The Effect of Interferon Beta and Natalizumab on miR-20b Expression in Patients with Relapsing-Remitting Multiple Sclerosis is Potentially Mediated by Modulation of the Jak-STAT Signaling Pathway: A Case-control Study.

Background: The mechanisms of the function of interferon beta (IFN-ß) and natalizumab (NTZ) in multiple sclerosis (MS) patients have not yet been fully understood. Over the past decades, many studies have been conducted to evaluate gene expression changes especially regulatory non-coding RNAs such as microRNAs (miRNAs) following therapy in MS patients. Objective: To assess the changes in the expression of miR-20b in MS patients treated with IFN-ß or NTZ. Methods: Sixty patients with relapsing-remitting MS (RRMS) and 30 healthy controls (HCs) were enrolled. The patients were categorized as untreated (N=20), IFN-ß-treated (N=20), and NTZtreated (N=20). For the expression analysis, real-time PCR was performed on the whole blood. The bioinformatic tools were applied for signaling pathways enrichment analysis of miR-20b targetome. Results: The relative expression of miR-20b was significantly downregulated in the untreated patients compared with the HCs (-1.726-fold, p<0.001), while IFN-ß-treated and NTZ-treated patients showed no statistical difference compared with the HCs (0.733-fold, p=0.99 for IFN-ß and 1.025-fold, p=0.18 for NTZ). This indicates the restoration of miR-20b expression to normal level in the treated patients. Additionally, in silico analysis demonstrated that the Jak-STAT signaling pathway is enriched with miR-20b targets (p<0.0001). Conclusion: Our findings suggest that the positive effects of IFN-ß and NTZ in the RRMS patients could be potentially mediated by returning miR-20b expression to baseline.

RARS1-related hypomyelinating leukodystrophy-9 (HLD-9) in two distinct Iranian families: Case report and literature review.

BACKGROUND: Hypomyelinating leukodystrophy-9 (HLD-9) is caused by biallelic pathogenic variants in RARS1, which codes for the cytoplasmic tRNA synthetase for arginine (ArgRS). This study aims to evaluate the clinical, neuroradiological, and genetic characteristics of patients with RARS1-related disease and determine probable genotype-phenotype relationships. METHODS: We identified three patients with RARS1 homozygous pathogenic variants. Furthermore, we performed a comprehensive review of the literature. RESULTS: Homozygous variants of RARS1 (c.2T>C (p.Met1Thr)) were identified in three patients with HLD-9. Clinical symptoms were severe in all patients. Following the literature review, thirty HLD-9 cases from eight studies were found. The 33 patients' main symptoms were hypomyelination, language delay, and intellectual disability or developmental delay. The mean age of onset for HLD9 in the group of 33 patients with a known age of onset was 5.8 months (SD = 8.1). The interquartile range of age of onset was 0-10 months. Of the 25 variants identified, c.5A>G (p.Asp2Gly) was identified in 11 patients. CONCLUSION: Pathogenic variants in RARS1 decrease ArgRS activity and cause a wide range of symptoms, from severe, early onset epileptic encephalopathy with brain atrophy to a mild condition with relatively maintained myelination. These symptoms include the classic hypomyelination presentation with nystagmus and spasticity. Furthermore, the pathogenicity of the variation c.2T>C (p.Met1Thr) has been shown.

Significant heightened methylation levels of RUNX3 gene promoter in patients with systemic lupus erythematosus.

OBJECTIVE: Researchers are actively investigating new diagnostic and prognostic biomarkers that offer improved sensitivity and specificity for systemic lupus erythematosus (SLE). One area of interest is DNA methylation changes. Previous studies have shown a connection between the RUNX3 gene dysfunction and SLE. In this study, the focus was on examining the methylation level of the RUNX3 promoter in peripheral blood mononuclear cells (PBMCs) of SLE patients and healthy individuals. METHODS: A total of 80 individuals diagnosed with SLE from Iran, along with 77 healthy individuals, were included. The methylation levels of the RUNX3 gene in the extracted DNA were evaluated using the MethyQESD method. To determine the diagnostic effectiveness of the RUNX3 promoter methylation level, a receiver operating characteristic (ROC) curve was generated. RESULTS: The methylation of the RUNX3 promoter was found to be significantly higher in patients with SLE compared to healthy individuals (p < .001). This difference in methylation levels was observed between SLE patients and healthy individuals and between SLE patients with renal involvement and those without renal involvement (86.29 ± 10.30 vs 40.28 ± 24.21, p < .001). ROC analyses revealed that the methylation level of the RUNX3 promoter had a diagnostic power of 0.769 [95% CI (0.681-0.814)] for SLE. Additionally, there was a positive correlation between the RUNX3 methylation level and levels of creatinine and C4. CONCLUSION: The findings of this study emphasize the potential use of RUNX3 methylation levels in PBMCs of SLE patients as biomarkers for diagnosing the disease, predicting renal damage, and assessing disease activity.

Characterizing Homozygous Variants in Bardet-Biedl Syndrome-Associated Genes Within Iranian Families: Unveiling a Founder Variant in BBS2, c.471G>A.

Bardet-Biedl syndrome (BBS) is a rare inherited ciliopathy disorder characterized by a broad spectrum of clinical symptoms such as retinal dystrophy, obesity, polydactyly, genitourinary and kidney anomalies, learning disability, and hypogonadism. The understanding of the variants involved in BBS-causing genes remains incomplete, highlighting the need for further research to develop a molecular diagnostic strategy for this syndrome. Singleton whole-exome sequencing (WES) was performed on sixteen patients. Our study revealed (1) nine patients carried eight homozygous pathogenic variants with four of them being novel (2) Specifically, a synonymous splicing variant (c.471G > A) in BBS2 gene in six patients with Baloch ethnicity. The identification of runs of homozygosity (ROH) calling was performed using the BCFtools/RoH software on WES data of patients harboring c.471G > A variant. The presence of shared homozygous regions containing the identified variant was confirmed in these patients. In-silico analysis predicted the effect of the c.471G > A variants on BBS2 mRNA splicing. This variant results in disrupted wild-type donor site and intron retention in the mature mRNA. (3) And a deletion of exons 14 to 17 in the BBS1 gene was identified in one patient by Copy-Number Variation (CNV) analysis using the ExomeDepth pipeline. Our results identified the founder variant c.471G > A in the BBS2 gene in the Baloch ethnicity of the Iranian population. This finding can guide the diagnostic approach of this syndrome in future studies.

Discriminative features in White-Sutton syndrome: literature review and first report in Iran.

White-Sutton Syndrome is one of the rare neurodevelopmental disorder inherited in an autosomal dominant manner, mainly caused by de novo mutations in the POGZ gene and shows many phenotypic signs such as intellectual disability, Autism Spectrum Disorder and other spectra. About 70 patients with this syndrome have been reported worldwide. In this paper, we have described different phenotypic features of the White-Sutton Syndrome with a brief review of recent literatures. Finally, we have reported an Iranian male with intellectual disability and visual impairment. We have explained the clinical symptoms of the patient and have compared the patient's phenotype with existing data from individuals with White-Sutton Syndrome. The results of Whole Exome Sequencing test, performed for the patient, declared the presence of a de novo mutation in POGZ gene and confirmed the White-Sutton Syndrome diagnosis.

Association of MMP2 and MMP9 gene polymorphisms with nonsyndromic cleft lip/palate in an Iranian population.

Background: Cleft lip/palate (CL/P) is a prevalent congenital disorder. Matrix metalloproteinases (MMPs) play a role in palatogenesis and have been proposed to be associated with nonsyndromic CL/P development. This study aimed to examine the association of MMP2 (rs243866) and MMP9 (rs3918242) gene polymorphism with nonsyndromic CL/P in an Iranian population. Methods: Blood samples were collected from 120 nonsyndromic CL/P patients and 140 healthy newborns in this case-control study. DNA extraction was performed by the salting-out method, and the samples underwent polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP), using Pag and SphI enzymes, for genotyping MMP2 and MMP9 gene polymorphisms. Statistical analysis was performed with SPSS 11.5. Univariate and multivariate logistic regression models were used to calculate the odds ratios and 95% confidence intervals (CIs). The level of statistical significance was set at P<0.05. Results: No significant association was found between MMP2 gene polymorphism and nonsyndromic CL/P. However, the MMP9 gene polymorphism had a significant association with nonsyndromic CL/P, with a higher prevalence of the T allele and TT genotype in the case group than the control group. Conclusion: This study indicated a potential link between MMP9 gene polymorphism and nonsyndromic CL/P in an Iranian population. Future investigations with greater sample diversity and larger sample sizes are required to obtain more comprehensive and robust evidence. In-depth analyses and studies involving different ethnic groups can further enhance our understanding of the genetic underpinnings of CL/P.

Whole-exome sequencing revealed a novel homozygous missense variant in OSGEP gene: a case report of Galloway-Mowat syndrome in Iran.

Galloway-Mowat syndrome is a rare autosomal-recessive genetic disorder that is characterized by variety of complications such as neurological abnormalities and early-onset progressive kidney disease. Studies have been shown that pathogenic mutations in genes that belong to the KEOPS complex lead to Galloway-Mowat syndrome. Several pathogenic mutations in OSGEP gene, a member of the KEOPS complex, have been detected in Galloway-Mowat syndrome. Here we describe a 12-year-old male with intellectual disability, poor speech, seizures, microcephaly, and nephrotic syndrome that were in favor of Galloway-Mowat syndrome, born to a healthy Iranian consanguineous parents. Extracted genomic DNA from blood sample was used to perform whole-exome sequencing in the patient. The mutational screening revealed a novel homozygote OSGEP gene missense variant. Our finding established whole-exome sequencing as a valuable technic for the detection of rare variants.

Protective effects of Herbal Compound (IM253) on the inflammatory responses and oxidative stress in a mouse model of multiple sclerosis.

Multiple sclerosis (MS) is a multifactorial chronic inflammatory demyelinating disease of the central nervous system with both immune and neurodegenerative components as the underlying causes. Cytokines are key components of the inflammatory processes and their crucial roles in the inflammatory aspect of MS are undeniable. Several studies have pointed to the apparent change in Cytokines in MS. The aim of this study was to investigate the effects of IM253 treatment on inflammation and antioxidant defense in the cerebral corpus callosum of the C57BL/6 mouse, an Experimental autoimmune encephalomyelitis (EAE) model and as a most commonly used experimental model of MS. During the course of study, clinical evaluation was performed and eventually histological and molecular analysis on brain samples was carried out. Gene expression analyses demonstrated that treatment with IM253 causes a significant reduction in the expression of pro-inflammatory cytokine coding genes including IL-6, TNF-α, IFN-γ, and IL-17 as well as a significant increase in the expression of anti-inflammatory and anti-oxidant enzyme coding genes including TGF-ß, GPX-1, and Cat. Histological studies also show that treatment with IM253 can reduce demyelination and inflammation (p<0.001). In addition, the GPX-1 enzyme activity evaluation also demonstrated that total antioxidant capacity was significantly higher in IM253 treated mice (p<0.001). Overall, our results suggest that IM253 could ameliorate the severity of EAE, probably because of its anti-inflammatory and anti-oxidant properties, and support the preclinical effects of IM253 as a potential therapeutic intervention.

miRNA-binding site polymorphism in IL-15RA gene in rheumatoid arthritis and systemic lupus erythematosus: correlation with disease risk and clinical characteristics.

INTRODUCTION/OBJECTIVES: MiRSNPs may interfere with mRNA stability through effects on microRNAs (miRNAs)-mRNA interactions via direct changes in miRNA binding site or effect on the secondary structure of this region and changes in accessibility of this region to miRNAs. Studies have confirmed that an elevated level of interleukin-15 receptor alpha (IL-15RA) has an important role in the pathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In the present study, for the first time, we aimed to evaluate the possible correlation between a miRSNP, rs2296135, in IL-15RA gene with the risk of SLE and RA. METHODS: In this case-control study, 100 SLE patients, 100 RA patients, and 110 healthy participants were enrolled to assess rs2296135 genotypes with real-time PCR high-resolution melting method. RESULTS: According to our findings, AA genotype and A allele of rs2296135 were considerably associated with enhanced risk of RA (for AA genotype, OR = 2.29; 95% CI [1.06-5.02]; for A allele, OR = 1.65; 95% CI [1.10-2.48]). However, this common variant was not significantly correlated with SLE risk in population under study. Stratification analysis in the RA group verified that patients with the A allele had considerably higher serum concentrations of C-reactive protein (CRP) (P < 0.001). In SLE subjects, the frequency of arthritis (P: 0.021) and renal involvement (P: 0.025) in patients with A allele was significantly higher than in other SLE individuals. CONCLUSION: The current study proposes a substantial association between rs2296135 polymorphism in IL-15RA gene with augmented risk of RA and some clinical characteristics in RA and SLE patients.

Association of rs2013162 and rs2235375 Polymorphisms in IRF6 Gene with Susceptibility to Non-Syndromic Cleft Lip and Palate.

Background: Non-syndromic cleft lip occurs by the interaction of environmental and genetic factors. The purpose of the current study was to analyze the association of Single Nucleotide Polymorphisms (SNPs) in IRF6 and NSCL/P in an Iranian population. Methods: A group of 105 children with NSCL/P and 185 normal controls were included in the current study. Genotyping of IRF6 rs2013162 and rs2235375 was performed by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. Results: A substantial association of AA and CA genotypes in rs2013162 with the risk of NSCL/P (AA vs. CC; OR=2.36; 95%CI [1.05-5.29], p=0.004; and CA vs. CC; OR=0.47; 95%CI [0.28-0.79], p=0.018) was found. However, there were no important associations between A allele and risk of NSCL/P (p=0.980). According to logistic regression analysis results, subjects with GG genotype and G allele in rs2235375 polymorphism had increased risk of NSCL/P. Conclusion: The IRF6 polymorphisms are associated with the susceptibility to NSCL/P in Iranian population.

Association of a miRNA-binding site polymorphism in IL-16 gene with disease risk and clinical characteristics of rheumatoid arthritis and systemic lupus erythematosus.

INTRODUCTION: /objectives. Single nucleotide polymorphisms (SNPs) located at the 3'-UTR region of the target genes of microRNAs (miRNAs) can dysregulate their expression via disrupting the binding site of miRNAs. Interleukin-16 (IL-16) is involved in the pathogenesis of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In the current study, we assessed the possible association between rs1131445 polymorphism in IL-16 gene with risk and clinical characteristics of RA and SLE in the Iranian population. METHODS: In this case-control study, 120 patients with RA, 120 patients with SLE, and 120 unrelated healthy subjects were collected to estimate rs1131445 (T > C) polymorphism in IL-16 gene using real-time PCR high-resolution melting (HRM) method. RESULTS: Our results demonstrated considerable associations between TC genotype and C allele of rs1131445 with enhanced risk of RA (ORfor TC genotype = 3.01; 95%CI [1.667-5.526], P < 0.001; ORfor C allele = 1.96; 95%CI [1.314-2.941], P < 0.001). Besides, there was a marginal association between CC genotype and increased risk of RA (P: 0.031). However, there was an insignificant correlation between genotypes and allele frequencies of rs1131445 with incidence risk of SLE (P > 0.05). Moreover, stratification analysis indicated that the C allele in rs1131445 was linked with disease activity-associated laboratory parameters such as CRP and ESR in both RA and SLE patients, as well as the higher incidence of neurological symptoms in SLE subjects (P < 0.05). CONCLUSION: These results proposed a significant association between IL-16 polymorphism and augmented risk of RA and clinical characteristics of RA and SLE.

Identification of causative gene mutation in an Iranian family with coloboma and nephropathy using whole exome sequencing.

Pathogenic variants in FAT1 gene have recently been described in association with coloboma, nephropathy, and facial dismorphism. Here we describe a 5-year-old Iranian boy with iris coloboma and nephropathy, born to an Iranian family. Extracted genomic DNA from blood sample was used to perform whole exome sequencing in the patient. The mutational screening revealed a homozygote Fat1 gene mutation c.5320A > G (p.17747Val), not previously reported in homozygote state in Iran. Our findings establish FAT1 as a gene with pleiotropic effects in human, emphasizing it as one of the causative genes in syndromic nephropathies.

Impact of miRNA-binding site polymorphisms in STAT3 gene on occurrence and clinical characteristics of systemic lupus erythematosus.

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) is a major regulator of immune response and chronic inflammatory conditions acting through regulation of B cells, T-helper 17 (Th17) cells, and IL-17 production. Previous studies have demonstrated that dysregulation of STAT3 is crucial for SLE pathogenesis and disease severity. It is believed that single nucleotide polymorphisms (SNPs) located at the 3'-UTR sequence of the target genes could dysregulate their expression by disrupting the binding site of miRNAs. In the present study, we assessed the possible association between rs1053005 and rs1053023 SNPs at miRNA binding sites in the STAT3 gene and the risk of SLE in the Iranian population for the first time. METHODS: 112 SLE cases and 120 healthy controls were genotyped for rs1053005 (A>G) and rs1053023 (A>G) polymorphisms in STAT3 using real-time PCR high resolution melting method (HRM). RESULTS: Our results revealed substantial associations between GG genotype and G allele of rs1053023 with enhanced risk of SLE (OR for GG genotype= 3.13; 95%CI [1.61-6.1], OR for G allele = 2.22; 95%CI [1.51-3.25]). However, no important correlations have been found between rs1053005 polymorphism and SLE susceptibility in this population (p>0.05). Moreover, stratification analysis showed that these polymorphisms are correlated with parameters indicating disease activity and more severe course of the disease. These factors include some laboratory test results and clinical manifestations such as renal involvements. CONCLUSION: The current study suggests a significant association between STAT3 polymorphisms and augmented risk of SLE, clinical symptoms, disease activity, and severity.

Whole Exome Sequencing Identified the Causative Mutation in a 4-Year-Old Female with Mulibrey Nanism: A Case Report.

Mulibrey Nanism is a rare multisystem disorder inherited in an autosomal recessive manner caused by mutations in the TRIM37 gene. Most of the reported cases are from Finland, but this condition has rarely occurred in other countries. Although the clinical diagnosis of Mulibrey nanism is a challenge during the first months of life, the disease can be suspected clinically due to the distinctive features of the patients. A 4-year-old female with pneumonia, cardiomyopathy, growth retardation, peripheral edema, and characteristic craniofacial features was referred to Tehran Hope Generation Foundation Genetic diagnosis Center, in October 2021. Genomic DNA was isolated from peripheral blood samples of the patient and her parents and Whole exome sequencing was performed for the patient. Whole exome sequencing revealed a homozygous G>A splice site variant (TRIM37; c.370-1G>A). Sanger sequencing confirmed the segregation of the variant with phenotype in this family. Whole exome sequencing can be helpful in the diagnosis of the patients suspecting to Mulibrey nanism and lacking sufficient clinical presentation according to the diagnostic algorithm.

Frequency of HLA Alleles in a Group of Severe COVID-19 Iranian Patients.

BACKGROUND: Human Leukocyte Antigen (HLA) system composed of a group of related proteins with important functions in the immune system. Several studies have reported that there is a significant association between specific HLA alleles and the susceptibility to different infectious diseases. This study aimed to detect the specific HLA alleles that cause higher susceptibility to COVID-19, we analyzed the HLA allele frequency distribution in Iranian patients with a severe form of COVID-19. METHODS: Overall, 48 severe cases of COVID-19 that were hospitalized and required intensive care unit (ICU) admission between Oct and Dec 2020 were included in this study. Genomic DNA was extracted from the peripheral blood samples and HLA typing (Locus A, B, and DR) was performed for the patients. RESULTS: After analyzing and comparing the results with a reference group of 500 Iranian individuals, a significant association was found for HLA-B*38, HLA-A*68, HLA-A*24, and HLA-DRB1*01. CONCLUSION: These results may be valuable for studying the potential association of specific HLA alleles with susceptibility to COVID-19 and mortality due to the disease.

Association of Three Functional Polymorphisms in the NLRP3 Gene with Susceptibility to Rheumatoid Arthritis in the Iranian Population.

BACKGROUND: Rheumatoid arthritis (RA) is a complex systemic autoimmune disorder with multifactorial nature. Numerous previous studies have shown that several genes are involved in the pathogenesis and increased risk of RA. The Nod-like receptor pyrin domain containing 3 (NLRP3) is involved in the regulation of innate immunity and its upregulation has previously been reported in RA. OBJECTIVE: To evaluate the correlation between 3 functional polymorphisms of NLRP3 and its gene expression and RA risk. METHOD: One hundred and fourteen patients with RA and 120 healthy participants were recruited to this case-control study. Genotyping of rs4612666 (intronic variant), rs10754558 (3UTR variant), and rs6672995 (downstream variant) were performed applying the real­time polymerase chain reaction high­resolution melting (HRM) method. RESULTS: Based on logistic regression analysis, subjects with CC genotype and C allele in rs4612666 had increased risk of RA (OR for CC genotype= 3.10; 95%CI [1.78-8.26]/ OR for C allele= 2.00; 95%CI [1.45-3.10]). Furthermore, in the patient groups, there was a significant relationship between the concentration of C-reactive protein (CRP) and rs4612666 and rs10754558 polymorphism (p < 0.05). Besides, our results revealed no significant association between the genotype and allele frequency of rs10754558 and rs6672995 and the risk of RA (P> 0.05). CONCLUSION: Our findings propose a significant association between rs4612666 polymorphism and increased risk of RA in the Iranian population. Moreover, rs4612666 and rs10754558 were correlated with disease activity.

Investigation of rs531564 Polymorphism in the Primary MicroRNA-124 Gene in Patients with Systemic Lupus Erythematosus and Rheumatoid Arthritis: Association with Disease Susceptibility and Clinical Characteristics.

MicroRNA-124 (miR-124) is known as an important regulator of the immune system and inflammatory response. Studies have reported that this miRNA is dysregulated in autoimmune disorders such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). A functional analysis demonstrated that rs531564 (C>G) affects the biogenesis of primary microRNA transcript-124 (pri-miR-124) and changes the expression of mature miR-124. In the present study, for the first time, we intended to evaluate the possible association between rs531564 polymorphism with SLE and RA risk.  In this case-control study, 110 patients with SLE, 115 patients with RA, and 120 healthy subjects were enrolled to evaluate rs531564 genotypes with real-time polymerase chain reaction (PCR) high resolution melting method. Our findings demonstrated that frequency of GC genotype and G allele were considerably higher in the control group than RA patients, demonstrating that that GC genotype and G allele have a protective effect for healthy individuals (GC vs CC; OR: 0.29; 95%CI [0.12,0.67] and G vs C; OR: 0.42; 95%CI [0.23,0.78]). However, no significant correlation was confirmed between allele and genotype frequencies of rs531564 with SLE risk (p>0.05). However, the G allele in rs531564 polymorphism was associated with serum level of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti-dsDNA antibody, C3, C4, and creatinine, and frequency of renal involvements in SLE patients (p<0.05). Moreover, in RA patients, the G was correlated with lower concentration ESR and CRP (p<0.001).  Our findings propose a considerable association between rs531564 polymorphism in the pri-miR-124 gene with susceptibility and clinical characteristics of RA and SLE in the Iranian population.

Strong association of common variants in the miRNA-binding site of NOD2 gene with clinicopathological characteristics and disease activity of systemic lupus erythematosus.

INTRODUCTION/OBJECTIVES: Systemic lupus erythematosus (SLE) is a multifactorial systemic autoimmune disease, in which genetic susceptibility plays a pivotal role. The nucleotide oligomerization domain 2 (NOD2) gene is one of the main regulators of chronic inflammatory conditions and could be involved in SLE pathogenesis. Single nucleotide polymorphisms (SNPs) in miRNA binding sites which are located in 3'UTR of the NOD2 gene could be associated with SLE risk by dysregulation of NOD2 expression. In the present study, we assessed the possible association between SNPs rs3135500 and rs3135499 in the NOD2 gene with SLE risk in the Iranian population. METHODS: A case-control study using 110 SLE patients and 120 control subjects was undertaken to estimate rs3135500 (G > A) and rs3135499 (A > C) genotypes via real-time PCR high-resolution melting method (HRM). RESULTS: No significant association was observed between allele and genotype frequencies of rs3135500 and rs3135499 polymorphisms and SLE risk in this population (P > 0.05). However, there was an obvious association between rs3135500 (A allele) with laboratory factors that are associated with disease activity (P < 0.05) and some clinical manifestations that are associated with disease severity such as neurological symptoms, skin manifestations, renal involvements, and higher serum concentration of creatinine (P < 0.05). Besides, rs3135499 (C allele) was correlated with renal involvement and also the concentration of creatinine (P < 0.05). Moreover, in the patients group, the risk alleles in these polymorphisms were associated with lower age of onset (P < 0.05). CONCLUSIONS: Our results suggest a substantial association between NOD2 polymorphisms with clinicopathological characteristics and SLE disease activity. Key Points • Single nucleotide polymorphisms (SNPs) in miRNA binding sites which are located in 3'UTR of the NOD2 gene could be associated with SLE risk by dysregulation of NOD2 expression. • Our results suggested that two miRSNPs (rs3135500 and rs3135499) in the NOD2 gene were meaningfully correlated with clinicopathological characteristics and disease activity of SLE.

Three functional variants in the NLRP3 gene are associated with susceptibility and clinical characteristics of systemic lupus erythematosus.

OBJECTIVE: Nod-like receptor pyrin domain containing 3 (NLRP3) gene encodes an intracellular receptor whose dysregulation in systemic lupus erythematosus (SLE) has been reported in multiple studies. Activation of NLRP3 inflammasome leads to the induction of inflammatory response via cleaving and producing of specific cytokines. In the present study, we assessed the possible association between three functional polymorphisms in this gene and SLE risk in the Iranian population. These variants include two gain of function (rs4612666 and rs10754558) and one loss of function (rs6672995) which are correlated with modulation of expression of NLRP3. METHODS: A case-control study involving 110 SLE patients and 116 control subjects was undertaken to estimate the frequency of rs4612666, rs10754558, and rs6672995 genotypes using real-time PCR high resolution melting method (HRM). RESULTS: Our findings revealed significant associations between GG genotype and G allele of rs10754558 with increased risk of SLE (OR for GG genotype= 2.82; 95%CI [1.45-5.46]/OR for G allele= 1.97; 95%CI [1.36-2.87]). Although, no significant associations were recognized between allele and genotype frequencies of rs4612666 and rs6672995 polymorphisms with SLE risk (P > 0.05). Also, our analysis revealed that the C allele in rs4612666 and G allele in rs10754558 was correlated with the severity of disease activity (P < 0.001). Moreover, these common variants were associated with lower age of onset and some clinical symptoms in the patient group, such as skin manifestation, neurological symptom and, renal involvement (P < 0.05). CONCLUSION: This study demonstrates a substantial association between NLRP3 polymorphisms with increased risk, clinical symptoms, and the severity of disease activity of SLE.