Multiple Sclerosis In Iranian Population Research Articles

MicroRNAs expression in peripheral blood mononuclear cells of patients with multiple sclerosis propose.

MicroRNAs (miRs) are involved in the autoimmune and neurological diseases, including multiple sclerosis (MS), through modulating post-transcriptional gene regulation. Accumulating evidence indicates that miR-10, miR-24a, miR-124, and miR-21 play an imperative role in MS pathogenesis. Therefore, the current research aimed to analyze the expression of the selected miRNAs for MS in Iranian population. Blood sample of 75 relapsing-remitting MS (RRMS) patients and 75 healthy individuals suffering no neurodegenerative illness was collected. Subsequently, the isolation of peripheral blood mononuclear cells (PBMCs) was performed by employing Ficoll-Hypaque density gradient method. Afterward, total RNA was extracted and subjected to qRT-PCR analysis. The obtained results evidenced that the relative expression of miR-10 (P = 0.0002), miR-21 (P = 0.0014), and miR-124 (P = 0.0091) significantly decreased in RRMS patients compared to healthy participants. On the contrary, no notable change was observed between the studies groups regarding miR-24a expression levels (P = 0.107). ROC curve analysis estimated an area under the curve (AUC) value equal to 0.75 with P = 0.0006 for miR-10, while it was decreased for miR-21 (AUC = 0.67 and P = 0.0054) and miR-124 (AUC = 0.66 and P = 0.012). The change in miR-10, miR-124, and miR-21 expression patterns was implied to participate in MS development. Further large scale observational studies are recommended.

Investigating the association of polymorphisms of ANKRD55 and MMEL1 with susceptibility to multiple sclerosis in Iranian population

Objective Multiple sclerosis (MS) is an autoimmune neurological disability in which immune cells attack the myelin sheaths that protect nerve fibers. The pathogenesis of the disease involves both complex genetic effects as well as multifaceted gene-environment interactions. In the present study, we examined the association of two Single nucleotide polymorphisms (SNPs) in ANKRD55 (rs6859219) and MMEL (rs3748816) with MS in the Iranian population. ANKRD55 is specifically expressed in human peripheral blood mononuclear cells and CD4 + T cells, while MMEL1is involved in the degradation of both neuropeptides and β-amyloid. Methods In this case-control study, 110 patients with MS and 110 matched healthy controls were enrolled. The Participants were genotyped for ANKRD55 and MMEL1 SNPs using PCR-RFLP and Real-Time TaqMan SNP Genotyping respectively. The results were finally analyzed using SPSS software version 22. Results Our results did not show significant differences in allelic frequencies of two SNPs among cases and controls (P-Value >0.05). However, for ANKRD55 (rs6859219), CA genotype was shown to have a protective effect (p = 0.035 and OR = 0.55), while CC genotype was a susceptive genotype to MS (p = 0.036 and OR = 1.8). There was no significant difference in genotypic frequencies of SNP rs3748816 in MMEL1. Conclusion We could successfully replicate the association of ANKRD55 (rs6859219) with susceptibility to MS in the Iranian population. Our result can provide an insight into better understanding the pathogenesis of MS and also improve the genetic counseling for patients affected with multiple sclerosis in Iran.

Association of rs12487066, rs12044852, rs10735781, rs3135388, rs6897932, rs1321172, rs10492972, and rs9657904 Polymorphisms with Multiple Sclerosis in Iranian Population.

ObjectivesMultiple sclerosis (MS) is a chronic disease of the central nervous system. The pathogenesis of MS is best described by a multifactorial model incorporating interactions between genetic and environmental factors with the role of genetic factors increasingly taken into account. The main goal of this study was to investigate the associations of rs12487066, rs12044852, rs10735781, rs3135388, rs6897932, rs1321172, rs10492972, and rs9657904 polymorphisms with MS in the Iranian population.MethodsA total of 83 patients with MS (82.0% female and 18.0% male; mean age = 35.2±8.6 years) and 100 physically and mentally healthy subjects (81.0% female and 19.0% male; mean age = 40.4±6.4 years) were selected using convenient sampling. A 5 mL blood sample was taken from each case and control patient. We used the tetra-primer ARMS-PCR method to genotype the desired polymorphisms. The associations between polymorphisms and the disease were studied based on codominant, dominant, recessive, and overdominant models.ResultsThe rs10735781 polymorphism was codominantly (p = 0.029), overdominantly (p = 0.008), and dominantly (p = 0.009) associated with the disease. The rs6897932 was also found to be codominantly (p = 0.012), dominantly (p = 0.019), and recessively (p = 0.011) associated with the disease.ConclusionsWe found an association between the rs10735781 and rs6897932 polymorphisms on the EVI5 and IL7RA genes, respectively, with increased MS in the Iranian population. Therefore, single nucleotide polymorphisms in the EVI5 and IL7RA genes can be considered a prognostic marker of MS.

Association between interleukin 2 receptor A gene polymorphisms (rs2104286 and rs12722489) with susceptibility to multiple sclerosis in Iranian population

Multiple sclerosis (MS) is an organ-specific autoimmune disorder with remarkable heritability. For MS disorder, interleukin 2 receptor α subunit (IL2RA) is regarded as a genetic risk factor.There was a statistically significant association between alleles and genotypes of rs12722489 SNP and MS risk. The levels of mRNA expression and serum IL-2RA were higher in MS patients than in healthy controls. mRNA expression and serum concentrations of IL-2RA were higher in MS patients with CC genotype for rs12722489 compared with the rest of patients.Our result demonstrate that the rs12722489 SNP within IL2RA gene might be associated with MS pathogenesis through regulating the levels of IL-2RA (or CD25), which is important in the regulation of T cells.

RAGE p.82G>S Polymorphism Is Not Associated with the Risk of Multiple Sclerosis in Iranian Population

Background and Aims: Multiple sclerosis (MS) is known as a partially inheritable inflammatory autoimmune disease which involves the nervous system. Different studies suggest that immune dysregulation has an important role in the pathogenesis of MS, but its exact pathomechanism has not yet been explicated. The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules. In MS patients, the expression of membrane-bound RAGE on peripheral blood mononuclear cells, as well as the serum levels of the RAGE ligands are upregulated. Materials and Methods: In this case-control study, we evaluated the association between MS incidence and RAGE p.82G>S polymorphism (rs2070600) compared with healthy controls in an Iranian population. A total of 158 patients and 156 healthy blood donors were enrolled. This polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Results: Allele frequencies (p=0.319) and genotype distribution (p=0.315) of the RAGE p.82G>S gene polymorphism in MS patients and controls were not significantly different. Conclusions: The present study indicated no relationship between RAGE p.82G>S polymorphism and the risk of MS in Iranian population.

The rs4759314 SNP within Hotair lncRNA is associated with risk of multiple sclerosis

Recent studies have demonstrated the role of long non-coding RNAs (lncRNAs) in the pathophysiology of autoimmune disorders such as multiple sclerosis (MS). Among these transcripts is HOX transcript antisense intergenic RNA (HOTAIR) whose contribution in MS has been verified both in animal models and in human studies. In the current study, we genotyped three single nucleotide polymorphisms (SNPs) with this lncRNA (rs12826786, rs1899663 and rs4759314) in 403 Iranian MS patients and 420 healthy subjects. After correction of P values for multiple comparisons, the rs4759314 SNP was associated with risk of MS in allelic model (OR (95% CI)= 1.34 (1.08–1.67), adjusted P value=0.02). The other SNPs were not associated with risk of MS in any inheritance model. The C G A haplotype (rs12826786, rs1899663 and rs4759314, respectively) was less prevalent in cases compared with controls (OR (95% CI)= 0.73 (0.59–0.90), adjusted P value=0.03). The T G A haplotype was more common among cases compared with controls (OR (95% CI)= 1.58 (1.20–2.08), adjusted P value=0.01). Taken together, HOTAIR might be regarded as a risk locus for MS in Iranian population.

The association analysis between rs1544410 and rs10735810 polymorphisms located at VDR gene and susceptibility to Multiple Sclerosis in Iranian population

Multiple Sclerosis (MS) has been known to be one of the most common chronic inflammatory diseases with incidence almost 1 in 1000 individuals. Given that the vitamin D was involved in the regulation of immune response, the association of polymorphisms of this gene with MS risk has been reported in different Caucasian populations as well as Asians. In the present study, the association of two vitamin D receptor (VDR) polymorphisms including rs1544410 and rs10735810 with susceptibility to MS in Iranians was investigated. This study was performed on 118 MS patients and 120 healthy individuals. After extraction of genomic DNA from peripheral blood, the polymorphisms rs1544410 and rs10735810 were genotyped by PCR-RLFP. The results obtained from this study indicated that there was a significant association between rs1544410 and risk of affecting by MS in Iranians (OR = 1.96, 95% CI = 1.0–3.86, P = 0.047). In contrast, no association was observed between rs10735810 and MS susceptibility in the studied population (P > 0.05). These observations provided more understanding from the role of vitamin D metabolism in the pathogenesis of MS in Iranian population.

Single nucleotide polymorphisms of lncRNA H19 are not associated with risk of multiple sclerosis in Iranian population

Multiple Sclerosis (MS) as a chronic demyelinating disorder of the central nervous system (CNS) has been associated with dysregulation of several genetic and epigenetic factors. Long non-coding RNAs (lncRNAs) as important epigenetic regulators of gene expression might also contribute in the pathogenesis of MS. In the current study, we genotyped two single nucleotide polymorphisms (SNPs) within the lncRNA H19 (rs2839698 and rs217727) in a population of 402 MS patients and 392 healthy subjects using tetra-primer amplification-refractory mutation system-PCR technique. No significant association was found between the mentioned SNPs and MS risk in any of inheritance model. Moreover, the distributions of the four expected haplotypes were similar in MS patients and controls. Despite the previously acknowledged role of H19 in regulation of immune response, the mentioned SNPs do not contribute in the pathogenesis of MS in Iranian population. Future studies are needed to assess the associations between other SNPs within this lncRNA and risk of MS.

RAGE polymorphisms are not associated with risk of multiple sclerosis in Iranian population

Multiple sclerosis (MS) as a chronic demyelinating disorder has been related with advanced glycoxidation end products (AGEs). Receptor for AGEs (RAGE) in encoded by a gene which contains several functional single nucleotide polymorphisms (SNPs). In this investigation, we have genotyped two SNPs within this gene in 376 MS patients and 400 healthy individuals. No significant difference was detected in genotype and allele frequencies of rs184003 between cases and controls. Primarily, the rs1800625 was associated with MS risk in recessive model. However, after correction for multiple comparison, the association did not reach the level of significance. The four estimated haplotypes were similarly distributed between MS patients and healthy subjects. Consequently, our study excludes the role of mentioned SNPs in conferring risk of MS in Iranian patients. However, other SNPs within this gene might influence the risk of MS. So future genotyping of other functional variants within this gene are necessary to unravel the role of RAGE in MS.

Association study of G+2044A (R130Q) polymorphism in IL-13 gene with risk of developing Multiple Sclerosis in Iranian population

BackgroundMultiple Sclerosis (MS) is an autoimmune and progressive neurodegeneration disease of the central nervous system (CNS) that diagnosed by inflammation and demyelination of neurons. MS is a multifactorial disease that occurs due to interactions between environment and genetic factors. IL-13 is a cytokine and one of the candidate genes for MS that its expression reduces in MS patients. Material and methodsIn this study, 174 unrelated MS patients and 283 healthy individuals were examined. We assessed G+2044A (R130Q) polymorphism in exon 4, a single nucleotide polymorphism (SNP), in the coding region of the IL-13 gene. Genotyping of G+2044A polymorphism was performed using sequence-specific primer-polymerase chain reaction (SSP-PCR). ResultsNo significant association was found between Genotypes and allele frequency in patients and healthy individuals (P > 0.05). Comparison of the frequency of MS cases and healthy individuals based on ethnicity, a significant association was observed between Turkmen patients and MS with a protective role [P < 0.05, OR = 0.01, CI (0.004–0.04)] Moreover no significant association was seen between the inheritance models for the G+2044A SNP, but there is a significant association between gender and susceptibility to MS (P = 0.01). ConclusionAccording to our results, there is no significant difference in Genotype and allele frequency of G+2044A polymorphism among MS patients and healthy individuals. But a significant association was observed between Turkmen patients and MS with a protective role.

The protective role of TBX21-1514T&gt;C polymorphism in susceptibility to multiple sclerosis

Background: As a T-cell mediated disease, multiple sclerosis (MS) pathogenesis might be associated with the immune system and its involved genes. TBX21, which encodes T-bet transcription factor, is a critical regulator of the commitment to the Th1 lineage and Interferon gamma (IFNγ) production. Investigation of the association of -1514T > C polymorphism located upstream of TBX21 gene with MS susceptibility is reasonable due to its demonstrated significant association with some other immune-mediated diseases. Methods: We analyzed the genotype frequencies of -1514T > C polymorphism between 248 Iranian patients with MS and 163 matched healthy controls. By applying polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP)- technique, the single-strand conformation patterns of the amplicons were compared and sequenced. Results: Strong association between the wild -1514T allele and MS susceptibility was found with the allelic frequency of 99.6% in patients vs. 95.1% in controls (P = 0.002), and the CC genotype frequency of the TBX21 polymorphism (-1514T > C) reported potential protective effect against the disease (P = 0.014). Conclusion: The TBX21-1514T > C polymorphism confers possible protective effect on MS in Iranian population. Further comprehensive studies in different settings are required to clarify the exact role of TBX21 gene in MS disease.

A single nucleotide polymorphism in the metabotropic glutamate receptor 7 gene is associated with multiple sclerosis in Iranian population

Glutamate excitotoxicity has been previously associated with development of multiple sclerosis (MS). The metabotropic glutamate receptor 7 (GRM7) gene is a G protein-coupled receptor that suppresses the cyclic AMP cascade after activation by glutamate. Single nucleotide polymorphisms (SNPs) within this gene have been reported to be associated with neuropsychiatric disorders. In the present study, we assessed associations between two intronic variants of GRM7 (rs6782011 and rs779867) and risk of MS in an Iranian population. The rs779867 was associated with MS risk in recessive model (OR (95% CI) = 0.67 (0.48–0.94)), P-value = 0.02, adjusted P-value = 0.04). There was no significant difference in allele and genotype frequencies of rs6782011 between cases and controls. None of the estimated haplotype blocks of rs6782011 and rs779867 were associated with MS risk in the assessed population. The current study provides some evidence for participation of GRM7 in the pathogenesis of MS and warrants further studies in larger sample sizes.

Ecotropic Viral Integration Site 5 (EVI5) variants are associated with multiple sclerosis in Iranian population

BackgroundMultiple sclerosis (MS) is a multifactorial disorder with immunological basis. Numerous genetic and environmental factors contribute in its pathogenesis. Several genetic loci have been shown to be associated with MS risk. Among genes whose participation in MS has been evaluated is Ecotropic Viral Integration Site 5 (EVI5). EVI5 is a common site of retroviral integration with a possible role in T-cell lymphomagenesis. MethodsIn the current study, we aimed to confirm association of the single nucleotide polymorphisms (SNPs) within EVI5 gene with MS in 410 relapsing-remitting MS patients and 410 controls from Iranian population. The rs6680578, rs10537781 and rs11810217 genotypes were defined by amplification-refractory mutation system (ARMS)-PCR method. Results: The allele and genotype frequencies of rs6680578 and rs11810217 were not significantly different between cases and controls. However, in the rs10735781 the GG genotype was significantly associated with MS risk in recessive (P = 0.03, OR (95%CI) = 1.84 (1.05–3.19)) and co-dominant models (P = 0.02, OR 95%CI) = 1.90 (1.08–3.35)). In addition, T G T haplotype (rs6680578, rs10735781 and rs11810217 respectively) was associated with MS risk while T C C, A G T and A C T had a protective effect against MS. ConclusionThe results of the current study provide further evidences for participation of EVI5 in MS pathogenesis.

Single nucleotide polymorphisms in the FOXP3 gene are associated with increased risk of relapsing-remitting multiple sclerosis

Although Multiple Sclerosis (MS) is an autoimmune multifactorial disease with unknown etiology, various genetic and environmental factors are known to contribute to the pathogenesis of the disease. Recent studies have confirmed that the suppressive function of regulatory T cells (T (reg)) is impaired in MS patients and that the FOXP3 gene is a crucial transcription factor in the regulation of CD4+CD25+FOXP3+ Treg cells. Polymorphisms in the promoter region of the FOXP3 gene may alter the gene expression level and, therefore, contribute to the disease susceptibility. The present study aimed to investigate the possible association between single nucleotide polymorphisms (SNPs) rs3761548 and rs2232365 in the FOXP3 gene and predisposition to MS. We conducted a case-control study on 410 patients with sporadic MS and 446 healthy controls. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Significant differences in distribution of both rs3761548 and rs2232365 A allele were found in MS patients in comparison to controls. Haplotype frequencies were also different among the studied groups. The A-A and C-G haplotype blocks showed a significant difference between case and controls. we have provided further evidence for the association between genetic variations and haplotypes in FOXP3 and MS in Iranian population.

Polymorphisms of RPS6KB1 and CD86 associates with susceptibility to multiple sclerosis in Iranian population

Objective: Multiple sclerosis (MS) is the most prevalent disorder of nervous system inflammation which involves demyelination of spinal cord; this process depends on both environmental and genetic susceptibility factors. In the present study, we examined the association between two SNPs in RPS6KB1 (rs180515) and CD86 (rs9282641) with MS in Iranian population. RPS6KB1gene encodes p70S6K1 protein which plays a key role in mTOR signaling pathway, while CD86 gene codes a membrane protein type I which belongs to immunoglobulin super family act on co-stimulation signaling pathway. Methods: In this case-control study 130 patients with MS and 128 matched healthy controls were enrolled, genomic DNA was isolated and genotyping was performed using mismatched PCR-RFLP. The results were finally analyzed using SPSS. Results: Our results showed significant difference in allelic frequency of SNP rs180515 among cases and controls (P = 0.004). For this variation, AA genotype was shown to have protective effect (P = 0.016 and OR = 0.6), while GG genotype was a susceptive genotype to MS (P = 0.04 and OR = 2.2). Allelic frequency of SNP rs9282641 also showed significant difference between cases and controls (P = 0.006). For this SNP, AG genotype had predisposing effect (P = 0.04, OR = 2.3), and GG genotype showed protective (P = 0.01, OR = 0.411).Conclusion: We successfully replicated the association of two novel SNPs introduced by a GWAS study, and MS in the Iranian population. This result can open ways for better understanding the mechanisms involved in MS.

Smoking as a risk factor for development of Secondary Progressive Multiple Sclerosis: A study in IRAN, Guilan

BackgroundCigarette smoking seems to contribute to susceptibility and progression of multiple sclerosis (MS).Although the incidence of MS in Iranian population has increased during recent years, the effects of smoking on progression of MS have not been studied. The aim of this study was to investigate the association between cigarette smoking and development of secondary progressive MS (SPMS) in Iranian patients with MS. MethodsThis study was carried out on patients registered in the MS Society (Guilan, Iran) database. Using a structured questionnaire, information on smoking status of 400 of patients could be obtained. The association between cigarettes smoking and SPMS was analyzed by Cox regression model. ResultsThe relationship between smoking and development of SPMS was still evident after adjusting for age at disease onset, gender and number of relapses per year (P =0.004). Smoking more than 10 cigarettes per day increased risk of development of SPMS (HR: 2.43; 95% CI: 1.28 to 4.6; P =0.007). ConclusionsOur results indicated that smokers have an increased risk for progression of relapsing-remitting MS (RRMS) to SPMS compared with non-smokers. We also showed that the disease progression may be influenced by increase of cigarette smoking.

Interaction of HLA-DRB1*1501 allele and TNF-alpha −308 G/A single nucleotide polymorphism in the susceptibility to multiple sclerosis

Multiple sclerosis is a multifactorial disorder with complex genetic basis. It is believed that genes encoding HLA molecule and cytokines are involved in the pathogenesis of MS. In this study, we have evaluated the impact of HLA-DRB1*1501 allele and TNF-alpha -308 G/A single nucleotide polymorphism, and their interaction, in the susceptibility to MS in Iranian population. Genomic DNA samples were prepared from whole blood of 366 MS Patients and 414 control subjects. The genotypes were determined by SSP-PCR method. Frequency of alleles and genotypes were compared between the two groups by using Fisher's exact test. HLA-DRB1*1501 allele was more frequent among patients (OR=1.57, P=0.0026). TNF-α -308 G allele and G/G genotype had higher frequency among MS patients than control subjects (G vs. A: OR=1.26, P<0.05); G/G vs. A/A: OR=4.59, P=0.0003). The odds ratio was higher among HLA-DRB1*1501 positive individuals. Co-existence of TNF G and HLA-DRB1*1501 alleles showed higher prevalence among MS patients (OR=7.07, P=0.0007). Our results have shown that HLA-DRB1*1501 allele and TNF-α -308 G/A polymorphism are associated with the risk of multiple sclerosis in Iranian population. We also observed an interaction between these two loci that support the role of HLA alleles and cytokine genes and gene-gene interaction in the development and pathogenesis of MS.

Cytokines Genes Polymorphisms and Risk of Multiple Sclerosis

Association studies of proinflammatory and anti-inflammatory cytokines single nucleotide polymorphisms with multiple sclerosis (MS) in population with different ethnic background have shown inconsistent results. To study the possible role of tumor necrosis factor-α G-308A, interleukin-6G-174C, interleukin-10 C-592A, C-819T, G-1082A, transforming growth factor (TGF)-β (codons 10 and 25), and interferon-γ T+874A polymorphisms in susceptibility to MS in Iranian population, DNA samples from 98 patients and 97 healthy controls were genotyped using polymerase chain reaction- sequence-specific primers. Analysis of the genotypes revealed a significant lower frequencies of tumor necrosis factor-a GA and TGF β C/C G/G genotypes and higher frequency of TGF β T/C G/C genotype in patients (P<0.05). Our data suggest that these polymorphisms play a role in susceptibility to MS, which is possibly mediated by dysregulated production of these cytokines.