RESUMEN
OBJECTIVE: Multiple sclerosis (MS) is a chronic inflammatory disease affecting the central nervous system. A human leukocyte antigen (HLA) class II association is well established (DRB1*1501-DQB1*0602), but more recently HLA class II-independent associations with HLA class I variants have also been reported. The HLA class I (HLA-A, -B, -C) molecules serve as ligands for both T-cell receptors and killer immunoglobulin-like receptors (KIRs). We investigated the HLA class I alleles defined by their KIR binding motifs and the KIR genes to evaluate whether these genes could influence MS susceptibility or severity, alone or in combination. METHODS: We typed Norwegian MS patients (n = 631) and controls (n = 555) for HLA-A, -B, -C and -DRB1 alleles as well as the presence or absence of genes encoding inhibitory (KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5, KIR3DL1, KIR3DL2, KIR3DL3) and activating (KIR2DS1, KIR2DS2, KIR2DS3, KIR2DL4, KIR2DS4, KIR2DS5, KIR3DS1) KIRs. RESULTS: The frequency of the HLA-Bw4 specificity, which is the ligand for the inhibitory KIR3DL1, was significantly reduced in MS patients as compared with controls (41.4% vs 55.1%, p(uncorrected (uc)) = 4.6 x 10(-6)). Also after stratifying for known HLA class II associations, the HLA-Bw4 association was seen (p(uc) = 0.002). No significant differences in gene carrier frequencies of inhibitory and activating KIRs were observed. However, our data indicate that MS patients who carry the activating KIR2DS2 and the inhibitory KIR2DL2 genes have more severe disease than patients not carrying these genes. INTERPRETATION: Carriage of the ligand of the inhibitory KIR3DL1 receptor, HLA-Bw4, was found to protect against MS in an HLA-DRB1 independent manner.
Asunto(s)
Antígenos HLA-B/fisiología , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/prevención & control , Receptores KIR/metabolismo , Adolescente , Adulto , Niño , Femenino , Tamización de Portadores Genéticos , Antígenos HLA-B/genética , Antígenos HLA-B/metabolismo , Antígenos HLA-DR/fisiología , Cadenas HLA-DRB1 , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/metabolismo , Unión Proteica/inmunología , Receptores KIR/genética , Receptores KIR/fisiología , Adulto JovenRESUMEN
We previously reported an association between the SH2D2A gene encoding TSAd and multiple sclerosis (MS). Here a total of 2128 Nordic MS patients and 2004 controls were genotyped for the SH2D2A promoter GA repeat polymorphism and rs926103 encoding a serine to asparagine substitution at amino acid position 52 in TSAd. The GA(16)-rs926103()A haplotype was associated with MS in Norwegians (OR 1.4, P=0.04). A similar trend was observed among Danes. In the independent Norwegian, Danish and Swedish sample sets the GA(16) allele showed a combined OR of 1.13, P=0.05. Thus, the present study shows that the SH2D2A gene may contribute to susceptibility to MS.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Predisposición Genética a la Enfermedad , Esclerosis Múltiple/genética , Polimorfismo Genético/genética , Regiones Promotoras Genéticas/genética , Adolescente , Adulto , Niño , Intervalos de Confianza , Repeticiones de Dinucleótido/genética , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/epidemiología , Oportunidad Relativa , Países Escandinavos y Nórdicos/epidemiologíaRESUMEN
Brain-derived neurotrophic factor (BDNF) has been proposed a protective role in multiple sclerosis (MS) in several studies. The val(66)met polymorphism alters the function of the BDNF protein, and has along with rs56164415 previously been reported to be associated with MS. We genotyped BDNF SNPs val(66)met and rs56164415 in 2149 Norwegian MS patients and 2747 healthy controls. No association was found for any of the SNPs to disease susceptibility or any clinical or demographic parameters including sex, age at onset, disease course, disease severity and cognitive impairment.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Esclerosis Múltiple/genética , Polimorfismo Genético , Adulto , Edad de Inicio , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Metionina/genética , Esclerosis Múltiple/epidemiología , Noruega/epidemiología , Valina/genéticaRESUMEN
Recently, several non-HLA loci have been shown to be convincingly associated with Multiple Sclerosis (MS) susceptibility, assumingly indicating important pathways in the pathogenesis. A genotype influence on disease outcome measures by these genes would support a role of these pathways in ongoing tissue damage. Here, however, we report a consistent dissociation between causation and progression for five non-HLA genotypes (IL7R, IL2RA, CLEC16A, CD226 and SH2B3) in 1776 Scandinavian MS patients.
Asunto(s)
Antígenos de Superficie/genética , Antígenos de Superficie/inmunología , Predisposición Genética a la Enfermedad/genética , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Proteínas Adaptadoras Transductoras de Señales , Adulto , Antígenos de Diferenciación de Linfocitos T/genética , Antígenos de Diferenciación de Linfocitos T/inmunología , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad/etnología , Antígenos HLA/inmunología , Humanos , Subunidad alfa del Receptor de Interleucina-2/genética , Subunidad alfa del Receptor de Interleucina-2/inmunología , Péptidos y Proteínas de Señalización Intracelular , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Masculino , Proteínas de Transporte de Monosacáridos/genética , Proteínas de Transporte de Monosacáridos/inmunología , Esclerosis Múltiple/patología , Noruega/epidemiología , Proteínas/genética , Proteínas/inmunología , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/inmunología , Suecia/epidemiologíaRESUMEN
Multiple sclerosis (MS) is an inflammatory, demyelinating disease affecting the central nervous system. MS-associated variants have been reported at both HLA and non-HLA loci, the latter including chromosome 13q31-32 and the Glypican-5 and Glypican-6 genes. In order to further explore the 13q31-32 region in MS, we genotyped 33 SNPs in 1355 Norwegian MS patients and 1446 Norwegian controls. An intronic SNP in the Glypican-5 gene (rs9523787) showed association with MS (p(corr)=0.006). Thus, this study supports that MS susceptibility at 13q31-32 may localize to the Glypican-5 gene, which should lead to further fine-mapping, replication and functional studies of this gene.
Asunto(s)
Predisposición Genética a la Enfermedad , Glipicanos/genética , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Niño , Cromosomas Humanos Par 13/genética , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Noruega , Adulto JovenRESUMEN
A rare functional variant within the TYK2 gene (rs34536443) has been reported as protective in multiple sclerosis (MS) in recent studies. However, because of the low frequency of the minor allele (minor allele frequency=0.04), genome-wide significant association has been hard to establish. We genotyped 5429 Nordic MS cases and 6167 healthy controls for this TYK2 non-synonymous single-nucleotide polymorphism (ns-SNP), and combined the Nordic genotype data with raw genotypes from previous studies. The combined Nordic analysis showed significant association with MS (P=5 x 10(-4), odds ratio (OR) 0.78), and by mega-analysis of 10 642 MS patients, 10 620 controls and 2110 MS trios, the association at genome-wide significance level (P=5.08 x 10(-9), OR 0.77) was shown.
Asunto(s)
Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple/genética , TYK2 Quinasa/genética , Estudios de Casos y Controles , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , HumanosRESUMEN
Amyloid myopathy is a rare complication of primary amyloidosis usually presenting with proximal muscle weakness. We report a woman with multiple myeloma in whom marked atrophy and weakness of finger flexor muscles were the first manifestations of systemic amyloidosis. Muscle biopsy revealed amyloid angiopathy with deposits of lambda light chains in vessel walls. The recognition of amyloid myopathy is important because clinical symptoms may respond to chemotherapy.