KIF5A and the contribution of susceptibility genotypes as a predictive biomarker for multiple sclerosis.
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ABSTRACT:
SUBMITTER: Hares K
PROVIDER: S-EPMC8179895 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundClinicians caring for patients with Multiple Sclerosis (MS) need improved biomarkers to aid them in disease management.ObjectiveWe assessed the predictive value of the candidate biomarker CXCL13 index in comparison to oligoclonal bands (OCBs) and CSF neurofilament light (NfL) concentration, examining the ability of each biomarker to predict future disease activity in clinically and radiologically isolated syndromes, relapsing-remitting MS, and progressive MS.MethodsMatched serum and CSF samples were obtained from 67 non-inflammatory neurologic disease patients and 67 MS patients. CSF and serum CXCL13 and CSF NfL were analyzed by Luminex and ELISA, respectively. CXCL13 data were also analyzed as CSF/serum ratios and indices. Electronic medical records were accessed to determine diagnosis, CSF profiles, and disease activity after the lumbar puncture.ResultsAmong CXCL13 measures, CXCL13 index was the best predictor of future disease activity in MS patients (AUC = 0.82; CI = 0.69-0.95; p = 0.0002). CXCL13 index values were significantly elevated in activity-positive MS patients compared to activity-negative patients (p < 0.0001). As a single predictor, CXCL13 index outperformed both OCBs and CSF NfL in sensitivity, specificity, and positive and negative predictive value, for future disease activity in MS patients. Moreover, combining CXCL13 index and CSF NfL status improved sensitivity and predictive values for disease activity in MS patients.ConclusionsThe CXCL13 index is an excellent candidate prognostic biomarker for disease activity in patients with MS.
| S-EPMC7747124 | biostudies-literature
Project description:BackgroundMultiple sclerosis is a demyelinating autoimmune disease, for which there is no blood-borne biomarker. Erythrocytes may provide a source of such biomarkers as they contain microRNAs. MicroRNAs regulate protein translation through complementary binding to messenger RNA. As erythrocytes are transcriptionally inactive, their microRNA profiles may be less susceptible to variation. The aim of this study was to assess the biomarker potential of erythrocyte microRNAs for multiple sclerosis and assess the potential contribution of erythrocyte-derived extracellular vesicle microRNAs to pathology.MethodsErythrocytes were isolated from whole blood by density gradient centrifugation. Erythrocyte microRNAs of a discovery cohort (23 multiple sclerosis patients and 22 healthy controls) were sequenced. Increased expression of miR-183 cluster microRNAs (hsa-miR-96-5p, hsa-miR-182-5p and hsa-miR-183-5p) was validated in an independent cohort of 42 patients and 45 healthy and pathological (migraine) controls. Erythrocyte-derived extracellular vesicles were created ex vivo and their microRNAs were sequenced. Targets of microRNAs were predicted using miRDIP.ResultsHsa-miR-182-5p and hsa-miR-183-5p were able to discriminate relapsing multiple sclerosis patients from migraine patients and/or healthy controls with 89-94% accuracy and around 90% specificity. Hsa-miR-182-5p and hsa-miR-183-5p expression correlated with measures of physical disability and hsa-miR-96-5p expression correlated with measures of cognitive disability in multiple sclerosis. Erythrocytes were found to selectively package microRNAs into extracellular vesicles and 34 microRNAs were found to be differentially packaged between healthy controls and multiple sclerosis patients. Several gene targets of differentially expressed and packaged erythrocyte microRNAs overlapped with multiple sclerosis susceptibility genes. Gene enrichment analysis indicated involvement in nervous system development and histone H3-K27 demethylation.ConclusionsErythrocyte miR-183 cluster members may be developed into specific multiple sclerosis biomarkers that could assist with diagnosis and disability monitoring. Erythrocyte and their extracellular microRNAs were shown to target multiple sclerosis susceptibility genes and may be contributing to the pathophysiology via previously identified routes.
| S-EPMC7240864 | biostudies-literature
Project description:BackgroundThe influence of the microbiome on neurological diseases has been studied for years. Recent findings have shown a different composition of gut microbiota detected in patients with multiple sclerosis (MS). The role of this dysbiosis is still unknown.ObjectiveWe analyzed the gut microbiota of 15 patients with active relapsing-remitting multiple sclerosis (RRMS), comparing with diet-matched healthy controls.MethodTo determine the composition of the gut microbiota, we performed high-throughput sequencing of the 16S ribosomal RNA gene. The specific amplified sequences were in the V3 and V4 regions of the 16S ribosomal RNA gene.ResultsThe gut microbiota of RRMS patients differed from healthy controls in the levels of the Lachnospiraceae, Ezakiella, Ruminococcaceae, Hungatella, Roseburia, Clostridium, Shuttleworthia, Poephyromonas, and Bilophila genera. All these genera were included in a logistic regression analysis to determine the sensitivity and the specificity of the test. Finally, the ROC (receiver operating characteristic) and AUC with a 95% CI were calculated and best-matched for Ezakiella (AUC of 75.0 and CI from 60.6 to 89.4) and Bilophila (AUC of 70.2 and CI from 50.1 to 90.4).ConclusionsThere is a dysbiosis in the gut microbiota of RRMS patients. An analysis of the components of the microbiota suggests the role of some genera as a predictive factor of RRMS prognosis and diagnosis.
| S-EPMC9140870 | biostudies-literature
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
Project description:Genome-wide association studies identified over 200 risk loci for multiple sclerosis (MS) focusing on common variants, which account for about 50% of disease heritability. The goal of this study was to investigate whether low-frequency and rare functional variants, located in MS-established associated loci, may contribute to disease risk in a relatively homogeneous population, testing their cumulative effect (burden) with gene-wise tests. We sequenced 98 genes in 588 Italian patients with MS and 408 matched healthy controls (HCs). Variants were selected using different filtering criteria based on allelic frequency and in silico functional impacts. Genes showing a significant burden (n = 17) were sequenced in an independent cohort of 504 MS and 504 HC. The highest signal in both cohorts was observed for the disruptive variants (stop-gain, stop-loss, or splicing variants) located in EFCAB13, a gene coding for a protein of an unknown function (p < 10-4). Among these variants, the minor allele of a stop-gain variant showed a significantly higher frequency in MS versus HC in both sequenced cohorts (p = 0.0093 and p = 0.025), confirmed by a meta-analysis on a third independent cohort of 1298 MS and 1430 HC (p = 0.001) assayed with an SNP array. Real-time PCR on 14 heterozygous individuals for this variant did not evidence the presence of the stop-gain allele, suggesting a transcript degradation by non-sense mediated decay, supported by the evidence that the carriers of the stop-gain variant had a lower expression of this gene (p = 0.0184). In conclusion, we identified a novel low-frequency functional variant associated with MS susceptibility, suggesting the possible role of rare/low-frequency variants in MS as reported for other complex diseases.
| S-EPMC8762330 | biostudies-literature
Project description:Smoking is one of the most established risk factors for multiple sclerosis (MS). The aim of this study was to investigate how age at smoking debut, duration, intensity and cumulative dose of smoking, and smoking cessation influence the association between smoking and MS risk. In two Swedish population-based case-control studies (7,883 cases, 9,264 controls), subjects with different smoking habits were compared regarding MS risk, by calculating odds ratios with 95% confidence intervals. We observed a clear dose response association between cumulative dose of smoking and MS risk (p value for trend <10(-35)). Both duration and intensity of smoking contributed independently to the increased risk of MS. However, the detrimental effect of smoking abates a decade after smoking cessation regardless of the cumulative dose of smoking. Age at smoking debut did not affect the association between smoking and MS. Smoking increases the risk of MS in a dose response manner. However, in contrary to several other risk factors for MS that seem to affect the risk only if the exposure takes place during a specific period in life, smoking affects MS risk regardless of age at exposure, and the detrimental effect slowly abates after smoking cessation.
| S-EPMC3898140 | biostudies-literature
Project description:Several studies have highlighted the association of the 12q13.3-12q14.1 region with coeliac disease, type 1 diabetes, rheumatoid arthritis and multiple sclerosis (MS); however, the causal variants underlying diseases are still unclear. The authors sought to identify the functional variant of this region associated with MS.Tag-single nucleotide polymorphism (SNP) analysis of the associated region encoding 15 genes was performed in 2876 MS patients and 2910 healthy Caucasian controls together with expression regulation analyses.rs6581155, which tagged 18 variants within a region where 9 genes map, was sufficient to model the association. This SNP was in total linkage disequilibrium (LD) with other polymorphisms that associated with the expression levels of FAM119B, AVIL, TSFM, TSPAN31 and CYP27B1 genes in different expression quantitative trait loci studies. Functional annotations from Encyclopedia of DNA Elements (ENCODE) showed that six out of these rs6581155-tagged-SNPs were located in regions with regulatory potential and only one of them, rs10877013, exhibited allele-dependent (ratio A/G=9.5-fold) and orientation-dependent (forward/reverse=2.7-fold) enhancer activity as determined by luciferase reporter assays. This enhancer is located in a region where a long-range chromatin interaction among the promoters and promoter-enhancer of several genes has been described, possibly affecting their expression simultaneously.This study determines a functional variant which alters the enhancer activity of a regulatory element in the locus affecting the expression of several genes and explains the association of the 12q13.3-12q14.1 region with MS.
| S-EPMC3538279 | biostudies-literature
Project description:Purpose of reviewTo examine the financial effect of the multiple sclerosis (MS) specialist on the academic health center (AHC).Recent findingsUsing data derived from an academic MS center with respect to patient numbers and practice pattern regarding diagnostic studies and disease-modifying therapies (DMT) coupled with reasonable assumptions regarding the profit margin for tests and treatments, 1 full-time MS specialist (1 clinical full-time equivalent [cFTE]) may annually generate downstream revenue exceeding $8,000,000. If all diagnostic studies and therapies were obtained at the facility, the potential revenue generated for the facility can exceed $25,000,000 per 1 cFTE. These calculations do not include the professional net revenue generated by referrals to other professionals.SummaryWith current models of reimbursement for health care, the MS specialist provides an enormous potential source of revenue for the AHC. This information is critically important in obtaining institutional support for the provision of labor-intensive MS care.
| S-EPMC6081969 | biostudies-literature
Project description:Expression of matrix metalloproteinase-1 (MMP1), an interstitial collagenase regulating the extracellular matrix, plays a major role in carcinogenesis of gastric cancer, a leading cause of death worldwide. In literature, the single-nucleotide polymorphism (SNP) promoter -1607 1G/2G (rs1799750) at the MMP1 gene promoter has been reported to alter its own transcription level. While the importance's of the genotype of MMP1 promoter -1607 has not yet been studied in gastric cancer in Taiwan, our aim was to investigate MMP1 promoter -1607 genotypes and gastric cancer (GC) susceptibility in central Taiwan population. In the current hospital-based case-control study, the contribution of MMP1 promoter -1607 genotypes to GC risk was investigated among 121 GC patients and 363 gender- and age-matched healthy controls recruited and genotyped by the polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) methodology. We found that the genotypic and allelic frequencies were not differentially distributed between GC patient and control groups. The variant 1G containing genotypes have interactions with cigarrete smoking behaviors and Helicobacter pylori infection status, but not alcoholism on GC susceptibility determination. Our findings suggest that the variant 1G allele on MMP1 promoter -1607 may contribute to GC carcinogenesis and may be useful for GC early detection and prevention when combined with cigarrete smoking behaviors and Helicobacter pylori infection status.
| S-EPMC5479427 | biostudies-literature
Project description:Multiple sclerosis (MS) is an autoimmune demyelinating disease characterized by complex genetics and multifaceted gene-environment interactions. Compared to whites, African Americans have a lower risk for developing MS, but African Americans with MS have a greater risk of disability. These differences between African Americans and whites may represent differences in genetic susceptibility and/or environmental factors. SNPs from 12 candidate genes have recently been identified and validated with MS risk in white populations. We performed a replication study using 918 cases and 656 unrelated controls to test whether these candidate genes are also associated with MS risk in African Americans. CD6, CLEC16a, EVI5, GPC5, and TYK2 contained SNPs that are associated with MS risk in the African American data set. EVI5 showed the strongest association outside the major histocompatibility complex (rs10735781, OR=1.233, 95% CI=1.06-1.43, P-value=0.006). In addition, RGS1 seems to affect age of onset whereas TNFRSF1A seems to be associated with disease progression. None of the tested variants showed results that were statistically inconsistent with the effects established in whites. The results are consistent with shared disease genetic mechanisms among individuals of European and African ancestry.
| S-EPMC2880217 | biostudies-literature