Browse
Submit Data
Databases
API
Help

Dataset Information

20 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Alzheimer’s Disease Risk Variant rs3865444 in the CD33 Gene: A Possible Role in Susceptibility to Multiple Sclerosis

ABSTRACT: Polymorphisms in genes encoding receptors that modulate the activity of microglia and macrophages are attractive candidates for participation in genetic susceptibility to multiple sclerosis (MS). The aims of the study were to (1) investigate the association between Alzheimer’s disease-linked variant rs3865444:C>A in the CD33 gene and MS risk, (2) assess the effect of the strongest MS risk allele HLA-DRB1*15:01 on this association, and (3) analyze the correlation of rs3865444 with selected clinical phenotypes, i.e., age of onset and disease severity. CD33 rs3865444 was genotyped in a cohort of 579 patients and 1145 controls and its association with MS risk and clinical phenotypes was analyzed by logistic and linear regression analysis, respectively. Statistical evaluation revealed that rs3865444 reduces the risk of MS in the HLA-DRB1*15:01-positive subpopulation but not in the cohort negative for HLA-DRB1*15:01. A significant antagonistic epistasis between rs3865444 A and HLA-DRB1*15:01 alleles in the context of MS risk was detected by the interaction synergy factor analysis. Comparison of allele and genotype distribution between relapsing-remitting MS, secondary progressive MS, and control groups revealed that rs3865444 C to A substitution may also be associated with a decreased risk of transition of MS to its secondary progressive form, irrespective of the HLA-DRB1*15:01 carrier status. On the other hand, no correlation could be found between rs3865444 and the age of disease onset or MS severity score. Future studies are required to shed more light on the role of CD33 in MS pathogenesis.

SUBMITTER: Javor J

PROVIDER: S-EPMC9324428 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Multiple Sclerosis: Shall We Target CD33?

Project description:Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS). Myeloid lineage cells (microglia and macrophages) may participate in the pathogenic mechanisms leading to MS. CD33 is a transmembrane receptor, mainly expressed by myeloid lineage cells. CD33 rs3865444 is a promoter variant previously associated with Alzheimer's disease, whose role in MS remains obscure. To assess the role of CD33 rs3865444 in MS risk. We genotyped 1396 patients with MS and 400 healthy controls for the presence of the CD33 rs3865444 variant. Odds ratios (ORs) with the respective 95% confidence intervals (CIs), were calculated with the SNPStats software, assuming five genetic models (co-dominant, dominant, recessive, over-dominant, and log-additive), with the G allele as the reference allele. The value of 0.05 was set as the threshold for statistical significance. CD33 rs3865444 was associated with MS risk in the dominant (GG vs. GT + TT; OR (95% C.I.) = 0.79 (0.63-0.99), p = 0.041) and the over-dominant (GG + TT vs. GT; OR (95% C.I.) = 0.77 (0.61-0.97), p = 0.03) modes of inheritance. Given that the GG genotype was more frequent and the GT genotype was less frequent in MS patients compared to controls-while the observed frequency of the TT genotype did not differ between the two groups-the observed difference in MS risk may be stemming from either the GG (as a risk factor) or the GT (as a protective factor) genotype of CD33 rs3865444. Our preliminary results suggest a possible contribution of CD33 rs3865444 to MS. Therefore, larger multiethnic studies should be conducted, investigating the role of CD33 rs3865444 in MS.

| S-EPMC7696272 | biostudies-literature

Exome sequencing identifies a novel multiple sclerosis susceptibility variant in the TYK2 gene.

Project description:ObjectiveTo identify rare variants contributing to multiple sclerosis (MS) susceptibility in a family we have previously reported with up to 15 individuals affected across 4 generations.MethodsWe performed exome sequencing in a subset of affected individuals to identify novel variants contributing to MS risk within this unique family. The candidate variant was genotyped in a validation cohort of 2,104 MS trio families.ResultsFour family members with MS were sequenced and 21,583 variants were found to be shared among these individuals. Refining the variants to those with 1) a predicted loss of function and 2) present within regions of modest haplotype sharing identified 1 novel mutation (rs55762744) in the tyrosine kinase 2 (TYK2) gene. A different polymorphism within this gene has been shown to be protective in genome-wide association studies. In contrast, the TYK2 variant identified here is a novel, missense mutation and was found to be present in 10/14 (72%) cases and 28/60 (47%) of the unaffected family members. Genotyping additional 2,104 trio families showed the variant to be transmitted preferentially from heterozygous parents (transmitted 16: not transmitted 5; χ(2) = 5.76, p = 0.016).ConclusionsRs55762744 is a rare variant of modest effect on MS risk affecting a subset of patients (0.8%). Within this pedigree, rs55762744 is common and appears to be a modifier of modest risk effect. Exome sequencing is a quick and cost-effective method and we show here the utility of sequencing a few cases from a single, unique family to identify a novel variant. The sequencing of additional family members or other families may help identify other variants important in MS.

| S-EPMC3405256 | biostudies-literature

Genetic Susceptibility to Multiple Sclerosis: The Role of FOXP3 Gene Polymorphism.

Project description:IntroductionIt is well recognized that both genetic and environmental factors play an important role in the pathogenesis of multiple sclerosis (MS). Immune pathogenesis of MS focuses on pathogenic CD4+ T lymphocytes. CD4+CD25+ regulatory T cells have suppressive function in this cell group. FOXP3 (forkhead boxP3) transcription factor is a key structure in the development and function of regulatory cells. Functional alterations in FOXP3 gene expression have been observed in various autoimmune diseases.MethodsWe screened a non-synonymous coding single nucleotide polymorphism (exon +2710 C/T) (rs2232369) of human FOXP3 gene in 148 MS patients (118 with Relapsing Remitting MS, 30 with Secondary Progressive MS) and 102 age- and sex-matched healthy controls. The association of polymorphisms with susceptibility, and course of the disease was evaluated.ResultsWe could not detect any single nucleotide polymorphism in MS patients, however, polymorphic allele was detected in 3% of the control group. Consequently, a genetic association between the FOXP3 gene polymorphism and MS was not revealed.ConclusionThe distribution of this polymorphism has not been screened in any other MS populations before. Although we could not succeed to find any association between susceptibility to MS and screened FOXP3 gene polymorphisms, we suggest that this particular polymorphism is not appropriate for these kind of studies in the future.

| S-EPMC5370262 | biostudies-literature

NQO1 gene rs1800566 variant is not associated with risk for multiple sclerosis.

Project description:BACKGROUND: A possible role of oxidative stress in the pathogenesis of multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis has been suggested. The detoxification enzyme NAD(P)H dehydrogenase, quinone 1 (NQO1) has been found up-regulated in MS lesions. A previous report described an association between the SNP rs1800566 in the NQO1 gene and the risk for MS in the Greek population. The aim of this study was to replicate a possible influence of the. SNP rs1800566 in the NQO1 gene in the risk for MS in the Spanish Caucasian population. METHODS: We analyzed allelic and genotypic frequency of NQO1 rs1800566 in 290 patients with MS and 310 healthy controls, using TaqMan Assays. RESULTS: NQO1 rs1800566 allelic and genotypic frequencies did not differ significantly between MS patients and controls, and were unrelated with age of onset of MS, gender, and clinical type of MS. CONCLUSIONS: Our results indicate that NQO1 rs1800566 does not have an effect on MS disease risk.

| S-EPMC4022329 | biostudies-literature

Molecular mechanism for the multiple sclerosis risk variant rs17594362.

Project description:Multiple sclerosis (MS) is known as an autoimmune demyelinating disease of the central nervous system. However, its cause remains elusive. Given previous studies suggesting that dysfunctional oligodendrocytes (OLs) may trigger MS, we tested whether single nucleotide polymorphisms (SNPs) associated with MS affect OL enhancers, potentially increasing MS risk by dysregulating gene expression of OL lineage cells. We found that two closely spaced OL enhancers, which are 3 Kb apart on chromosome 13, overlap two MS SNPs in linkage disequilibrium-rs17594362 and rs12429256. Our data revealed that the two MS SNPs significantly up-regulate the associated OL enhancers, which we have named as Rgcc-E1 and Rgcc-E2. Analysis of Hi-C data and epigenome editing experiments shows that Rgcc is the primary target of Rgcc-E1 and Rgcc-E2. Collectively, these data indicate that the molecular mechanism of rs17594362 and rs12429256 is to induce Rgcc overexpression by potentiating the enhancer activity of Rgcc-E1 and Rgcc-E2. Importantly, the dosage of the rs17594362/rs12429256 risk allele is positively correlated with the expression level of Rgcc in the human population, confirming our molecular mechanism. Our study also suggests that Rgcc overexpression in OL lineage cells may be a key cellular mechanism of rs17594362 and rs12429256 for MS.

| S-EPMC6927461 | biostudies-literature

mtDNA nt13708A variant increases the risk of multiple sclerosis.

Project description:BACKGROUND: Mitochondrial DNA (mtDNA) polymorphism is a possible factor contributing to the maternal parent-of-origin effect in multiple sclerosis (MS) susceptibility. METHODS AND FINDINGS: In order to investigate the role of mtDNA variations in MS, we investigated six European MS case-control cohorts comprising >5,000 individuals. Three well matched cohorts were genotyped with seven common, potentially functional mtDNA single nucleotide polymorphisms (SNPs). A SNP, nt13708 G/A, was significantly associated with MS susceptibility in all three cohorts. The nt13708A allele was associated with an increased risk of MS (OR = 1.71, 95% CI 1.28-2.26, P = 0.0002). Subsequent sequencing of the mtDNA of 50 individuals revealed that the nt13708 itself, rather than SNPs linked to it, was responsible for the association. However, the association of nt13708 G/A with MS was not significant in MS cohorts which were not well case-control matched, indicating that the significance of association was affected by the population structure of controls. CONCLUSIONS: Taken together, our finding identified the nt13708A variant as a susceptibility allele to MS, which could contribute to defining the role of the mitochondrial genome in MS pathogenesis.

| S-EPMC2217590 | biostudies-literature

Quantitative susceptibility mapping in multiple sclerosis.

Project description:To apply quantitative susceptibility mapping (QSM) in the basal ganglia of patients with multiple sclerosis (MS) and relate the findings to R2* mapping with regard to the sensitivity for clinical and morphologic measures of disease severity.The local ethics committee approved this study, and all subjects gave written informed consent. Sixty-eight patients (26 with clinically isolated syndrome, 42 with relapsing-remitting MS) and 23 control subjects underwent 3-T magnetic resonance (MR) imaging. Susceptibility and R2* maps were reconstructed from the same three-dimensional multiecho spoiled gradient-echo sequence. Mean susceptibilities and R2* rates were measured in the basal ganglia and were compared between different phenotypes of the disease (clinically isolated syndrome, MS) and the control subjects by using analysis of variance, and regressing analysis was used to identify independent predictors.Compared with control subjects, patients with MS and clinically isolated syndrome had increased (more paramagnetic) magnetic susceptibilities in the basal ganglia. R2* mapping proved less sensitive than QSM regarding group differences. The strongest predictor of magnetic susceptibility was age. Susceptibilities were higher with increasing neurologic deficits (r = 0.34, P < .01) and lower with normalized volumes of gray matter (r = -0.35, P < .005) and the cortex (r = -0.35, P < .005).QSM provides superior sensitivity over R2* mapping in the detection of MS-related tissue changes in the basal ganglia. With QSM but not with R2* mapping, changes were already observed in patients with clinically isolated syndrome, which suggests that QSM can serve as a sensitive measure at the earliest stage of the disease.

| S-EPMC3632806 | biostudies-other

ZFAT gene variant association with multiple sclerosis in the Arabian Gulf population: A genetic basis for gender-associated susceptibility.

Project description:Single nucleotide polymorphisms (SNPs) are useful genetic markers to investigate the onset of multiple sclerosis (MS). A genome wide association study identified 7 SNPs associated with interferon?? therapy response, however, not with MS risk in a Spanish population. To investigate these findings in a different cohort, the 7 SNPs were investigated in an Arabian Gulf population. The SNPs were analyzed in 268 subjects (156 patients and 112 healthy volunteers) from the Arabian Gulf region using restriction fragment length polymorphism-polymerase chain reaction (PCR) and KBioscience Competitive Allele Specific PCR genotyping methods. Associations between the SNPs and MS were investigated using logistic regression. The present study observed, for the first time, that in an Arabian Gulf population, the ZFAT rs733254 polymorphism (T>G) is a gender?specific risk marker for MS. ZFAT was associated with MS in women but not in men. The G variant was highly associated with the risk of MS [odds ratio (OR)=2.38 and 95% confidence interval (CI), 1.45?3.91); P=0.0014]. Whereas variant T was a significantly protective factor [OR=0.420 (95% CI, 0.25?0.69); P=0.0014, recessive model]. The findings of the present study provide a genetic basis for the gender?associated susceptibility to MS. In addition, this MS-associated rs733254 SNP may predict MS onset in females from the Arabian Gulf population.

| S-EPMC5042798 | biostudies-literature

Investigation of the role of mitochondrial DNA in multiple sclerosis susceptibility.

Project description:Several lines of evidence suggest that mitochondrial genetic factors may influence susceptibility to multiple sclerosis. To explore this hypothesis further, we re-sequenced the mitochondrial genome (mtDNA) from 159 patients with multiple sclerosis and completed a haplogroup analysis including a further 835 patients and 1,506 controls. A trend towards over-representation of super-haplogroup U was the only evidence for association with mtDNA that we identified in these samples. In a parallel analysis of nuclear encoded mitochondrial genes, we also found a trend towards association with the complex I gene, NDUFS2. These results add to the evidence suggesting that variation in mtDNA and nuclear encoded mitochondrial genes may contribute to disease susceptibility in multiple sclerosis.

| S-EPMC2494944 | biostudies-literature

PROTECTIVE EFFECT OF SHINGLES VACCINE ON ALZHEIMER’S DISEASE CAN BE MODULATED BY RISK VARIANT OF NECTIN2 GENE

Project description: Not available

| S-EPMC10736522 | biostudies-literature