A novel approach toward optimal workflow selection for DNA methylation biomarker discovery.

DNA methylation is a major epigenetic modification involved in many physiological processes. Normal methylation patterns are disrupted in many diseases and methylation-based biomarkers have shown promise in several contexts. Marker discovery typically involves the analysis of publicly available DNA methylation data from high-throughput assays. Numerous methods for identification of differentially methylated biomarkers have been developed, making the need for best practices guidelines and context-specific analyses workflows exceedingly high. To this end, here we propose TASA, a novel method for simulating methylation array data in various scenarios. We then comprehensively assess different data analysis workflows using real and simulated data and suggest optimal start-to-finish analysis workflows. Our study demonstrates that the choice of analysis pipeline for DNA methylation-based marker discovery is crucial and different across different contexts.

Sex-based Dysregulation of Inflammation-related Genes in Periodontitis.

Periodontitis is a chronic inflammatory condition affecting a large population all over the world. This condition is linked with abnormal expression of numerous genes. We measured levels of CYFIP1, KDR, RABGGTA, RABGGTB and FOXD2 in gingival tissue and circulation of people with periodontitis and healthy controls. KDR was more expressed in tissue samples of female patients compared with female controls (Ratio of mean expression (RME) =4.16, P=0.02). However, this gene was less expressed in the blood of female patients compared with female control subjects (RME=0.12, P=0.04). RABGGTB was less expressed in the blood of male patients compared with male controls (RME=0.20, P=0.02). Finally, FOXD2 was less expressed in total blood samples compared with total controls (RME=0.3, P<0.001) and in blood samples of female patients compared with female control subjects (RME=0.02, P<0.001). RABGGTA had the best area under curve (AUC) value in differentiation of patients' tissues from normal tissues (AUC=0.60, sensitivity=0.37, specificity=0.92). In distinction of abnormal blood samples from controls, FOXD2 had the best performance (AUC=0.85, sensitivity=0.66, specificity=0.91). In brief, we demonstrated a sex-dependent dysregulation of KDR, RABGGTB and FOXD2 genes in circulation or tissue of patients with periodontitis.

Altered expression of SOCS genes periodontitis.

Suppressor of cytokine signalling (SOCS) family comprises a group of proteins that impede JAK/STAT signalling, thus being involved in the pathogenesis of immune-related conditions. In the present work, we aimed at identification of the role of SOCS genes in the pathogenesis of periodontitis through evaluation of their expression levels both in the circulation and in the affected tissues of patients. Thus, we measured expression levels of SOCS1-3 and SOCS5 transcripts in the blood and gingival samples of patients with periodontitis in comparison with control samples obtained during dental crown lengthening. Expressions of SOCS1, SOCS2, SOCS3 and SOCS5 genes were similar between gingival tissues of patients and controls. However, our results demonstrated under-expression of SOCS1 in blood samples of patients compared with controls (Ratio of mean expression (RME) = 0.47, P value = 0.04). The same pattern was observed among female subjects (RME = 0.38, P value = 0.04). SOCS2 was down-regulated in blood samples of female patients compared with female controls (RME = 0.22, P value = 0.04). SOCS3 was also under-expressed in the circulation of total cases versus total controls (RME = 0.29, P value = 0.02) and in female patients compared with female controls (RME = 0.19, P value = 0.04). Expression of SOCS5 was not different between blood samples two study groups. SOCS2 had the best function in separation of affected tissues from unaffected ones (AUC = 0.66, sensitivity = 0.39, specificity = 0.83). SOCS3 was superior to other transcripts in differentiation of blood samples of patients from normal blood samples (AUC = 0.69, sensitivity = 0.81, specificity = 0.68). Combination of transcript levels of SOCS1, SOCS2, SOCS3 and SOCS5 genes enhanced the AUC values to 0.64 and 0.67 in tissue and blood specimens, respectively. Taken together, certain SOCS genes have been found to be dysregulated in the circulation of patients with periodontitis.

Downregulation of oxytocin-related genes in periodontitis.

Periodontitis is a common oral disorder leading to tooth loss in both developed and developing regions of the world. This multifactorial condition is related to the abnormal activity of several molecular pathways, among them are oxytocin-related pathways. In this study, we enrolled 26 patients and 28 controls and assessed the expression of four oxytocin-related genes, namely, FOS, ITPR, RCAN1, and RGS2, in circulation and affected tissues of enrolled individuals using real-time PCR. Expression of FOS was downregulated in total periodontitis tissues compared with total control tissues [ratio of mean expression (RME) = 0.23, P-value = 0.03]. Expression of FOS was also lower in total blood samples of patients compared with total controls. Expression of ITPR was downregulated in total periodontitis tissues compared with total control tissues (RME = 0.16, P-value = 0.01). Moreover, the expression of ITPR was reduced in total blood samples of patients compared with controls (RME = 0.25, P-value = 0.03). Expression of RCAN1 was downregulated in total periodontitis tissues compared with total control tissues (RME = 0.17, P-value = 0.01). However, the expression of RCAN1 was not different in blood samples of affected vs. unaffected individuals. Finally, the expression of RGS2 was lower in total periodontitis tissues compared with total control tissues (RME = 0.24, P-value = 0.01) and in total blood samples of affected individuals compared with controls (RME = 0.42, P-value = 0.05). This study provides data about the association between expressions of oxytocin-related genes and the presence of periodontitis. Future studies are needed to unravel the mechanistic links and find the correlation between expressions of these genes and the pathological stage of periodontitis.

CRISPRi-mediated knock-down of PRDM1/BLIMP1 programs central memory differentiation in ex vivo-expanded human T cells.

Introduction: B lymphocyte-induced maturation protein 1 (BLIMP1) encoded by the positive regulatory domain 1 gene (PRDM1), is a key regulator in T cell differentiation in mouse models. BLIMP1-deficiency results in a lower effector phenotype and a higher memory phenotype. Methods: In this study, we aimed to determine the role of transcription factor BLIMP1 in human T cell differentiation. Specifically, we investigated the role of BLIMP1 in memory differentiation and exhaustion of human T cells. We used CRISPR interference (CRISPRi) to knock-down BLIMP1 and investigated the differential expressions of T cell memory and exhaustion markers in BLIMP1-deficient T cells in comparison with BLIMP1-sufficient ex vivo expanded human T cells. Results: BLIMP1-deficiency caused an increase in central memory (CM) T cells and a decrease in effector memory (EM) T cells. There was a decrease in the amount of TIM3 exhaustion marker expression in BLIMP1-deficient T cells; however, there was an increase in PD1 exhaustion marker expression in BLIMP1-deficient T cells compared with BLIMP1-sufficient T cells. Conclusion: Our study provides the first functional evidence of the impact of BLIMP1 on the regulation of human T cell memory and exhaustion phenotype. These findings suggest that BLIMP1 may be a promising target to improve the immune response in adoptive T cell therapy settings.

HLA alleles and haplotype frequencies in Iranian population.

BACKGROUND: HLA genotyping is a prerequisite for selection of suitable donors in the process of bone marrow transplantation. METHODS: In the current study, the frequencies of HLA-A, -B, -C and -DRB1 alleles and A-B-C-DRB1 haplotypes were assessed in 855 healthy Iranian persons using a low-resolution sequence specific primer (SSP) kit. RESULTS: Frequencies were compared between 11 subpopulations including Armani, Balouch, Bandari, Turk, Turkaman, Arab, Fars, Kurd, Gilaki, Lor and Mazani. In total, 17 HLA-A alleles were detected, one of which (HLA-A*74) was present only among Lors. HLA-A*23 and -A*26 were the most frequent HLA-A alleles among Armanis. HLA-A*23 was also common among Turkamans. HLA-A*11 and -A*26 were most frequent among the Balouch subpopulation. The former allele was also frequent among Bandaris. HLA-A*02 was identified as the most common HLA-A allele among Turk, Arab and Fars subpopulations. HLA-A*30 were strongly enriched among Gilakis. A total of 31 HLA-B alleles were detected across the target population. While all alleles were present among Fars subgroup, Armanis and Turkamans had the lowest degree of diversity among the alleles examined. Moreover, HLA-B*35 and B*49 alleles were strongly enriched among Armanis and Turkamans, respectively. A total of 13 HLA-C alleles were identified across the population, all of which were present in the Fars subpopulation. HLA-C*03 and C*04 were the only HLA-C alleles identified among the Bandari subpopulation. HLA-DRB1*08 was not detected in any subpopulation other than Fars. HLA-DRB1*16 was significantly enriched among Bandaris. These data have practical significance in anthropological studies, disease association investigations and bone marrow transplantation.

Distribution of HLA Alleles and Genotypes in Patients with Chronic Inflammatory Demyelinating Polyneuropathy.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired immunological disorder. Although the precise pathoetiology of CIDP has not been clarified yet, it is believed that both B and T cells of immune system contribute in this disorder. Based on the importance of human leukocyte antigen (HLA) cluster in the regulation of immune responses, this family of proteins is putative determinants of risk of CIDP. We conducted the current investigation to appraise association between HLA alleles/genotypes/haplotypes and risk of CIDP in Iranian patients. HLA-DQB1*02 allele was significantly more prevalent among cases compared with controls (OR [95% CI] = 4.82 [2.06, 11.3], P value = 0.000215, adjusted P value = 0.0124). A*01-B*52-C*12-DRB1*15-DQB1*02 and A*23-B*35-C*04-DRB1*11-DQB1*03 haplotypes with frequency of 0.03 were the most frequent HLA haplotypes. These haplotypes were not detected among healthy controls. The present study introduces HLA-DQB1*02 allele as a risk allele for CIDP among Iranian patients and further supports the importance of HLA region in this immunological condition.

Dysregulation of lncRNAs in circulation of patients with periodontitis: results of a pilot study.

BACKGROUND: Periodontitis is a chronic inflammatory disorder with a complex etiology. Long non-coding RNAs (lncRNAs) have been shown to affect pathoetiology of periodontitis. We aimed at identification of expression of five lncRNAs, namely Linc0116, Linc00667, CDK6-AS1, FENDRR and DIRC3 in the circulation and gingival tissues of these patients compared with healthy controls. METHODS: In a pilot case-control study, we compared expressions of Linc0116, Linc00667, CDK6-AS1, FENDRR and DIRC3 lncRNAs between blood and tissue samples of patients with periodontitis and healthy controls using real time quantitative PCR technique. The present work was performed on samples got from 26 patients with periodontitis and 28 controls. Female/male ratio was 16/10 and 12/16 in cases and controls, respectively. RESULTS: There was no significant difference in the expressions of Linc0116, Linc00667, CDK6-AS1, FENDRR and DIRC3 genes between affected and unaffected tissues. However, expressions of Linc0116, Linc00667, CDK6-AS1, FENDRR and DIRC3 genes were significantly lower in the blood samples of patients when compared with control samples (Ratio of mean expression = 0.16, 0.14, 0.13, 0.10 and 0.14, respectively). Subsequently, we compared expressions of these lncRNAs between patients and controls in a sex-based manner. Expressions of Linc00667, FENDRR and DIRC3 genes were significantly lower in female patients compared with female controls (RME = 0.09, 0.07 and 0.10, respectively). Yet, there was no significant difference in expression of any of mentioned lncRNAs among male subgroups. Consistent with the similar levels of Linc0116, Linc00667, CDK6-AS1, FENDRR and DIRC3 in tissue samples of patients and controls, none of them could separate these two sets of samples. However, AUC values for of Linc0116, Linc00667, CDK6-AS1, FENDRR and DIRC3 expression levels in blood samples were 0.66, 0.72, 0.70, 0.72, 0.70 and 0.68, respectively with FENDRR having the best sensitivity value. CONCLUSION: Taken together, lncRNAs might be involved in the pathologic events in the circulation of patients with periodontitis.

Abnormal expression of NF-κB-related transcripts in blood of patients with inflammatory peripheral nerve disorders.

The NF-κB family includes some transcription factors which have important functions in the regulation of immune responses, therefore participating in the pathophysiology of inflammatory conditions such as peripheral neuropathies. We have quantified expression of a number of NF-κB-related transcripts in patients with Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP) versus healthy subjects. These transcripts have been previously shown to be functionally related with this family of transcription factors. Expressions of ATG5, DICER-AS1, PACER, DILC, NKILA and ADINR have been increased in both CIDP and GBS patients compared with controls. However, expression of ATG5 was not different between female CIDP cases and female controls. Moreover, expression of PACER was not different between male GBS cases and male controls. Expression levels of CHAST and CEBPA were not different between patients and controls. Expression of none of the assessed genes was different between GBS and CIDP cases. Significant correlations have been revealed between expression amounts of NF-κB-related transcripts both among CIDP/ GBS patients and among controls except for NKILA/ATG5, ADINR/ATG5 and PACER/ATG5 and DICER-AS1/ATG5 pairs among controls whose expression levels have not been correlated. In the patient group, CEBPA/PACER, CHAST/PACER and CHAST/DICER-AS1 pairs had the most robust correlations (r = 0.94). Among controls, NKILA/ADINR pair had the most strong correlation (r = 0.78). ADINR and DICER-AS1 levels could differentiate CIDP cases from controls with 100% sensitivity and specificity. In differentiation of GBS cases from controls, these two transcripts had the AUC values of 0.99 and 1. Combination transcript levels of NF-κB-related transcripts similarly detects CIDP and GBS cases from healthy controls with 100% sensitivity and specificity. Therefore, NF-κB-related transcripts are possibly involved in the pathophysiology of inflammatory peripheral nerve disorders and can be used as diagnostic markers for these conditions.

A Comparative Overview of Epigenomic Profiling Methods.

In the past decade, assays that profile different aspects of the epigenome have grown exponentially in number and variation. However, standard guidelines for researchers to choose between available tools depending on their needs are lacking. Here, we introduce a comprehensive collection of the most commonly used bulk and single-cell epigenomic assays and compare and contrast their strengths and weaknesses. We summarize some of the most important technical and experimental parameters that should be considered for making an appropriate decision when designing epigenomic experiments.

Dysregulation of lncRNAs in autoimmune neuropathies.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Guillain-Barré syndrome (GBS) are inflammatory neuropathies with different clinical courses but similar underlying mechanisms. Long non-coding RNAs (lncRNAs) might affect pathogenesis of these conditions. In the current project, we have selected HULC, PVT1, MEG3, SPRY4-IT1, LINC-ROR and DSCAM-AS1 lncRNAs to appraise their transcript levels in the circulation of CIDP and GBS cases versus controls. Expression of HULC was higher in CIDP patients compared with healthy persons (Ratio of mean expression (RME) = 7.62, SE = 0.72, P < 0.001). While expression of this lncRNA was not different between female CIDP cases and female controls, its expression was higher in male CIDP cases compared with male controls (RME = 13.50, SE = 0.98, P < 0.001). Similarly, expression of HULC was higher in total GBS cases compared with healthy persons (RME = 4.57, SE = 0.65, P < 0.001) and in male cases compared with male controls (RME = 5.48, SE = 0.82, P < 0.001). Similar pattern of expression was detected between total cases and total controls. PVT1 was up-regulated in CIDP cases compared with controls (RME = 3.04, SE = 0.51, P < 0.001) and in both male and female CIDP cases compared with sex-matched controls. Similarly, PVT1 was up-regulated in GBS cases compared with controls (RME = 2.99, SE = 0.55, P vale < 0.001) and in total patients compared with total controls (RME = 3.02, SE = 0.43, P < 0.001). Expression levels of DSCAM-AS1 and SPRY4-IT1 were higher in CIDP and GBS cases compared with healthy subjects and in both sexes compared with gender-matched healthy persons. Although LINC-ROR was up-regulated in total CIDP and total GBS cases compared with controls, in sex-based comparisons, it was only up-regulated in male CIDP cases compared with male controls (RME = 3.06, P = 0.03). Finally, expression of MEG3 was up-regulated in all subgroups of patients versus controls except for male GBS controls. SPRY4-IT could differentiate CIDP cases from controls with AUC = 0.84, sensitivity = 0.63 and specificity = 0.97. AUC values of DSCAM-AS1, MEG3, HULC, PVT1 and LINC-ROR were 0.80, 0.75, 0.74, 0.73 and 0.72, respectively. In differentiation between GBS cases and controls, SPRY4-IT and DSCAM-AS1 has the AUC value of 0.8. None of lncRNAs could appropriately differentiate between CIDP and GBS cases. Combination of all lncRNAs could not significantly enhance the diagnostic power. Taken together, these lncRNAs might be involved in the development of CIDP or GBS.

Expression analysis of cytokine transcripts in inflammatory demyelinating polyradiculoneuropathy.

Inflammatory demyelinating polyradiculoneuropathies are a group of peripheral nerve system disorders in which immune reactions are dysregulated. Cytokines have noticeable roles in the regulation of these responses. We compared transcript levels of nine cytokine coding genes namely IL-1B, IL-2, IL-4, IL-6, IL-8, IL-17A, IFN-G, TGF-B and TNF-A in the peripheral blood of patients with acute and chronic kinds of this condition (AIDP and CIDP) and healthy persons. Expression of IL-17A was significantly lower in female AIDP cases compared with female controls (Expression Ratio = 0.02, P value = 0.02). Expression of this cytokine was higher in female CIDP cases compared with female AIDP cases (Expression ratio = 65.69, P value = 0.02). Moreover, expression of IL-6 tended to be diminished in female AIDP cases compared with normal females (Expression Ratio = 0.06, P value = 0.05). Expression of TGF-B was lower in female AIDP cases compared with female controls (Expression Ratio = 0.06, P value = 0.01). Transcript amounts of IL-1B were lower in whole CIDP cases compared with whole controls and in female AIDP cases compared with female controls (Expression Ratios = 0.09 and 0.00; P values = 0.04 and 0.01, respectively). Expression of this gene was considerably increased in female CIDP cases compared with female AIDP cases (Expression Ratio = 764.10, P value = 0.02). Finally, expression of this gene was lower in total cases compared with total controls (Expression ratio = 0.19, P value = 0.03). Diagnostic power of IL-4 was estimated to be 0.7 in differentiating between CIDP cases and controls. IL-1B had the diagnostic power of 0.72 in distinguishing between ADP cases and controls. Finally, TNF-A had the diagnostic power of 0.71 in differentiating between AIDP cases and CIDP cases. The current results suggest the possible role of these cytokines in the pathogenesis of inflammatory demyelinating polyradiculoneuropathies.

Expression Analysis of Protein Inhibitor of Activated STAT in Inflammatory Demyelinating Polyradiculoneuropathy.

Protein inhibitors of activated STAT (PIAS) are involved in the regulation of the JAK/STAT signaling pathway and have interactions with NF-κB, p73 and p53. These proteins regulate immune responses; therefore dysregulation in their expression leads to several immune-mediated disorders. In the present study, we examined expression of PIAS1-4 in peripheral blood of patients with acute/chronic inflammatory demyelinating polyradiculoneuropathy (AIDP/CIDP) compared with healthy subjects. We demonstrated down-regulation of all PIAS genes in both AIDP and CIDP cases compared with controls. Similarly, comparisons in gender-based groups revealed down-regulation of these gene0s in patients of each gender compared with gender-matched controls. There was no significant difference in expression of PIAS genes between AIDP and CIDP cases. Based on the area under the receiver operating characteristic curves, PIAS1-4 genes could distinguish between inflammatory demyelinating polyradiculoneuropathy and healthy status with accuracy values of 0.87, 0.87, 0.79 and 0.80, respectively. In differentiation between AIDP cases and healthy controls, these values were 0.92, 0.92, 0.83 and 0.86, respectively. Finally, PIAS1-4 genes could discriminate CIDP from healthy status with accuracy values of 0.82, 0.83, 0.75 and 0.75, respectively. The current study underscores the role of PIAS genes in the pathogenesis of inflammatory demyelinating polyradiculoneuropathy and their potential usage as biomarkers.

Altered expression of STAT genes in periodontitis.

Signal Transducer and Activator of Transcription (STAT) pathway is functionally located downstream of Janus kinases proteins and can integrate signals from diverse pathways, thus regulating several aspects of immune responses. Although contribution of STAT proteins in the pathogenesis of several inflammatory conditions has been confirmed, their role in the development of periodontitis has been less appraised. Thus, we assessed levels of STAT transcripts in the periodontal tissues and circulation of affected individuals compared with the corresponding controls. Expression of STAT1 was remarkably lower in tissues samples of patients compared with control tissues (Ratio of mean expression (RME) = 0.15, SE = 0.99, P value = 0.01). Expression of STAT3 was lower in total periodontitis tissues compared with total control tissues (RME = 0.20, SE = 0.95, P value = 0.02). Expression of STAT6 was higher in total periodontitis tissues compared with total control tissues (RME = 0.5.38, SE = 0.74, P value < 0.001). Expressions of other STAT genes were statistically similar in tissues obtained from cases and controls. Moreover, blood levels of all STAT genes were statistically similar between patients and controls. Correlation analysis demonstrated significant correlations between tissues levels of individual STAT genes as well as between their blood levels. However, tissue and blood levels of each STAT gene were not correlated. The current investigation potentiates the role of certain STAT genes in the development of this immune-related condition and warrants functional assays to clarify the mechanism.

Expression of PIAS Genes in Migraine Patients.

Migraine is a complex disabling condition which is associated with dysregulation of several pathways particularly those being associated with immune responses. In order to assess contribution of protein inhibitor of activated STAT (PIAS) in the pathogenesis of migraine, we quantified expression levels of PIAS1-PIAS4 genes in the circulation of patients with migraine compared with controls. Expression of PIAS1 was substantially lower in total migraineurs compared with controls (ratio of mean expressions (RME) = 0.18, SE = 0.29, P value < 0.001) and in both male and female migraineurs compared with sex-matched controls. Expression of PIAS2 was lower in migraineurs without aura compared with controls (RME = 0.64, SE = 0.31, P value = 0.04) and in male subgroup of these patients compared with male controls (RME = 0.60, SE = 0.22, P value < 0.001). In migraineurs with aura, downregulation of PIAS2 was only observed among male subgroups (RME = 0.37, SE = 0.49, P value = 0.01). PIAS3 was downregulated in total male migraineurs (RME = 0.52, SE = 0.43, P value = 0.04) and in male migraineurs with aura (RME = 0.49, SE = 0.45, P value = 0.03) compared with male controls. Finally, PIAS4 was upregulated in total migraineurs (RME = 3.78, SE = 0. 34, P value < 0.001), female migraineurs (RME = 5.26, SE = 0.36, P value < 0.001), migraineurs with aura (RME = 4.24, SE = 0.42, P value < 0.001), female migraineurs with aura (RME = 6.13, SE = 0.47, P value < 0.001), migraineurs without aura (RME = 3.33, SE = 0.38, P value < 0.001), and female migraineurs without aura (RME = 4.47, SE = 0.41, P value < 0.001) compared with the corresponding controls. The present study suggests contribution of PIAS genes in the pathogenesis of migraine and warrants future studies to clarify the functional routes of their contribution.

Opposite trends of GAS6 and GAS6-AS expressions in breast cancer tissues.

Growth arrest-specific gene 6 (GAS6) is a growth factor-like cytokine whose function is related with vitamin K. This protein interacts with receptor tyrosine kinase proteins such as Tyro3, Axl, and TAM Receptor family, therefore affecting the tumorigenic processes via different mechanisms. GAS6-antisense 1 (GAS6-AS1) is a long non-coding RNAs (lncRNAs) that is transcribed from a genomic regions nearby GAS6. This lncRNA is also implicated in the pathobiology of cancer. We intended to judge the role of GAS6 and GAS6-AS1 in the pathogenesis of breast cancer through appraisal of their expression levels in breast cancer tissues and their paired neighboring non-cancerous samples. Expression of GAS6 was up-regulated in breast cancer tissues compared with neighboring tissues (Ratio of Mean Expressions = 2.18, P value = 4.98E-02). On the other hand, expression of GAS6-AS1 was down-regulated in breast tumor tissues compared with controls (Ratio of Mean Expressions = 0.37, P value = 4.26E-03). There were substantial correlations between expression levels GAS6 and GAS6-AS1 in non-cancerous tissues (r = 0.74, P value = 1.47e-13) and cancer tissues (r = 0.85, P value = 2.28e-20). Expression of GAS6-AS was associated with progesterone receptor status (P value = 1.36E-02). However, expressions of this gene and the sense transcript were not linked with any other clinical or demographic variable. Taken together, GAS6 and GAS6-AS1 might partake in the development of breast cancer.

Expression analysis of BDNF, BACE1 and their antisense transcripts in inflammatory demyelinating polyradiculoneuropathy.

Acute and chronic inflammatory demyelinating polyradiculoneuropathies (AIDP and CIDP) are two immune-related conditions in the peripheral nervous system. In the current study, we assessed expression levels of Beta-secretase (BACE1), brain-derived neurotrophic factor (BDNF) and their antisense transcripts in the peripheral blood of AIDP and CIDP patients compared with age- and sex-matched controls to assess their potential as biomarkers for these conditions. Expressions of BACE1 and BACE1-AS were down-regulated in CIDP cases compared with controls (Ratios of mean expressions=0.01 and 0.03; P values= 1.07E-08, respectively). On the other hand, expressions of BDNF and BDNF-AS were up-regulated in CIDP cases compared with controls (Ratios of mean expressions=4.78 and 25.71; P values= 7.84E-03 and 2.66E-07, respectively). Expressions of BACE1 and BACE1-AS were lower in AIDP cases compared with controls (Ratios of mean expressions=0.00; P values= 6.92E-10 and 8.04E-10, respectively). While expression of BDNF was not different between AIDP cases and controls, expression of its antisense transcript was higher in total AIDP cases compared with total controls (Ratio of mean expression= 8.61, P value=3.69E-04). Expressions of BACE1-AS, BDNF and BDNF-AS were significantly higher in CIDP cases compared with AIDP cases (Ratios of mean expression=1.98, 3.49 and 2.99; P values=4.67E-02, 4.67E-04 and 8.94E-03 respectively). Expression levels of BACE1, BACE1-AS and BDNF-AS could distinguish AIDP and CIDP cases from healthy subjects. BACE1 had the best diagnostic values in differentiation of CIDP and AIDP cases from controls (AUC values=0.88 and 0.91, respectively). Combination of all genes enhanced the diagnostic power to 0.96, 0.97 and 0.97 for differentiation between CIDP/controls, AIDP/controls and all patients/controls, respectively. Taken together, these genes might be implicated in the pathogenesis of AIDP and CIDP and can be suggested as putative markers for these conditions.

Over-Expression of Immune-Related lncRNAs in Inflammatory Demyelinating Polyradiculoneuropathies.

Long non-coding RNAs (lncRNAs) have crucial roles in the pathogenesis of immune-related disorders. However, their role in the pathobiology of inflammatory demyelinating polyradiculoneuropathies remains unclear. In the current study, we measured peripheral expression of four lncRNAs, namely TUG1, FAS-AS1, NEAT1, and GAS5, in patients with acute/chronic inflammatory demyelinating polyradiculoneuropathies (AIDP/CIDP) compared with healthy subjects. Notably, all lncRNAs were over-expressed in patients compared with controls (P < 0.0001 for all lncRNAs). When assessing their expressions in AIDP and CIDP groups separately, TUG1 and NEAT1 were up-regulated in both patient groups compared with controls, yet FAS-AS1 and GAS5 were only up-regulated in CIDP cases. There were remarkable pairwise correlations between expression levels of these lncRNAs in all study groups. Based on the above-mentioned data, we suggest participation of these for lncRNAs in the pathogenesis of inflammatory demyelinating polyradiculoneuropathies. Moreover, FAS-AS1 and GAS5 lncRNAs have type-specific roles in this regard. Future functional studies are needed to elaborate the molecular mechanisms of the contribution of these transcripts in AIDP/CIDP.