Etiology Of Multiple Sclerosis Research Articles

Hospital diagnosed pneumonia before age 20 years and multiple sclerosis risk

IntroductionRespiratory inflammation has been proposed as a risk factor for MS. This study aims to determine if hospital-diagnosed pneumonia in adolescence (before age 20 years) is associated with subsequent multiple...

Organic compound farnesol as possible inhibitor of inflammasome complex, in murine macrophages and mouse model of multiple sclerosis

Abstract Many advancements in the understanding of multiple sclerosis (MS) have been made through the use of laboratory models. One commonly used model is experimental autoimmune encephalomyelitis (EAE), a mouse model characterized by central nervous system (CNS) inflammation and demyelination, allowing for symptoms resembling some of the most prominent features of the human disease. Although the exact etiology of MS is still being investigated, experiments with EAE have shown that the NLRP3 inflammasome complex of the innate immune system is critical and necessary for disease development. The inflammasome complex can be assembled in all innate immune cells, including microglia and astrocytes in the CNS. Dysregulation of inflammasome activity can result in uncontrolled inflammation, which underlies many chronic diseases, and metabolic and autoimmune disorders such as MS. Our lab has shown that farnesol a 15-carbon organic sesquiterpene and primary alcohol, reduced EAE disease severity and onset and also decreased T-cell infiltration into the CNS. However, the mechanisms of its action have yet to be fully defined. Therefore, in-vitro work on murine macrophages is being conducted to investigate how farnesol may be potentially affecting the pathway of the inflammasome complex and providing this protection. Furthermore, since farnesol is a quorum-sensing molecule that impacts biofilm formation, other studies of ours are aimed at evaluating how farnesol affects the gut-brain axis and specifically the gut microbiome of EAE mice.

CD8 T-cell Recruitment Into the Central Nervous System of Cuprizone-Fed Mice: Relevance to Modeling the Etiology of Multiple Sclerosis

Cuprizone (CPZ)-feeding in mice induces atrophy of peripheral immune organs (thymus and spleen) and suppresses T-cell levels, thereby limiting its use as a model for studying the effects of the immune system in demyelinating diseases such as Multiple Sclerosis (MS). To investigate whether castration (Cx) can protect the peripheral immune organs from CPZ-induced atrophy and enable T-cell recruitment into the central nervous system (CNS) following a breach of the blood-brain barrier (BBB), three related studies were carried out. In Study 1, Cx prevented the dose-dependent reductions (0.1% < 0.2% CPZ) in thymic and splenic weight, size of the thymic medulla and splenic white pulp, and CD4 and CD8 (CD4/8) levels remained comparable to gonadally intact (Gi) control males. Importantly, 0.1% and 0.2% CPZ were equipotent at inducing central demyelination and glial activation. In Study 2, combining Cx with 0.1% CPZ-feeding and BBB disruption with pertussis toxin (PT) enhanced CD8+ T-cell recruitment into the CNS. The increased CD8+ T-cell level observed in the parenchyma of the cerebrum, cerebellum, brainstem and spinal cord were confirmed by flow cytometry and western blot analyses of CNS tissue. In Study 3, PT+0.1% CPZ-feeding to Gi female mice resulted in similar effects on the peripheral immune organs, CNS demyelination, and gliosis comparable to Gi males, indicating that testosterone levels alone were not responsible for the immune response seen in Study 2. The combination of Cx+0.1% CPZ-feeding+PT indicates that CPZ-induced demyelination can trigger an “inside-out” immune response when the peripheral immune system is spared and may provide a better model to study the initiating events in demyelinating conditions such as MS.

Aluminium in Brain Tissue in Non-neurodegenerative/Non-neurodevelopmental Disease: A Comparison with Multiple Sclerosis

Human exposure to aluminium is a burgeoning issue. The brain is a sink for systemically available aluminium and a putative target of neurotoxicity. An increasing number of studies continue to confirm the presence of aluminium in human brain tissue though primarily in relation to donors who have died of a neurodegenerative or neurodevelopmental disorder. Herein, we have measured aluminium in brain tissue in donors who died of a specific disease or condition though without showing any neurodegeneration. The donors were diagnosed as not suffering from multiple sclerosis. Herein, these novel data are compared with recent data on aluminium in brain tissue in multiple sclerosis. Brain tissues from all four lobes were obtained from the Multiple Sclerosis Society Tissue Bank. Tissues were digested using microwave-assisted acid digestion and their aluminium content was measured by transversely heated graphite furnace atomic absorption spectrometry. Both are established methods in our laboratory. Detailed statistical analyses were used to compare new data with recent data for multiple sclerosis. Aluminium was found in brain tissue in each donor with a high proportion of measurements (189/291) being below 1.00 μg/g dry weight. The data for all cases (median and IQR) were 0.74 (0.48–1.28), 1.23 (0.62–1.63), 0.84 (0.45–1.14) and 1.01 (0.62–1.65) μg/g dry weight for occipital, parietal, temporal and frontal lobes, respectively. There was a statistically significant positive correlation between aluminium content of brain tissue and the age of donor. Comparison of data for this non-multiple sclerosis group with brain aluminium data for donors dying with a diagnosis of multiple sclerosis showed that the latter had a statistically significant higher content of brain aluminium. The data reinforce a previous conclusion that the aluminium content of brain tissue in multiple sclerosis is elevated and support the suggestion that human exposure to aluminium may have a role to play in the aetiology of multiple sclerosis.

Air pollution, a possible risk factor for multiple sclerosis.

Studies focusing attention on the effects of environmental pollution on the etiology of multiple sclerosis (MS) are on the increase. The aim of this study was to determine MS prevalence in a city home to an iron and steel factory which causes air pollution. The study was designed as a cross-sectional, population-based, descriptive epidemiologic study. Ereğli city, which has an iron and steel factory and proven air pollution, was screened. Additionally, Devrek city, which is a rural and clean city, located 40km away from Ereğli was assigned and results were compared. A validated questionnaire was used for screening. McDonald 2010 criteria were used to diagnose cases. 32261 people were screened in Ereğli, and 21963 people were screened in Devrek. In total, 41 patients were diagnosed with clinical definite MS. Crude prevalence was found to be 96.1/100000 in Ereğli and 45.5/100000 in Devrek. The mean age of patients was 39.8, and the female/male ratio was 1.9. The results of this study indicate a more than double MS prevalence rate in the area home to an iron and steel factory when compared to the rural city. This supports the hypothesis that air pollution may be a possible etiological factor in MS.

Georg Schaltenbrand (1897-1979) and his research without moral boundaries on multiple sclerosis

In 1953 the prominent German neurologist Georg(es) Schaltenbrand became president of the German Neurological Society (DGN) and in 1967 honorary president. Less well known is the fact that from 1933 to 1936 he was member of the "Stahlhelm" and the Storm Troopers (SA). In 1937 he joined the National Socialist German Workers' Party (NSDAP) and other Nazi organizations. For the last three decades Schaltenbrand's name has primarily been associated with human experiments performed in 1940. His objective was to prove the viral etiology of multiple sclerosis (MS). To that end he injected cerebrospinal fluid (CSF) drawn from allegedly infected monkeys and MS patients into severely handicapped patients from the psychiatric asylum Werneck near Schweinfurt as well as into severely ill patients from the University Hospital of Würzburg without their consent. Weeks later he withdrew CSF samples from the recipients, sometimes repeatedly to control parameters of inflammation. Although not all details of his test series can be clarified, there is no doubt that he violated prevailing laws and ethical standards. According to the present state of knowledge, he was the only German professor of neurology during the Nazi era who performed such experiments on humans in terms of "research without moral boundaries". He later justified his actions by arguing that he had intended to exert apositive effect on the mentally ill. Judicial investigations ended in 1948 without an indictment. Long after his death, in 1994 the "Schaltenbrand experiments" became known to awider public and three years later the Medical Faculty of Würzburg condemned the unethical research and distanced itself from its former member. Today, Schaltenbrand's study is assessed as an unacceptable form of research on particularly vulnerable patients for the benefit of third parties. As aresult, ethical norms formulated in the 1930s were reinforced by international guidelines, e.g. the Declaration of Helsinki drafted by the World Medical Association.

Neuroinflammation in Demyelinating Diseases: Oxidative Stress as a Modulator of Glial Cross-Talk.

Myelin is a specialized membrane allowing for saltatory conduction of action potentials in neurons, an essential process to achieve the normal communication across the nervous system. Accordingly, in diseases characterized by the loss of myelin and myelin forming cells -oligodendrocytes in the CNS-, patients show severe neurological disabilities. After a demyelinated insult, microglia, astrocytes and oligodendrocyte precursor cells invade the lesioned area initiating a spontaneous process of myelin repair (i.e. remyelination). A preserved hallmark of this neuroinflammatory scenario is a local increase of oxidative stress, where several cytokines and chemokines are released by glial and other cells. This generates an environment that determines cell interaction resulting in oligodendrocyte maturity and the ability to synthesize new myelin. Herein we review the main features of the regulatory aspect of these molecules based on recent findings and propose new putative signal molecules involved in the remyelination process, focused in the etiology of Multiple Sclerosis, one of the main demyelinating diseases causing disabilities in the population.

A Controlled Descriptive Study to Determine the Nutritional Status and Biochemical Parameters of Multiple Sclerosis Patients.

There is an ongoing research on the etiology of multiple sclerosis (MS). It is still unclear whether nutritional status and biochemical parameters such as serum 25(OH)D, magnesium, and potassium influence the development of disease. This study aimed to make contributions to the literature in terms of the recognition of MS by comparing nutritional status and biochemical information of people with and without MS. The study was designed as a controlled descriptive study. Total of 112 individuals were included (control group, n = 56 and MS group, n = 56). Socioeconomic and demographic characteristics, nutritional status, and biochemical information were collected from the participants. A decision tree model was built to evaluate the impact of these parameters on the presence of MS. The parameters were compared using Student's t tests and Mann-Whitney U tests. A decision tree model having an accuracy rate of 86.52% was constructed. Strong statistical differences were observed among the vitamin and mineral intakes of the groups. In terms of biochemical parameters, especially for serum levels of 25(OH)D and potassium, the differences were significantly different (P < 0.001). Constructed decision tree indicated that the main parameters differed between an MS patient and a healthy person were as follows: serum levels of 25(OH)D, magnesium, calcium, and intakes of potassium and carbohydrate. Based on the findings of this study, nutritional precautions might be taken against MS.

A link between promoter polymorphisms of the transforming growth factor β1 (TGFB1) and TGF-β1 receptor II (TGFBR2) genes and relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) is achronic progressive autoimmune disease characterised by nerve demyelination, mediated by myelin-specific Th1 autoreactive cells. Transforming growth factor1 (TGF-1) is aregulatory cytokine involved in MS aetiology by maintaining CD4+ cell differentiation and preventing autoimmune responses. Because of the important role of the TGF-1 signalling pathway in MS aetiopathogenesis, we aimed to investigate the association of two DNA polymorphisms: TGFB1C[-509]T and TGFBR2G[-875]Aand their combined genotypes with the risk of MS development in acohort of Bulgarian patients. The effect of the two promoter polymorphisms on the disease onset was also assessed. In the study, acohort of 183 patients with relapsing-remitting multiple sclerosis (RRMS) and 307 sex- and age-matched healthy subjects were recruited. Genotyping of the TGFB1C[-509]T (rs1800469) and TGFBR2G[-875]A(rs3087465) polymorphisms was performed by PCR-RFLP and PIRA-PCR approaches. Frequencies of the TGFB1T[-509]T genotype and TGFB1[-509]*T-allele were lower in RRMS men than in control healthy men (15.7% vs. 26.9%, 37.3% vs. 50.7%, respectively). Among males, the TGFB1T[-509]T genotype was related to asignificantly reduced risk of RRMS (OR = 0.360, 95% CI: 0.126-1.028, p = 0.05) in comparison to the TGFB1C[-509]C genotype. Also, TGFB1[-509]*T-allele was more common in men with RRMS than in healthy men relative to the TGFB1[-509]*C-allele and was associated with astatistically significant protective effect (OR = 0.576, 95% CI: 0.341-0.974, p = 0.039). The combination of TGFB1T[-509]T/TGFB1T[-509]C and TGFBR2G[-875]Agenotypes among men was associated with asignificant protective effect compared to the wild-type homozygous TGFB1C[-509]C and TGFBR2G[-875]G genotypes (OR = 0.268, 95% CI: 0.088-0.818, p = 0.018). No significant association between rs1800469 and rs3087465 was observed among females with and without (controls) RRMS. In summary, we suggest that in males, ahigher TGF-1 level determined by TGFB1T[-509]T genotype in combination with the TGFBR2G[-875]Agenotype might be aprotective factor against RRMS development.

Epigenetics in Multiple Sclerosis.

Multiple sclerosis (MS) is an aggravating autoimmune disease that cripples young patients slowly with physical, sensory and cognitive deficits. The break of self-tolerance to neuronal antigens is the key to the pathogenesis of MS, with autoreactive T cells causing demyelination that subsequently leads to inflammation-mediated neurodegenerative events in the central nervous system. The exact etiology of MS remains elusive; however, the interplay of genetic and environmental factors contributes to disease development and progression. Given that genetic variation only accounts for a fraction of risk for MS, extrinsic risk factors including smoking, infection and lack of vitamin D or sunshine, which cause changes in gene expression, contribute to disease development through epigenetic regulation. To date, there is a growing body of scientific evidence to support the important roles of epigenetic processes in MS. In this chapter, the three main layers of epigenetic regulatory mechanisms, namely DNA methylation, histone modification and microRNA-mediated gene regulation, will be discussed, with a particular focus on the role of epigenetics on dysregulated immune responses and neurodegenerative events in MS. Also, the potential for epigenetic modifiers as biomarkers and therapeutics for MS will be reviewed.

Identification of novel non-myelin biomarkers in multiple sclerosis using an improved phage-display approach

Although the etiology of multiple sclerosis is not yet understood, it is accepted that its pathogenesis involves both autoimmune and neurodegenerative processes, in which the role of autoreactive T-cells has been elucidated. Instead, the contribution of humoral response is still unclear, even if the presence of intrathecal antibodies and B-cells follicle-like structures in meninges of patients has been demonstrated. Several myelin and non-myelin antigens have been identified, but none has been validated as humoral biomarker. In particular autoantibodies against myelin proteins have been found also in healthy individuals, whereas non-myelin antigens have been implicated in neurodegenerative phase of the disease. To provide further putative autoantigens of multiple sclerosis, we investigated the antigen specificity of immunoglobulins present both in sera and in cerebrospinal fluid of patients using phage display technology in a new improved format. A human brain cDNA phage display library was constructed and enriched for open-read-frame fragments. This library was selected against pooled and purified immunoglobulins from cerebrospinal fluid and sera of multiple sclerosis patients. The antigen library was also screened against an antibody scFv library obtained from RNA of B cells purified from the cerebrospinal fluid of two relapsing remitting patients. From all biopanning a complex of 14 antigens were identified; in particular, one of these antigens, corresponding to DDX24 protein, was present in all selections. The ability of more frequently isolated antigens to discriminate between sera from patients with multiple sclerosis or other neurological diseases was investigated. The more promising novel candidate autoantigens were DDX24 and TCERG1. Both are implicated in RNA modification and regulation which can be altered in neurodegenerative processes. Therefore, we propose that they could be a marker of a particular disease activity state.

Increased Serological Response Against Human Herpesvirus 6A Is Associated With Risk for Multiple Sclerosis.

Human herpesvirus (HHV)-6A or HHV-6B involvement in multiple sclerosis (MS) etiology has remained controversial mainly due to the lack of serological methods that can distinguish the two viruses. A novel multiplex serological assay measuring IgG reactivity against the immediate-early protein 1 from HHV-6A (IE1A) and HHV-6B (IE1B) was used in a MS cohort (8,742 persons with MS and 7,215 matched controls), and a pre-MS cohort (478 individuals and 476 matched controls) to investigate this further. The IgG response against IE1A was positively associated with MS (OR = 1.55, p = 9 × 10−22), and increased risk of future MS (OR = 2.22, p = 2 × 10−5). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, p = 6 × 10−6). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, p = 6 × 10−11). The association did not differ between MS subtypes or vary with severity of disease. The genetic control of HHV-6A/B antibody responses were located to the Human Leukocyte Antigen (HLA) region and the strongest association for IE1A was the DRB1*13:01-DQA1*01:03-DQB1*06:03 haplotype while the main association for IE1B was DRB1*13:02-DQA1*01:02-DQB1*06:04. In conclusion a role for HHV-6A in MS etiology is supported by an increased serological response against HHV-6A IE1 protein, an interaction with EBV, and an association to HLA genes.

Possible effects of dielectrophoretic fields in the brains of MRI operators and MSpatients: a radiologically isolated syndrome evaluation

Frequent use of magnetic resonance imaging (MRI) devices, which are major contributors in understanding health problems in the human body, is a subject that needs to be taken into consideration both for patients and for operators who are constantly in the vicinity of devices. In this context, electromagnetic impact assessment of an MRI device was performed at the point where the patient entered the device. Dielectrophoretic fields induced by radio frequency (RF) coils of an MRI scanner on male and female operator brain models were computed by using dispersive electrical medium parameters. The main cause of induced secondary dielectrophoretic fields by the RF coils of the MRI scanner is the veins modelled as monopole antennas on the lateral ventricle. The results explain that the dielectrophoretic fields near the veins on the ependymal surfaces are the main cause of Dawson fingers that may develop in the brains of multiple sclerosis (MS) patients and people at risk of the disease. Due to the use of the phantom results and the dispersive values of the electrical medium parameters, the results can be said to be close to the actual values and reliable. Therefore, the study will contribute to the confirmation of the hypotheses, developed by the author from a different perspective, related to the etiology of MS and will provide an accurate understanding of the concept of radiologically isolated syndrome. Everyone, including MRI designers, neurologists, radiologists, operators, and MS patients, can find any of the original information about MS that they need.

Herpes viruses in optic neuritis: Similar to Bell’s palsy

ObjectiveOptic Neuritis (ON) might unfold either as a single intracranial neuritis or as multiple sclerosis, a widespread demyelinating disorder. Different herpes viruses have been proposed as potential participants in the etiology of multiple sclerosis (MS).To analyze the potential presence of herpes viruses in blood and subarachnoid area at the time of ON and contrast the findings according to long-term evolution either as intracranial neuritis or as progression to multiple sclerosis. Patients and methodsIn a prospective investigation we searched the presence of DNA from 5 herpes viruses (HSV-1, HSV-2, VZV, EBV and HHV6) in CSF and blood lymphocytes from 54 patients with ON, patients were followed 62 ± 3 months; those who developed MS were separated from those with ephemeral ON. Long-term prognosis of ON was related to DNA findings. ResultsAs compared with controls, DNA from HSV-1 was significantly more frequent in CSF and blood from cases with ON; VZV and HSV-2 were found only in CSF; EBV was found only in blood samples (p < 0.006). ConclusionsOur results point out the potential participation of HSV, VZV and EBV in ON; suggesting the intervention of various herpes viruses as triggering agents of autoimmunity. However, the number of positive cases was minor than negative cases. Also, our results suggest that the etiological mechanisms in ON could be similar to those of neuritis of the facial nerve (Bell’s palsy).

Genetic Alterations in Patients with Two Clinical Phenotypes of Multiple Sclerosis.

The etiology of multiple sclerosis (MS) is still not known, but the interaction of genetic, immunological, and environmental factors seem to be involved. This study aimed to investigate genetic alterations and the vitamin D status in patients with relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS). A total of 53 patients (29 RRMS; 24 SPMS) and 25 healthy subjects were recruited to evaluate the micronucleated cell (MNC) frequency and nuclear abnormalities in the buccal mucosa, gene expression profiling in mononuclear cells, and plasmatic vitamin D concentration in the blood. Results showed a higher frequency of cells with karyorrhexis (SPMS) and lower frequencies of nuclear pyknosis (RRMS and SPMS) and karyolysis (SPMS) in patients with MS. Significant increase in the frequency of MNC was detected in the buccal mucosa of RRMS and SPMS patients. HIF1A, IL13, IL18, MYC, and TNF were differentially expressed in MS patients, and APP was overexpressed in cells of RRMS compared to SPMS patients. No relationship was observed between vitamin D level and the differentially expressed genes. In conclusion, the cytogenetic alterations in the buccal mucosa can be important indicators of genetic instability and degenerative processes in patients with MS. Furthermore, our data introduced novel biomarkers associated with the molecular pathogenesis of MS.

HLA DR2b-binding peptides from human endogenous retrovirus envelope, Epstein-Barr virus and brain proteins in the context of molecular mimicry in multiple sclerosis

The aetiology of multiple sclerosis (MS) is as yet poorly understood. Multiple mechanisms in different disease stages are responsible for immunopathology in MS. HLA Class II DR2b (DRB1*1501 β, DRA1*0101 α) is the strongest genetic risk factor for MS. Remnants of ancient retroviruses in the human genome, termed human endogenous retroviruses (HERV), and Epstein-Barr virus (EBV) infection are also associated with MS. In silico analyses of human endogenous retroviral envelope (HERV env) proteins and three myelin proteins that are principal targets of an autoimmune response in MS showed sequence similarities between potential TH epitopes within pairs of viral and myelin peptides predicted to bind HLA DR2b. This led to the proposal that such molecular mimicry may potentially trigger MS. HLA DR2b binding characteristics of previously identified peptides from the three myelin proteins and HERV env proteins as well as additional in silico predicted peptides from other encephalitogenic brain proteins and EBV proteins were studied to further investigate molecular mimicry. Peptides containing potential TH epitopes from the myelin oligodendrocyte glycoprotein and HERV env previously predicted to bind HLA DR2b as well as other pertinent potential HLA DR2b-restricted TH epitopes were confirmed to bind HLA DR2b molecules. Molecular modelling of HLA DR2b in complex with high affinity peptides derived from MOG and HERV env proteins showed that their binding could occur in a similar manner to a HLA DR2b-binding peptide containing a known TH epitope. A structurally related pair of peptides predicted to bind HLA DR2b from the EBV protein EBNA1 and β synuclein, a brain protein implicated in MS, were also shown to similarly bind HLA DR2b. The findings justify investigating CD4+ T cell responses to the identified peptides.

Seroprevalence of anti-Toxocara antibody among multiple sclerosis patients: a case-control study.

Although previous studies have shown an association between parasitic infections and multiple sclerosis, the possible role of Toxocara infection on the etiology of multiple sclerosis has been overlooked. The present study aimed to investigate the seroprevalence of anti-Toxocara IgG antibodies among patients with multiple sclerosis compared to healthy controls. Seventy patients with prior diagnosis of multiple sclerosis were selected as cases and 70 healthy matched individuals as controls. The presence of serum anti-Toxocara IgG antibody was investigated by ELISA technique. The Chi square test was used to test statistically significant differences for parametric data. A total of 140 serum samples were collected and analyzed. In the case and control groups, 20 (28.6%) and 8 (11.4%) participants had positive serum anti-Toxocara IgG antibodies, respectively, indicating a statistically significant difference (OR 3.1; 95% CI 1.26-7.63; p value = 0.02). The seroprevalence rate was also higher among individuals with a history of contact with dogs (OR 2.7; 95% CI 1.17-6.37; p value = 0.03).The results declare that a protective role of Toxocara canis against the development of multiple sclerosis is unlikely.

Biological models in multiple sclerosis.

Considering the etiology of multiple sclerosis (MS) is still unknown, experimental models resembling specific aspects of this immune-mediated demyelinating human disease have been developed to increase the understanding of processes related to pathogenesis, disease evolution, evaluation of therapeutic interventions, and demyelination and remyelination mechanisms. Based on the nature of the investigation, biological models may include in vitro, in vivo, and ex vivo assessments. Even though these approaches have disclosed valuable information, every disease animal model has limitations and can only replicate specific features of MS. In vitro and ex vivo models generally do not reflect what occurs in the organism, and in vivo animal models are more likely used; nevertheless, they are able to reproduce only certain stages of the disease. In vivo MS disease animal models in mammals include: experimental autoimmune encephalomyelitis, viral encephalomyelitis, and induced demyelination. This review examines and describes the most common biological disease animal models for the study of MS, their specific characteristics and limitations.

The place of environmental factors in multiple sclerosis: Genes, environment and the interactions thereof in the etiology of multiple sclerosis

The relative roles of genes and environment (not intra-familial environment) and interactions thereof continue to confound better understanding of the pathogenesis of multiple sclerosis (MS) and can also impact recurrence risks for family members as well as genetic family studies. Strong evidence for non-familial environmental factors is suggested by the change in the sex ratio (female:male) of MS patients over the last four decades.

The GTF2I rs117026326 polymorphism is associated with neuromyelitis optica spectrum disorder but not with multiple sclerosis in a Northern Han Chinese population

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) are common demyelinating disorders of the central nervous system. The etiology and pathogenesis of MS and NMOSD remain unclear. The pathogenesis of these two diseases involves a genetic predisposition as well as environmental factors. NMOSD sometimes co-exists with Sjögren's syndrome, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), and these diseases are frequently associated with central nervous system disorder involvement, as manifest in MS- and NMOSD-like clinical features. Genetic variant rs117026326 upstream of the general transcription factor II-I (GTF2I) has been associated with primary Sjögren's syndrome, SLE and RA in East Asian populations. In this study, we genotyped single nucleotide rs117026326 polymorphisms of the GTF2I gene in 168 patients with MS, 144 patients with NMOSD, and 1403 healthy controls. We observed a significant genetic association between the variant rs117026326 and NMOSD (P = 1.09 × 10−11, OR = 2.535), however, the association with MS was not significant (P = .4289, OR = 1.129). Gene expression analyses showed that there was no significant association between the messenger RNA expression of GTF2I and genotypes at the variant. We conclude that the risk T allele of rs117026326 increases the risk of NMOSD, suggesting that NMOSD and MS may have different genetic risk factors.