These preliminary results indicate that salivary analysis of NF-kappaB-dependent cytokines may be applied to monitoring the therapeutic response of OLP.
BackgroundSjögren's syndrome (SS) is a common autoimmune disorder characterized by immune-mediated exocrine gland destruction and systemic inflammation contributing to clinical heterogeneity. The complex regulatory mechanisms governing these responses are poorly understood. We previously performed an RNA-sequencing (RNA-seq) study and identified >2,600 differentially expressed (DE) transcripts associated with SS.ObjectivesThis study sought to validate, replicate, and functionally characterize one upregulated long non-coding RNA (lncRNA) mapped to chromosome 2p25.1 to better understand its role in SS pathogenesis.MethodsTechnical validation and replication of the 2p25.1 lncRNA upregulation was assessed by qPCR. Bioinformatic analysis using GAMMA-seq was used to identify co-expression patterns of this lncRNA with other transcripts. Cellular expression patterns of the 2p25.1 lncRNA were determined by FACS in 9 distinct immune cell subsets in a healthy control followed by RNA isolation and qPCR to assess expression. Statistical comparisons were made using t-tests and Pearson correlations.ResultsRNA-seq showed significant upregulation of the 2p25.1 lncRNA when comparing 27 healthy controls and 57 SS patients (Padj=3.69x10-5; Fold Change=2.4). Technical validation by qPCR confirmed this finding (P=0.0096), and correlation with RNA-seq results was observed (r=0.869). Transcript expression in an independent sample set of 36 SS patients and 21 controls confirmed the lncRNA upregulation (P=0.0183). Co-expression patterns showed T, NK, and dendritic cell activation, development, and proliferation. Expression levels of the 2p25.1 lncRNA were highest in the CD8+ T cells (RU=3.34), followed by CD56int NK cells (RU=2.08), CD56hi NK cells (RU=0.83), and CD4+ T cells (RU=0.81). Expression was not detected in CD141+ and CD1c+CD11c+ myeloid DCs, monocytes, B cells, or pDCs.ConclusionsWe have identified, technically validated, and independently replicated the upregulation of a novel SS lncRNA at 2p25.1. Furthermore, we have established that this transcript is highly expressed in CD4+ and CD8+ T cells, and NK cells. This study establishes the 2p25.1 lncRNA as the first associated with SS and lays the groundwork for further functional characterization in the pathogenesis of this complex disorder.Disclosure of InterestNone declared
Background Sjögren’s syndrome (SS) is a common, clinically heterogeneous autoimmune disease characterized by exocrine gland dysfunction that involves both innate and adaptive immune responses. A complex genetic architecture has been hypothesized; however, genetic studies to date have been limited to candidate gene approaches. Objectives We sought to perform the first genome-wide association scan (GWAS) in an unbiased manner to identify SS risk loci. Methods We used high-density Illumina OMNI1-Quad genotyping arrays in a discovery cohort of 395 European-derived SS cases and 1975 healthy controls for the GWAS discovery phase. Stringent quality control (QC) criteria, adjustments for population stratification, and standard GWA statistical methods were used to compare allele frequencies between cases and controls. For replication, an independent set of 1243 SS cases and 4779 healthy controls were genotyped using 2 custom array (CA) platforms. Meta-analysis between the GWAS and CAs were done using METAL (Pmeta). Results The most significantly associated region with SS was the MHC, with 6324 overlapping SNPs between the GWAS and CAs exceeding the genome-wide significance (GWS) threshold of P<5x10E-8 after imputation, peaking at HLA-DQB1 with Pmeta=7.65x10E-114. This study also identified 3 novel associations not previously reported as risk loci for SS. In the region of IL12A, 7 variants passed GWS, peaking at rs485497 (Pmeta=1.17x10E-10). Near CXCR5, 4 variants exceeded GWS with rs7119038 (Pmeta=1.10x10E-8) the most significant. One variant, rs6579837 (Pmeta=3.30x10E-8), in TNIP1 also surpassed GWS. Three regions previously implicated were now identified as surpassing GWS for the first time in the current study: IRF5 (rs3757387 Pmeta=2.73x10E-19), STAT4 (rs10553577 Pmeta=6.80x10E-15), and BLK (rs2736345 Pmeta=4.97x10E-10). Conclusions We present the first GWAS of SS identifying and confirming IL12A, CXCR5, and TNIP1 as novel susceptibility loci. We also observed IRF5, STAT4, and BLK for the first time at GWS establishing them as risk loci for SS. Collectively these genes illustrate the importance of both the innate and adaptive immune responses in the etiology of SS. Disclosure of Interest None Declared
Objectives/Introduction Clinical trial accrual for oral dysplasia is difficult in the U.S. and elsewhere. Patients with dysplastic oral leukoplakia progress to frank invasive carcinoma at a rate of 5-37% over 5 years. We compared two clinical trial screening efforts to hopefully devise better accrual strategies to these types of clinical trials. Methods For the first trial we identified 244 patients with dysplastic oral leukoplakia in our university database and a media campaign. Patients were notified, screened by examination and biopsy. For the second clinical trial we established a preneoplastic lesions clinic and teaching and communications network with regional oral health care professionals. Results Only one of 244 patients accrued to the first clinical trial through an organized screening effort based on database/medical records review. The second clinical trial accrued 16/30 screened patients through redirected efforts in teaching, communications and a preneoplastic lesions clinic. Conclusion We conclude that significant difficulties resulted from medical record /database review of leukoplakia patients as a screening method for leukoplakia clinical trial entry. We feel that persistent direct contact and education of health care professionals who are likely to examine leukoplakia patients improved accrual to the second clinical trial.
BackgroundSjögren's syndrome (SS) is a chronic autoimmune disorder in which exocrine dysfunction can lead to chronic, debilitating dryness. Expression studies in SS have identified the dysregulated expression of coding and non-coding transcripts enriched in innate and adaptive immune response pathways.ObjectivesIn our recent SS RNA-seq study, we identified 3748 transcripts showing differential expression (DE; FC>2 or <0.5, q<0.05) in SS patients compared to healthy controls. Of these SS-associated transcripts,[CL1] we sought to identify transcripts whose expression is significantly correlated with objective measures of dryness employed by the 2002 American-European Consensus Group (AECG) classification criteria of SS, including whole unstimulated salivary flow (WUSF), lissamine green (LG) staining, and Schirmer's (Sch) tear migration.MethodsNormalized expression data from a whole blood SS RNA-seq study was obtained for 57 cases and 11 healthy controls who underwent multidisciplinary clinical evaluation for the 2002 AECG classification criteria. Objective dryness measures (WUSF, LG, & Sch) were normalized by log2 transformation and correlation analysis (Spearman for WUSF and LG; Pearson for Sch) was performed for each clinical measure against all of 3748 DE transcripts. Both r or σ and a FDR-corrected p-value, or q-value, were calculated. Significantly correlated transcripts were defined by q<0.05.ResultsFor WUSF, the significant positive correlation between WUSF rate and the expression of 2 non-coding transcripts was observed: the small Cajal body-specific RNA 5 (SCARNA5; σ=0.50, q=0.018) and the uncharacterized antisense lncRNA RP11–137H2.4 (σ=0.50, q=0.018). For LG, positive correlation was observed for 31 transcripts (0.42<σ<0.51, 0.017
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