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Multiple Sclerosis (MS) is a heterogeneous inflammatory and neurodegenerative disease with an unpredictable course towards progressive disability. Treating progressive MS is challenging due to limited insights into the underlying mechanisms. We examined the molecular changes associated with primary progressive MS (PPMS) using a cross-tissue (blood and post-mortem brain) and multilayered data (genetic, epigenetic, transcriptomic) from independent cohorts. In PPMS, we found hypermethylation of the 1q21.1 locus, controlled by PPMS-specific genetic variations and influencing the expression of proximal genes (CHD1L, PRKAB2) in the brain. Evidence from reporter assay and CRISPR/dCas9 experiments supports a causal link between methylation and expression and correlation network analysis further implicates these genes in PPMS brain processes. Knock-down of CHD1L in human iPSC-derived neurons and knock-out of chd1l in zebrafish led to developmental and functional deficits of neurons. Thus, several lines of evidence suggest a distinct genetic-epigenetic-transcriptional interplay in the 1q21.1 locus potentially contributing to PPMS pathogenesis.
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Encéfalo , Cromosomas Humanos Par 1 , Metilación de ADN , Proteínas de Unión al ADN , Epigénesis Genética , Pez Cebra , Humanos , Pez Cebra/genética , Animales , Metilación de ADN/genética , Cromosomas Humanos Par 1/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , ADN Helicasas/genética , ADN Helicasas/metabolismo , Neuronas/metabolismo , Esclerosis Múltiple Crónica Progresiva/genética , Células Madre Pluripotentes Inducidas/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Predisposición Genética a la Enfermedad , AdultoRESUMEN
BACKGROUND: While multiple sclerosis (MS) affects less than 1 % of the general population, immune mediated inflammatory diseases (IMIDs) collectively influence 5-10 % of the population. Understanding familial co-aggregation of MS and other IMIDs carries important clinical and public health implications that will enable early detection and personalized treatment. OBJECTIVE: To estimate the familial association between MS and other IMIDs and to quantify their shared genetic basis. DESIGN: Register-based multi-generational nested case-control familial co-aggregation study and genetic correlation study. SETTING: Sweden. PARTICIPANTS: 24,995 individuals with MS matched with 253,870 controls and 1,283,502 first-degree relatives (mothers, fathers, full siblings, and offspring) for familial co-aggregation analysis; population of European ancestry for genetic correlation analysis. MEASUREMENTS: Logistic regressions with adjustment for covariates were used to estimate the odds ratios (ORs) of developing MS in individuals with first-degree relatives diagnosed with IMIDs compared to those without such family history. Pairwise genome-wide genetic correlations were estimated with linkage-disequilibrium score regression. RESULTS: We observed an OR for familial co-aggregation of MS of 1.09 (95 % confidence interval (95%CI) = 1.07-1.11) in families with IMIDs history compared to families without. The association remained broadly consistent after stratification by sex concordance of relative pairs and by kinships. 18 IMID subtypes showed a familial association with MS, 7 of which including other acute widespread myelin destruction, encephalitis or myelitis or encephalomyelitis, inflammatory bowel disease, autoimmune thyroid diseases, systemic lupus erythematosus, other inflammatory system diseases, and sarcoidosis withstood multiple correction. Genetic correlations further revealed a shared genetic basis between 7 IMID subtypes with MS. CONCLUSION: We demonstrated a modest familial co-aggregation of MS with several IMIDs, and such association is likely due to shared genetic factors.
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STUDY OBJECTIVES: Shift work, insufficient sleep, and poor sleep quality at young age have been associated with increased risk of multiple sclerosis (MS). This study aimed to investigate the potential interaction between aspects of inadequate sleep (short sleep, phase shift, and poor sleep quality) during adolescence and HLA-DRB1*15:01 in relation to MS risk. METHODS: We used a Swedish population-based case-control study (1253 cases and 1766 controls). Subjects with different sleep patterns during adolescence and HLA-DRB1*15:01 status were compared regarding MS risk by calculating odds ratios (OR) with 95% confidence intervals (CI) using logistic regression models. Additive interaction between aspects of inadequate sleep and HLA-DRB1*15:01 status was assessed by calculating the attributable proportion due to interaction (AP) with 95% CI. RESULTS: Short sleep duration (<7 hours/night) during adolescence acted synergistically with HLA-DRB1*15:01, increasing the risk of MS (AP 0.38, 95% CI 0.01-0.75, p=0.04). Similarly, subjective low sleep quality during adolescence interacted with HLA-DRB1*15:01 regarding risk of MS (AP 0.30, 95% CI 0.06-0.56, p=0.03), whereas phase shift did not significantly influence the risk of the disease, irrespective of HLA-DRB1*15:01 status. CONCLUSIONS: Our findings underscore the importance of addressing inadequate sleep during adolescence, particularly in the context of the HLA-DRB1*15:01 allele, as it appears to amplify the risk of subsequently developing MS.
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BACKGROUND: Multiple sclerosis (MS) is a demyelinating disease affecting millions of people worldwide. Hereditary susceptibility and environmental factors contribute to disease risk. Infection with Epstein-Barr virus (EBV) and human herpesvirus 6A (HHV-6A) have previously been associated with MS risk. Other neurotropic viruses, such as rubella virus (RV), are possible candidates in MS aetiopathogenesis, but previous results are limited and conflicting. METHODS: In this nested case-control study of biobank samples in a Swedish cohort, we analysed the serological response towards RV before the clinical onset of MS with a bead-based multiplex assay in subjects vaccinated and unvaccinated towards RV. The association between RV seropositivity and MS risk was analysed with conditional logistic regression. RESULTS: Seropositivity towards RV was associated with an increased risk of MS for unvaccinated subjects, even when adjusting for plausible confounders including EBV, HHV-6A, cytomegalovirus and vitamin D (adjusted odds ratio [AOR] = 4.0, 95% confidence interval [CI] 1.8-8.8). Cases also had stronger antibody reactivity towards rubella than controls, which was not seen for other neurotropic viruses such as herpes simplex or varicella zoster. Furthermore, we observed an association between RV seropositivity and MS in vaccinated subjects. However, this association was not significant when adjusting for the aforementioned confounders (AOR = 1.7, 95% CI 1.0-2.9). CONCLUSIONS: To our knowledge, these are the first reported associations between early RV seropositivity and later MS development. This suggests a broadening of the virus hypothesis in MS aetiology, where molecular mimicry between rubella epitopes and human central nervous system molecules could be an attractive possible mechanism.
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Synergistic interactions between human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) are hypothesized in the etiopathogenesis of multiple sclerosis (MS). This study investigated if HHV-6A and EBV seroreactivities interact regarding the risk of developing MS. Antibodies against viral antigens were analyzed in biobank samples from 670 individuals who later developed MS and matched controls. Additive interactions were analyzed. A significant interaction between HHV-6A and EBNA-1 seroreactivities was observed in study participants above the median age of 24.9 years (attributable proportion due to interaction = 0.45). This finding supports the hypothesis that HHV-6A and EBV infections interact in MS development. ANN NEUROL 2024;96:302-305.
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Anticuerpos Antivirales , Infecciones por Virus de Epstein-Barr , Antígenos Nucleares del Virus de Epstein-Barr , Herpesvirus Humano 4 , Herpesvirus Humano 6 , Esclerosis Múltiple , Infecciones por Roseolovirus , Humanos , Herpesvirus Humano 6/inmunología , Esclerosis Múltiple/virología , Esclerosis Múltiple/inmunología , Herpesvirus Humano 4/inmunología , Femenino , Estudios de Casos y Controles , Masculino , Adulto , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/complicaciones , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Antígenos Nucleares del Virus de Epstein-Barr/inmunología , Infecciones por Roseolovirus/inmunología , Infecciones por Roseolovirus/complicaciones , Adulto Joven , Persona de Mediana Edad , AdolescenteRESUMEN
Epstein-Barr virus (EBV) infection has been advocated as a prerequisite for developing multiple sclerosis (MS) and possibly the propagation of the disease. However, the precise mechanisms for such influences are still unclear. A large-scale study investigating the host genetics of EBV serology and related clinical manifestations, such as infectious mononucleosis (IM), may help us better understand the role of EBV in MS pathogenesis. This study evaluates the host genetic factors that influence serological response against EBV and history of IM and cross-evaluates them with MS risk and genetic susceptibility in the Swedish population. Plasma IgG antibody levels against EBV nuclear antigen-1 (EBNA-1, truncated=aa[325-641], peptide=aa[385-420]) and viral capsid antigen p18 (VCAp18) were measured using bead-based multiplex serology for 8744 MS cases and 7229 population-matched controls. The MS risk association for high/low EBV antibody levels and history of IM was compared to relevant clinical measures along with sex, age at sampling, and associated HLA allele variants. Genome-wide and HLA allele association analyses were also performed to identify genetic risk factors for EBV antibody response and IM history. Higher antibody levels against VCAp18 (OR=1.74, 95% CI=1.60-1.88) and EBNA-1, particularly the peptide (OR=3.13, 95% CI=2.93-3.35), were associated with an increased risk for MS. The risk increased with higher anti-EBNA-1 IgG levels up to twelve times the reference risk. We also identified several independent HLA haplotypes associated with EBV serology overlapping with known MS risk alleles (e.g., DRB1*15:01). Although there were several candidates, no variants outside the HLA region reached genome-wide significance. Cumulative HLA risk for anti-EBNA-1 IgG levels, particularly the peptide fragment, was strongly associated with MS. In contrast, the genetic risk for high anti-VCAp18 IgG levels was not as strongly associated with MS risk. IM history was not associated with class II HLA genes but negatively associated with A*02:01, which is protective against MS. Our findings emphasize that the risk association between anti-EBNA-1 IgG levels and MS may be partly due to overlapping HLA associations. Additionally, the increasing MS risk with increasing anti-EBNA-1 levels would be consistent with a pathogenic role of the EBNA-1 immune response, perhaps through molecular mimicry. Given that high anti-EBNA-1 antibodies may reflect a poorly controlled T-cell defense against the virus, our findings would be consistent with DRB1*15:01 being a poor class II antigen in the immune defense against EBV. Lastly, the difference in genetic control of IM supports the independent roles of EBNA-1 and IM in MS susceptibility.
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OBJECTIVE: Specific human leucocyte antigen (HLA) alleles are not only associated with higher risk to develop multiple sclerosis (MS) and other autoimmune diseases, but also with the severity of various viral and bacterial infections. Here, we analyzed the most specific biomarker for MS, that is, the polyspecific intrathecal IgG antibody production against measles, rubella, and varicella zoster virus (MRZ reaction), for possible HLA associations in MS. METHODS: We assessed MRZ reaction from 184 Swiss patients with MS and clinically isolated syndrome (CIS) and 89 Swiss non-MS/non-CIS control patients, and performed HLA sequence-based typing, to check for associations of positive MRZ reaction with the most prevalent HLA alleles. We used a cohort of 176 Swedish MS/CIS patients to replicate significant findings. RESULTS: Whereas positive MRZ reaction showed a prevalence of 38.0% in MS/CIS patients, it was highly specific (97.7%) for MS/CIS. We identified HLA-DRB1*15:01 and other tightly linked alleles of the HLA-DR15 haplotype as the strongest HLA-encoded risk factors for a positive MRZ reaction in Swiss MS/CIS (odds ratio [OR], 3.90, 95% confidence interval [CI] 2.05-7.46, padjusted = 0.0004) and replicated these findings in Swedish MS/CIS patients (OR 2.18, 95%-CI 1.16-4.02, padjusted = 0.028). In addition, female MS/CIS patients had a significantly higher probability for a positive MRZ reaction than male patients in both cohorts combined (padjusted <0.005). INTERPRETATION: HLA-DRB1*15:01, the strongest genetic risk factor for MS, and female sex, 1 of the most prominent demographic risk factors for developing MS, predispose in MS/CIS patients for a positive MRZ reaction, the most specific CSF biomarker for MS. ANN NEUROL 2024;95:1112-1126.
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Inmunoglobulina G , Esclerosis Múltiple , Humanos , Femenino , Masculino , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/líquido cefalorraquídeo , Inmunoglobulina G/sangre , Adulto , Persona de Mediana Edad , Herpesvirus Humano 3/inmunología , Herpesvirus Humano 3/genética , Cadenas HLA-DRB1/genética , Suecia/epidemiología , Estudios de Cohortes , Adulto Joven , Virus de la Rubéola/genética , Virus de la Rubéola/inmunología , Antígenos HLA/genética , Anticuerpos Antivirales/líquido cefalorraquídeo , Anticuerpos Antivirales/sangre , Alelos , Suiza/epidemiologíaRESUMEN
Although evidence exists for a causal association between 25-hydroxyvitamin D (25(OH)D) serum levels, and multiple sclerosis (MS), the role of variation in vitamin D receptor (VDR) binding in MS is unknown. Here, we leveraged previously identified variants associated with allele imbalance in VDR binding (VDR-binding variant; VDR-BV) in ChIP-exo data from calcitriol-stimulated lymphoblastoid cell lines and 25(OH)D serum levels from genome-wide association studies to construct genetic instrumental variables (GIVs). GIVs are composed of one or more genetic variants that serve as proxies for exposures of interest. Here, GIVs for both VDR-BVs and 25(OH)D were used in a two-sample Mendelian Randomization study to investigate the relationship between VDR binding at a locus, 25(OH)D serum levels, and MS risk. Data for 13,598 MS cases and 38,887 controls of European ancestry from Kaiser Permanente Northern California, Swedish MS studies, and the UK Biobank were included. We estimated the association between each VDR-BV GIV and MS. Significant interaction between a VDR-BV GIV and a GIV for serum 25OH(D) was evidence for a causal association between VDR-BVs and MS unbiased by pleiotropy. We observed evidence for associations between two VDR-BVs (rs2881514, rs2531804) and MS after correction for multiple tests. There was evidence of interaction between rs2881514 and a 25(OH)D GIV, providing evidence of a causal association between rs2881514 and MS. This study is the first to demonstrate evidence that variation in VDR binding at a locus contributes to MS risk. Our results are relevant to other autoimmune diseases in which vitamin D plays a role.
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Esclerosis Múltiple , Humanos , Esclerosis Múltiple/genética , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Alelos , Estudio de Asociación del Genoma Completo , Vitamina D/metabolismo , Calcitriol , Polimorfismo de Nucleótido SimpleRESUMEN
The many logistical and technical challenges associated with sample and data handling in largescale genotyping studies can increase the risk of sample misidentification, which may compromise subsequent analyses. However, the standard quality assurance methods typical for large genotyping arrays can often be further utilized to identify and recover problematic samples. This article emphasizes the importance of identifying and correcting underlying sample misidentification rather than simply excluding known discrepancies, which may potentially include undetected issues. Lastly, we provide a screening protocol to complement standard quality assessments as a guideline for identifying mismatched samples and a tool for assessing the most common causes of sample misidentification. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC.
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Análisis por Conglomerados , Análisis de Datos , Técnicas de GenotipajeRESUMEN
BACKGROUND: Large register-based studies have reported an association between head trauma and increased risk of multiple sclerosis (MS). We aimed to investigate possible interactions between head trauma and MS-associated HLA genes in relation to MS risk. METHODS: We used a Swedish population-based case-control study (2807 incident cases, 5950 matched controls with HLA genotypes available for 2057 cases, 2887 controls). Subjects with and without a history of self-reported head trauma were compared regarding MS risk, by calculating ORs with 95% CIs using logistic regression models. Additive interaction between head trauma, HLA-DRB1*1501 and absence of HLA-A*0201, was assessed by calculating the attributable proportion (AP) due to interaction. RESULTS: A history of head trauma was associated with a 30% increased risk of subsequently developing MS (OR 1.34, 95% CI 1.17 to 1.53), with a trend showing increased risk of MS with increasing number of head impacts (p=0.03). We observed synergistic effects between recent head trauma and HLA-DRB1*15:01 as well as absence of HLA*02:01 in relation to MS risk (each AP 0.40, 95% CI 0.1 to 0.7). Recent head trauma in individuals with both genetic risk factors rendered an 18-fold increased risk of MS, compared with those with neither the genetic risk factors nor a history of head trauma (OR 17.7, 95% CI 7.13 to 44.1). CONCLUSIONS: Our findings align with previous observations of a dose-dependent association between head trauma and increased risk of MS and add a novel aspect of this association by revealing synergistic effects between recent head trauma and MS-associated HLA genes.
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Traumatismos Craneocerebrales , Predisposición Genética a la Enfermedad , Cadenas HLA-DRB1 , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/genética , Esclerosis Múltiple/epidemiología , Femenino , Masculino , Estudios de Casos y Controles , Cadenas HLA-DRB1/genética , Predisposición Genética a la Enfermedad/genética , Traumatismos Craneocerebrales/epidemiología , Adulto , Suecia/epidemiología , Persona de Mediana Edad , Genotipo , Factores de Riesgo , Antígeno HLA-A2/genética , Adulto Joven , AncianoRESUMEN
Recent research indicates that multiple sclerosis is preceded by a prodromal phase with elevated levels of serum neurofilament light chain (sNfL), a marker of axonal injury. The effect of environmental risk factors on the extent of axonal injury during this prodrome is unknown. Human herpesvirus 6A (HHV-6A) is associated with an increased risk of developing multiple sclerosis. The objective of this study was to determine if HHV-6A serostatus is associated with the level of sNfL in the multiple sclerosis prodrome, which would support a causative role of HHV-6A. A nested case-control study was performed by crosslinking multiple sclerosis registries with Swedish biobanks. Individuals with biobank samples collected before the clinical onset of multiple sclerosis were included as cases. Controls without multiple sclerosis were randomly selected, matched for biobank, sex, sampling date and age. Serostatus of HHV-6A and Epstein-Barr virus was analysed with a bead-based multiplex assay. The concentration of sNfL was analysed with single molecule array technology. The association between HHV-6A serology and sNfL was assessed by stratified t-tests and linear regressions, adjusted for Epstein-Barr virus serostatus and sampling age. Within-pair ratios of HHV-6A seroreactivity and sNfL were calculated for each case and its matched control. To assess the temporal relationship between HHV-6A antibodies and sNfL, these ratios were plotted against the time to the clinical onset of multiple sclerosis and compared using locally estimated scatterplot smoothing regressions with 95% confidence intervals (CI). Samples from 519 matched case-control pairs were included. In cases, seropositivity of HHV-6A was significantly associated with the level of sNfL (+11%, 95% CI 0.2-24%, P = 0.045) and most pronounced in the younger half of the cases (+24%, 95% CI 6-45%, P = 0.007). No such associations were observed among the controls. Increasing seroreactivity against HHV-6A was detectable before the rise of sNfL (significant within-pair ratios from 13.6 years versus 6.6 years before the clinical onset of multiple sclerosis). In this study, we describe the association between HHV-6A antibodies and the degree of axonal injury in the multiple sclerosis prodrome. The findings indicate that elevated HHV-6A antibodies both precede and are associated with a higher degree of axonal injury, supporting the hypothesis that HHV-6A infection may contribute to multiple sclerosis development in a proportion of cases.
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Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 6 , Esclerosis Múltiple , Humanos , Anticuerpos , Biomarcadores , Estudios de Casos y Controles , Herpesvirus Humano 4 , Masculino , FemeninoRESUMEN
BACKGROUND: Multiple sclerosis (MS) and presymptomatic axonal injury appear to develop only after an Epstein-Barr virus (EBV) infection. This association remains to be confirmed across a broad preclinical time range, for lytic and latent EBV seroreactivity, and for potential cross-reacting antigens. METHODS: We performed a case-control study with 669 individual serum samples obtained before clinical MS onset, identified through cross-linkage with the Swedish MS register. We assayed antibodies against EBV nuclear antigen 1 (EBNA1), viral capsid antigen p18, glycoprotein 350 (gp350), the potential cross-reacting protein anoctamin 2 (ANO2) and the level of sNfL, a marker of axonal injury. RESULTS: EBNA1 (latency) seroreactivity increased in the pre-MS group, at 15-20 years before clinical MS onset, followed by gp350 (lytic) seroreactivity (p=0.001-0.009), ANO2 seropositivity appeared shortly after EBNA1-seropositivity in 16.7% of pre-MS cases and 10.0% of controls (p=0.001).With an average lag of almost a decade after EBV, sNfL gradually increased, mainly in the increasing subgroup of seropositive pre-MS cases (p=8.10-5 compared with non-MS controls). Seropositive pre-MS cases reached higher sNfL levels than seronegative pre-MS (p=0.038). In the EBNA1-seropositive pre-MS group, ANO2 seropositive cases had 26% higher sNfL level (p=0.0026). CONCLUSIONS: Seroreactivity against latent and lytic EBV antigens, and in a subset ANO2, was detectable on average a decade before the appearance of a gradually increasing axonal injury occurring in the last decade before the onset of clinical MS. These findings strengthen the hypothesis of latent EBV involvement in the pathogenesis of MS.
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Infecciones por Virus de Epstein-Barr , Esclerosis Múltiple , Humanos , Herpesvirus Humano 4 , Estudios de Casos y Controles , Antígenos Virales , Antígenos Nucleares del Virus de Epstein-Barr/metabolismoRESUMEN
Background: Biomarkers for diagnosis of inflammatory neuropathies, assessment of prognosis, and treatment response are lacking. Methods: CSF and EDTA plasma from patients with Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), healthy controls (HC) and disease controls were analyzed with Olink multiplex proximity extension assay (PEA) from two independent cohorts. Levels of interleukin-8 (IL8) were further analyzed with ELISA in patients with GBS, CIDP, paraproteinemia-related demyelinating polyneuropathy (PDN), multifocal motor neuropathy (MMN), HC and disease controls. ROC analysis was performed. Outcome was measured with the GBS-disability score (GBS-ds) or Inflammatory Neuropathy Cause and Treatment (INCAT) score. Results: In CSF, multiplex PEA analysis revealed up-regulation of IL8 in GBS compared to CIDP and HC respectively, and CIDP compared to HC. In addition, levels of IL2RA were upregulated in GBS compared to both HC and CIDP, SELE in GBS compared to HC, and ITGAM, IL6, and NRP1 in GBS compared to CIDP. In plasma, levels of MMP3, THBD and ITGAM were upregulated in CIDP compared to HC. Validation of multiplex IL8 results using ELISA, revealed increased levels of IL8 in CSF in patients with GBS and CIDP versus HC and non-inflammatory polyneuropathies (NIP) respectively, as well as in PDN versus NIP and HC. Levels of IL8 in CSF correlated with impairment in the acute phase of GBS as well as outcome at 6-months follow up. Conclusion: IL8 in CSF is validated as a diagnostic biomarker in GBS and CIDP, and a prognostic biomarker in GBS. Multiplex PEA hereby identifies several potential biomarkers in GBS and CIDP.
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Síndrome de Guillain-Barré , Polineuropatías , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Humanos , Biomarcadores , Ensayo de Inmunoadsorción Enzimática , Síndrome de Guillain-Barré/diagnóstico , Síndrome de Guillain-Barré/líquido cefalorraquídeo , Interleucina-8 , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/líquido cefalorraquídeoRESUMEN
Sensitive and reliable protein biomarkers are needed to predict disease trajectory and personalize treatment strategies for multiple sclerosis (MS). Here, we use the highly sensitive proximity-extension assay combined with next-generation sequencing (Olink Explore) to quantify 1463 proteins in cerebrospinal fluid (CSF) and plasma from 143 people with early-stage MS and 43 healthy controls. With longitudinally followed discovery and replication cohorts, we identify CSF proteins that consistently predicted both short- and long-term disease progression. Lower levels of neurofilament light chain (NfL) in CSF is superior in predicting the absence of disease activity two years after sampling (replication AUC = 0.77) compared to all other tested proteins. Importantly, we also identify a combination of 11 CSF proteins (CXCL13, LTA, FCN2, ICAM3, LY9, SLAMF7, TYMP, CHI3L1, FYB1, TNFRSF1B and NfL) that predict the severity of disability worsening according to the normalized age-related MS severity score (replication AUC = 0.90). The identification of these proteins may help elucidate pathogenetic processes and might aid decisions on treatment strategies for persons with MS.
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Esclerosis Múltiple , Humanos , Proteómica , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Biomarcadores , Progresión de la EnfermedadRESUMEN
The minor allele of the genetic variant rs10191329 in the DYSF-ZNF638 locus is associated with unfavorable long-term clinical outcomes in multiple sclerosis patients. We investigated if rs10191329 is associated with brain atrophy measured by magnetic resonance imaging in a discovery cohort of 748 and a replication cohort of 360 people with relapsing multiple sclerosis. We observed an association with 28% more brain atrophy per rs10191329*A allele. Our results encourage stratification for rs10191329 in clinical trials. Unraveling the underlying mechanisms may enhance our understanding of pathophysiology and identify treatment targets. ANN NEUROL 2023;94:1080-1085.
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Enfermedades del Sistema Nervioso Central , Esclerosis Múltiple , Enfermedades Neurodegenerativas , Humanos , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Enfermedades Neurodegenerativas/patología , Atrofia/patologíaRESUMEN
Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is influenced by genotype and the environment, making it an important molecular interface for studying disease etiology and progression. In this study, we examined the whole blood DNA methylation profiles of a large group of people with (pw) multiple sclerosis (MS) compared to those of controls. We reveal that methylation differences in pwMS occur independently of known genetic risk loci and show that they more strongly differentiate disease (AUC = 0.85, 95% CI 0.82-0.89, p = 1.22 × 10-29) than known genetic risk loci (AUC = 0.72, 95% CI: 0.66-0.76, p = 9.07 × 10-17). We also show that methylation differences in MS occur predominantly in B cells and monocytes and indicate the involvement of cell-specific biological pathways. Overall, this study comprehensively characterizes the immune cell-specific epigenetic architecture of MS.
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Monocitos , Esclerosis Múltiple , Humanos , Metilación de ADN , Esclerosis Múltiple/genética , Linfocitos B , Epigénesis GenéticaRESUMEN
BACKGROUND: Our study aims to investigate an intrinsic link underlying sex hormone-binding globulin (SHBG) and rheumatoid arthritis (RA), which remains inconclusive in observational settings. METHODS: Summary statistics were collected from the largest GWAS(s) on SHBG adjusted for BMI (SHBGadjBMI; Noverall = 368,929; Nmen = 180,094; Nwomen = 188,908), crude SHBG (Noverall = 370,125; Nmen = 180,726; Nwomen = 189,473), and RA (Ncase = 22,350; Ncontrol = 74,823). A genome-wide cross-trait design was performed to quantify global and local genetic correlation, identify pleiotropic loci, and infer a causal relationship. RESULTS: Among the overall population, a significant global genetic correlation was observed for SHBGadjBMI and RA ([Formula: see text] = 0.11, P = 1.0 × 10-4) which was further supported by local signal (1q25.2). A total of 18 independent pleiotropic SNPs were identified, of which three were highly likely causal variants and four were found to have effects on both traits through gene expression mediation. A putative causal association of SHBGadjBMI on RA was demonstrated (OR = 1.20, 95% CI = 1.01-1.43) without evidence of reverse causality (OR = 0.999, 95% CI = 0.997-1.000). Sex-specific analyses revealed distinct shared genetic regions (men: 1q32.1-q32.2 and 5p13.1; women: 1q25.2 and 22q11.21-q11.22) and diverse pleiotropic SNPs (16 in men and 18 in women, nearly half were sex-specific) underlying SHBGadjBMI and RA, demonstrating biological disparities between sexes. Replacing SHBGadjBMI with crude SHBG, a largely similar yet less significant pattern of results was observed. CONCLUSION: Our cross-trait analysis suggests an intrinsic, as well as a sex-specific, link underlying SHBG and RA, providing novel insights into disease etiology.
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Artritis Reumatoide , Globulina de Unión a Hormona Sexual , Masculino , Femenino , Humanos , Globulina de Unión a Hormona Sexual/genética , Genómica , Artritis Reumatoide/genética , Fenotipo , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND AND PURPOSE: Hybrid immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develops from a combination of natural infection and vaccine-generated immunity. Multiple sclerosis (MS) disease-modifying therapies (DMTs) have the potential to impact humoral and cellular immunity induced by SARS-CoV-2 vaccination and infection. The aims were to compare antibody and T-cell responses after SARS-CoV-2 mRNA vaccination in persons with MS (pwMS) treated with different DMTs and to assess differences between naïvely vaccinated pwMS and pwMS with hybrid immunity vaccinated following a previous SARS-CoV-2 infection. METHODS: Antibody and T-cell responses were determined in pwMS at baseline and 4 and 12 weeks after the second dose of SARS-CoV-2 vaccination in 143 pwMS with or without previous SARS-CoV-2 infection and 40 healthy controls (HCs). The MS cohort comprised natalizumab (n = 22), dimethylfumarate (n = 23), fingolimod (n = 38), cladribine (n = 30), alemtuzumab (n = 17) and teriflunomide (n = 13) treated pwMS. Immunoglobulin G antibody responses to SARS-CoV-2 antigens were measured using a multiplex bead assay and FluoroSpot was used to assess T-cell responses (interferon γ and interleukin 13). RESULTS: Humoral and T-cell responses to vaccination were comparable between naïvely vaccinated HCs and pwMS treated with natalizumab, dimethylfumarate, cladribine, alemtuzumab and teriflunomide, but were suppressed in fingolimod-treated pwMS. Both fingolimod-treated pwMS and HCs vaccinated following a previous SARS-CoV-2 infection had higher antibody levels 4 weeks after vaccination compared to naïvely vaccinated individuals. Antibody and interferon γ levels 12 weeks after vaccination were positively correlated with time from last treatment course of cladribine. CONCLUSION: These findings are of relevance for infection risk mitigation and for vaccination strategies amongst pwMS undergoing DMT.
Asunto(s)
COVID-19 , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Cladribina , Natalizumab , Vacunas contra la COVID-19/uso terapéutico , SARS-CoV-2 , Interferón gamma , Alemtuzumab , Dimetilfumarato , Clorhidrato de Fingolimod , COVID-19/prevención & control , Vacunación , Anticuerpos , Inmunidad Adaptativa , Anticuerpos AntiviralesRESUMEN
BACKGROUND: The two main phenotypes of multiple sclerosis (MS), primary progressive (PPMS) and relapsing Onset (ROMS), show clinical and demographic differences suggesting possible differential risk mechanisms. Understanding the heritable features of these phenotypes could provide aetiological insight. OBJECTIVES: To evaluate the magnitude of familial components in PPMS and ROMS and to estimate the heritability of disease phenotypes. METHODS: We used data from 25,186 MS patients of Nordic ancestry from the Swedish MS Registry between 1987 and 2019 with known disease phenotype (1593 PPMS and 16,718 ROMS) and 251,881 matched population-based controls and 3,364,646 relatives of cases and controls. Heritability was calculated using threshold-liability models. For familial odds ratios (ORs), logistic regression with robust sandwich estimator was utilized. RESULTS: The OR of MS diagnosis in those with a first-degree family member with ROMS was 7.00 and 8.06 in those with PPMS. The corresponding ORs for having a second-degree family member with ROMS was 2.16 and 2.18 in PPMS. The additive genetic effect in ROMS was 0.54 and 0.22 in PPMS. CONCLUSION: Risk of MS increases by several folds in those with a relative with MS. The likelihood of developing either disease phenotype appears independent of genetic predisposition.