RESUMEN
Multiple Sclerosis (MS) is the most common progressive and disabling neurological condition affecting young adults in the world today. From a genetic point of view, MS is a complex disorder resulting from the combination of genetic and non-genetic factors. We aimed to identify previously unidentified loci conducting a new GWAS of Multiple Sclerosis (MS) in a sample of 296 MS cases and 801 controls from the Spanish population. Meta-analysis of our data in combination with previous GWAS was done. A total of 17 GWAS-significant SNPs, corresponding to three different loci were identified:HLA, IL2RA, and 5p13.1. All three have been previously reported as GWAS-significant. We confirmed our observation in 5p13.1 for rs9292777 using two additional independent Spanish samples to make a total of 4912 MS cases and 7498 controls (ORpooled = 0.84; 95%CI: 0.80-0.89; p = 1.36 × 10-9). This SNP differs from the one reported within this locus in a recent GWAS. Although it is unclear whether both signals are tapping the same genetic association, it seems clear that this locus plays an important role in the pathogenesis of MS.
Asunto(s)
Cromosomas Humanos Par 5 , Estudio de Asociación del Genoma Completo , Esclerosis Múltiple/genética , Sitios de Carácter Cuantitativo , Adulto , Estudios de Casos y Controles , Enfermedad de Crohn/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Desequilibrio de Ligamiento , Masculino , Polimorfismo de Nucleótido Simple , España , Población Blanca/genética , Adulto JovenRESUMEN
BACKGROUND: Multiple sclerosis (MS) is a multifactorial disease with a genetic basis. The strongest associations with the disease lie in the Human Leukocyte Antigen (HLA) region. However, except for the DRB1*15:01 allele, the main risk factor associated to MS so far, no consistent effect has been described for any other variant. One example is HLA-DRB1*03:01, with a heterogeneous effect across populations and studies. We postulate that those discrepancies could be due to differences in the diverse haplotypes bearing that allele. Thus, we aimed at studying the association of DRB1*03:01 with MS susceptibility considering this allele globally and stratified by haplotypes. We also evaluated the association with the presence of oligoclonal IgM bands against myelin lipids (OCMB) in cerebrospinal fluid. METHODS: Genotyping of HLA-B, -DRB1 and -DQA1 was performed in 1068 MS patients and 624 ethnically matched healthy controls. One hundred and thirty-nine MS patients were classified according to the presence (M+, 58 patients)/absence (M-, 81 patients) of OCMB. Comparisons between groups (MS patients vs. controls and M+ vs. M-) were performed with the chi-square test or the Fisher exact test. RESULTS: Association of DRB1*03:01 with MS susceptibility was observed but with different haplotypic contribution, being the ancestral haplotype (AH) 18.2 the one causing the highest risk. Comparisons between M+, M- and controls showed that the AH 18.2 was affecting only M+ individuals, conferring a risk similar to that caused by DRB1*15:01. CONCLUSIONS: The diverse DRB1*03:01-containing haplotypes contribute with different risk to MS susceptibility. The AH 18.2 causes the highest risk and affects only to individuals showing OCMB.
Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Cadenas HLA-DRB1/genética , Haplotipos/genética , Inmunoglobulina M/líquido cefalorraquídeo , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/genética , Estudios de Casos y Controles , Humanos , Esclerosis Múltiple/inmunología , Factores de RiesgoRESUMEN
The unfolded protein response (UPR) is a stress response of the endoplasmic reticulum (ER), the first compartment of the secretory pathway. The UPR is activated in non-tangle bearing neurons in Alzheimer's disease (AD) brain, indicating it is an early phenomenon. We found that the level of Rab6, implicated in anterograde and retrograde trafficking in the secretory pathway, is increased in brains of AD patients. Rab6 expression, closely correlated with the extent of UPR activation, is not controlled by the UPR. This suggests that Rab6 and UPR activation are both increased in response to early pathogenic changes in AD. Here we demonstrate that Rab6 modulates the UPR, increased levels inhibit whereas decreased levels augment UPR induction. Rab6 is not involved in the initial phase of the UPR; it only affects the UPR after prolonged ER stress. We propose that Rab6 is involved in the recovery from an ER stress insult. The increased Rab6 levels in AD brain in combination with UPR activation suggest that a failure to recover from ER stress may contribute to neurodegeneration in AD. The Rab6 mediated recovery pathway may provide a target to selectively inhibit the destructive pathways of the UPR.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Respuesta de Proteína Desplegada , Proteínas de Unión al GTP rab/metabolismo , Enfermedad de Alzheimer/patología , Estrés del Retículo Endoplásmico , Células HeLa , Humanos , ARN Mensajero/metabolismoRESUMEN
We described previously that multiple sclerosis (MS) patients with oligoclonal IgM against myelin lipids (M+) develop an aggressive disease. Our aim was to assess possible mechanisms regulating the production of these antibodies. We studied B cell subsets in 180 patients with MS, and 69 with other neurological diseases. M+ MS patients showed a moderate increase of CD5(+) B-cell percentage in peripheral blood and a considerable augment of these cells in cerebrospinal fluid (CSF) that correlated with intrathecal IgM production. The appearance of CD5(+) B cells into the central nervous system (CNS) was related to increased CXCL13 and TNF-alpha levels in CSF. Moreover, the presence of oligoclonal IgM associated with a SNP at position -376 of the TNF-alpha promoter. These results help to elucidate the B lymphocytes responsible for intrathecal IgM secretion in MS and the origin of this abnormal B-cell response in patients with aggressive MS.
Asunto(s)
Inmunoglobulina M/inmunología , Esclerosis Múltiple/inmunología , Bandas Oligoclonales/inmunología , ADP-Ribosil Ciclasa 1/metabolismo , Adulto , Antígenos CD19/metabolismo , Subgrupos de Linfocitos B/citología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Células Sanguíneas/citología , Células Sanguíneas/inmunología , Células Sanguíneas/metabolismo , Antígenos CD5/metabolismo , Líquido Cefalorraquídeo/citología , Líquido Cefalorraquídeo/inmunología , Líquido Cefalorraquídeo/metabolismo , Quimiocina CXCL13/líquido cefalorraquídeo , Femenino , Frecuencia de los Genes/genética , Genotipo , Humanos , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/líquido cefalorraquídeo , Inmunoglobulina M/biosíntesis , Inmunoglobulina M/líquido cefalorraquídeo , Interleucina-5/líquido cefalorraquídeo , Interleucina-6/líquido cefalorraquídeo , Lípidos/inmunología , Masculino , Glicoproteínas de Membrana/metabolismo , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/diagnóstico , Vaina de Mielina/inmunología , Bandas Oligoclonales/biosíntesis , Bandas Oligoclonales/líquido cefalorraquídeo , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas/genética , Recurrencia , Factor de Necrosis Tumoral alfa/líquido cefalorraquídeo , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
A recent meta-analysis of genome-wide association screens coupled to a replication exercise in a combined US/UK collection led to the identification of 4 single nucleotide polymorphisms (SNPs) in three gene loci, i.e. TNFRSF1A, CD6 and IRF8, as novel risk factors for multiple sclerosis with genome-wide level of significance. In the present study, using a combined all-Spain collection of 2515 MS patients and 2942 healthy controls, we demonstrate significant association of rs17824933 in CD6 (P(CMH)=0.004; OR=1.14; 95% CI 1.04-1.24) and of rs1860545 in TNFRSF1A (P(CMH)=0.001; OR=1.15; 95% CI 1.06-1.25) with MS, while the low-frequency coding non-synonymous SNP rs4149584 in TNFRSF1A displayed a trend for association (P(CMH)=0.062; OR=1.27; 95% CI 0.99-1.63). This data reinforce a generic role for CD6 and TNFRSF1A in susceptibility to MS, extending to populations of southern European ancestry.
Asunto(s)
Antígenos CD/genética , Antígenos de Diferenciación de Linfocitos T/genética , Sitios Genéticos/genética , Sitios Genéticos/inmunología , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Niño , Estudios de Cohortes , Europa (Continente)/epidemiología , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/epidemiología , Polimorfismo de Nucleótido Simple/inmunología , Factores de Riesgo , España/epidemiología , Adulto JovenRESUMEN
Interleukin (IL)-2/IL-2R signalling promotes proliferation and survival of activated T cells and has an essential non-redundant role in the production of regulatory T cells. Associations with different autoimmune diseases of polymorphisms in a linkage disequilibrium block in which the IL2/IL21 genes map (4q27), and also in genes encoding the IL2RA and IL2RB subunits (located in 10p15 and 22q13, respectively), were identified through genome-wide studies. Polymorphisms in these three genes were studied in 430 multiple sclerosis (MS) patients and in 550 ethnically matched controls from Madrid (Spain). Replication and meta-analysis with results from an independent cohort of 771 MS patients and 759 controls from Andalucía (Spain) confirmed the association of polymorphisms in the IL2RA gene (P(Mantel-Haenszel,) odds ratio (OR)(M-H) (95% confidence interval, CI) for rs2104286: 0.0001, 0.75 (0.65-0.87); for rs11594656/rs35285258: 0.004, 1.19 (1.06-1.34); for rs41295061: 0.03, 0.77 (0.60-0.98)); showed a trend for association of the IL2/IL21 rs6822844 (P(M-H)=0.07, OR(M-H) (95% CI)=0.86 (0.73-1.01)), but did not corroborate the association for IL2RB. Regression analyses of the combined Spanish cohort revealed the independence of two IL2RA association signals: rs2104286 and rs11594656/rs35285258. The relevant role of the IL2RA gene on MS susceptibility adds support to its common effect on autoimmune risk and the suggestive association of IL2/IL21 warrants further investigation.