBJECTIVES: To estimate the prevalence of Behçet's disease (BD) in Jordan, with the additional aim of comparing this prevalence among hospital workers in other geographical areas. METHODS: In the first stage of our survey, 2,569 employees from 6 hospitals in north Jordan were interviewed using a screening questionnaire to identify individuals with recurrent oral ulcers (ROU), a previous diagnosis of BD (PDBD) and/or any major symptom related to BD. In the second stage, all individuals with ROU or PDBD identified at stage 1, were examined by 2 rheumatologists for the presence/confirmation of BD according to the International Study Group (ISG) criteria. Pathergy test was performed according to recommendations. RESULTS: ROU were present in 210 (8.2%) individuals. BD was confirmed in 10 employees with PDBD. Seven more BD patients were found. Mean age of 17 BD patients was 38.6±10.7 (range 26-65 y). M: F was 2.4:1. Pathergy test was positive in 8/17. A family history of ROU or BD was noted in 9 (52%) and 3 (25.0%), respectively, compared to 227 (8.9%) and 62 (2.6%) in the whole group, excluding the BD patients (p<0.001 and 0.008, respectively). The prevalence rate of BD in the north of Jordan was estimated as 66:10.000 (95% CI 34.8 to 97.5:10000). CONCLUSIONS: The results of this first ever survey indicated that the prevalence of BD in the north of Jordan is among the highest in the world. This prevalence can now be compared to hospital workers in other geographical areas.

[Single nucleotide polymorphism of IL-23 receptor gene is associated with susceptibility to recurrent oral ulceration].

Objective To explore whether single nucleotide polymorphism (SNP) in interleukin-23 receptor (IL-23R) gene is associated with the susceptibility to recurrent oral ulceration (ROU). Methods The genotype of SNP rs11465817 and rs1343152 was determined by MALDI-TOF-MS in 42 ROU patients and 86 age- and sex-matched healthy controls. The genotype and allele frequencies were analyzed by Chi-square test in both groups. Odds ratio (OR) and 95% confidence interval (95%CI) were calculated to analyze the associations between the susceptibility of ROU and the genotypes. Results The rs1343152 allele and genotype frequency distribution had no significantly difference between the case group and the control group. Compared with the control group, rs11465817 allele and genotype frequency distribution in the ROU group had significant difference (OR=2.715, 95%CI=1.543-4.777). The AA+AC genotype increased the risk of ROU occurrence by 2.44 times. Conclusion IL-23R rs11465817 contributes to the risk of ROU in Chinese.

A distinctive subgroup of oral EBV+ B-cell neoplasm with polymorphous features is potentially identical to EBV+ mucocutaneous ulcer.

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a newly recognized provisional entity included in mature B-cell neoplasm in the latest 2016 World Health Organization Classification. It has a self-limited growth potential with a high predilection for oral cavities and occurs in age-related or iatrogenic immunodeficiency with indolent clinical courses. However, it shares histological features with EBV-positive diffuse large B-cell lymphoma (DLBCL), and this often leads to diagnostic challenges and controversies in patients with an oral EBV-positive B-cell neoplasm. The aim of this study was to better characterize and comprehend the pathophysiology of DLBCL and EBVMCU in the oral cavity. We conducted clinicopathologic and recurrent gene mutation analysis of 49 cases (14 EBV positive, 35 EBV negative), including cases diagnosed as DLBCL or B-cell lymphoproliferative disorders with high-grade morphology in the oral cavity. All EBV-positive cases matched the criteria of EBVMCU, with significantly earlier clinical stages than the EBV-negative group (P=.0006). Besides, histological analysis showed that all EBV-positive cases presented polymorphous features, whereas 91.4% (32/35) of the EBV-negative cases showed diffuse and monotonous proliferation (P<.0001). Furthermore, EBV-positive cases presented favorable clinical outcomes without disease-related death or recurrence. Gene mutation analysis (MYD88, CD79A, CD79B, CARD11, and EZH2) revealed that 33.3% (9/27) of EBV-negative cases harbored at least 1 gene mutation, whereas no gene mutation was observed in the EBV-positive group (0/11). These results suggest that oral EBV-positive B-cell lymphoid proliferation with polymorphous features often fulfill the criteria for EBVMCU, with clinicopathologically and genetically distinctive properties.

Human RELA haploinsufficiency results in autosomal-dominant chronic mucocutaneous ulceration.

The treatment of chronic mucocutaneous ulceration is challenging, and only some patients respond selectively to inhibitors of tumor necrosis factor-α (TNF). TNF activates opposing pathways leading to caspase-8-mediated apoptosis as well as nuclear factor κB (NF-κB)-dependent cell survival. We investigated the etiology of autosomal-dominant, mucocutaneous ulceration in a family whose proband was dependent on anti-TNF therapy for sustained remission. A heterozygous mutation in RELA, encoding the NF-κB subunit RelA, segregated with the disease phenotype and resulted in RelA haploinsufficiency. The patients' fibroblasts exhibited increased apoptosis in response to TNF, impaired NF-κB activation, and defective expression of NF-κB-dependent antiapoptotic genes. Rela+/- mice have similarly impaired NF-κB activation, develop cutaneous ulceration from TNF exposure, and exhibit severe dextran sodium sulfate-induced colitis, ameliorated by TNF inhibition. These findings demonstrate an essential contribution of biallelic RELA expression in protecting stromal cells from TNF-mediated cell death, thus delineating the mechanisms driving the effectiveness of TNF inhibition in this disease.

Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology. Recent studies have suggested the existence of a genetic basis for SLE heterogeneity. The objective of the present study was to identify new genetic variation associated with the clinically relevant phenotypes in SLE. METHODS: A two-stage pathway-based approach was used to identify the genetic variation associated with the main clinical phenotypes in SLE. In the discovery stage, 482 SLE patients were genotyped using Illumina Human Quad610 microarrays. Association between 798 reference genetic pathways from the Molecular Signatures Database and 11 SLE phenotypes was tested using the set-based method implemented in PLINK software. Pathways significantly associated after multiple test correction were subsequently tested for replication in an independent cohort of 425 SLE patients. Using an in silico approach, we analyzed the functional effects of common SLE therapies on the replicated genetic pathways. The association of known SLE risk variants with the development of the clinical phenotypes was also analyzed. RESULTS: In the discovery stage, we found a significant association between the vascular endothelial growth factor (VEGF) pathway and oral ulceration (P value for false discovery rate (P FDR) < 0.05), and between the negative regulation signaling pathway of retinoic acid inducible gene-I/melanoma differentiation associated gene 5 and the production of antinuclear antibodies (P FDR < 0.05). In the replication stage, we validated the association between the VEGF pathway and oral ulceration. Therapies commonly used to treat mucocutaneous phenotypes in SLE were found to strongly influence VEGF pathway gene expression (P = 4.60e-4 to 5.38e-14). Analysis of known SLE risk loci identified a strong association between PTPN22 and the risk of hematologic disorder and with the development of antinuclear antibodies. CONCLUSIONS: The present study has identified VEGF genetic pathway association with the risk of oral ulceration in SLE. New therapies targeting the VEGF pathway could be more effective in reducing the severity of this phenotype. These findings represent a first step towards the understanding of the genetic basis of phenotype heterogeneity in SLE.

Investigation of CD40 gene rs4810485 and rs1883832 mutations in patients with recurrent aphthous stomatitis.

OBJECTIVES: Recurrent aphthous stomatitis (RAS) is a common painful disorder affecting oral health, mucosa and overall quality of life. The etiopathogenesis of RAS remains unclear. RAS shows a large genetic diversity among the patients. In present study, we investigated whether CD40 gene rs4810485 and rs1883832 are associated with RAS and its clinical findings in Turkish patients. MATERIALS AND METHODS: Genomic DNA obtained from 387 individuals (160 patients with RAS and 227 healthy controls) were used in the study. CD40 gene rs4810485 and rs1883832 mutations were determined by using polymerase chain reaction with the specific primers. RESULTS: There was no statistically significant difference between the groups with respect to genotype and allele distribution (p>0.05, OR 0.94, 95% CI 0.70-1.28, OR 1.01 95% CI 0.75-1.37, respectively). Additionally, there was no statistically significant difference in the combined genotype analysis of CD40 gene rs4810485 and rs1883832 mutations (p>0.05). CONCLUSIONS: According to our results, we found that CD40 gene mutations are not associated with RAS. We are convinced that CD40 gene mutations do not predispose to develop RAS in Turkish population. To our knowledge, this is the first study regarding CD40 gene rs4810485 and rs1883832 mutations investigated in RAS patients.