RESUMEN
BACKGROUND: Genome-wide association studies (GWAS) have identified over 100 germline variants that influence susceptibility to multiple sclerosis, most of which map within or near to genes with immunological function. However, the role of somatic mutations in multiple sclerosis has not been investigated. OBJECTIVE: The objective of this paper is to explore the role that somatic mutations might play in the development of multiple sclerosis. METHODS: We exome-sequenced in total 21 individual CD4+ lymphocytes isolated from cerebrospinal fluid of two patients. In addition we sequenced DNA from the patients' peripheral blood to serve as germline reference. RESULTS: In comparison with the respective germline sequence, each cell differed at an average of 1784 positions, but as anticipated subsequent analysis confirms that most, if not all, of these potential mutations are likely to represent artefacts generated during the amplification of a single genome and/or by sequencing. Fifty-six of the potential mutations were predicted to have likely functional effects on genes that have previously been implicated by GWAS, including three in the CD6 gene. CONCLUSION: More robust methods applied to larger numbers of cells will be needed to define the role of somatic mutations.
Asunto(s)
Exoma/genética , Estudio de Asociación del Genoma Completo , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/genética , Mutación/genética , Secuencia de Bases , Linfocitos T CD4-Positivos/citología , Predisposición Genética a la Enfermedad , Humanos , Masculino , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/inmunologíaRESUMEN
A previous study using cumulative genetic risk estimations in multiple sclerosis (MS) successfully tracked the aggregation of susceptibility variants in multi-case and single-case families. It used a limited description of susceptibility loci available at the time (17 loci). Even though the full roster of MS risk genes remains unavailable, we estimated the genetic burden in MS families and assess its disease predictive power using up to 64 single-nucleotide polymorphism (SNP) markers according to the most recent literature. A total of 708 controls, 3251 MS patients and their relatives, as well as 117 twin pairs were genotyped. We validated the increased aggregation of genetic burden in multi-case compared with single-case families (P=4.14e-03) and confirm that these data offer little opportunity to accurately predict MS, even within sibships (area under receiver operating characteristic (AUROC)=0.59 (0.55, 0.53)). Our results also suggest that the primary progressive and relapsing-type forms of MS share a common genetic architecture (P=0.368; difference being limited to that corresponding to ± 2 typical MS-associated SNPs). We have confirmed the properties of individual genetic risk score in MS. Comparing with previous reference point for MS genetics (17 SNPs), we underlined the corrective consequences of the integration of the new findings from GWAS and meta-analysis.
Asunto(s)
Carga Genética , Esclerosis Múltiple/genética , Linaje , Adulto , Estudios de Casos y Controles , Femenino , Sitios Genéticos , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
Genomewide association studies have implicated the CLEC16A gene in several autoimmune diseases, including multiple sclerosis (MS) and type 1 diabetes. However, the most associated single-nucleotide polymorphism (SNP) varies, and causal variants are still to be defined. In MS, two SNPs in partial linkage disequilibrium with each other, rs6498169 and rs12708716, have been validated at genomewide significance level. To explore the CLEC16A association in MS in more detail, we genotyped 57 SNPs in 807 Norwegian MS patients and 1027 Norwegian controls. Six highly associated SNPs emerged and were then replicated in two large independent sample sets (Norwegian and British), together including 1153 MS trios, 2308 MS patients and 4044 healthy controls. In combined analyses, SNP rs12708716 gave the strongest association signal in MS (P=5.3 x 10â»8, odds ratio 1.18, 95% confidence interval=1.11-1.25), and was found to be superior to the other SNP associations in conditional logistic regression analyses. Expression analysis revealed that rs12708716 genotype was significantly associated with the relative expression levels of two different CLEC16A transcripts in thymus (P=0.004), but not in blood, possibly implying a thymus- or cell-specific splice regulation.
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Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad/genética , Lectinas Tipo C/genética , Proteínas de Transporte de Monosacáridos/genética , Esclerosis Múltiple/genética , Timo/metabolismo , Adulto , Alelos , Femenino , Perfilación de la Expresión Génica , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Isoformas de Proteínas/genética , Adulto JovenRESUMEN
Several single-nucleotide polymorphism (SNP) genome-wide association studies (GWASs) have been completed in multiple sclerosis (MS). Follow-up studies of the variants with the most promising rankings, especially when supplemented by informed candidate gene selection, have proven to be extremely successful. In this study we report the results of a multi-stage replication analysis of the putatively associated SNPs identified in the Wellcome Trust Case Control Consortium non-synonymous SNP (nsSNP) screen. In total, the replication sample consisted of 3444 patients and 2595 controls. A combined analysis of the nsSNP screen and replication data provides evidence implicating a novel additional locus, rs3748816 in membrane metalloendopeptidase-like 1 (MMEL1; odds ratio=1.16, P=3.54 × 10â»6) in MS susceptibility.
Asunto(s)
ATP Citrato (pro-S)-Liasa/genética , Calicreínas/genética , Esclerosis Múltiple/genética , Neprilisina/genética , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple , Adulto , Estudios de Casos y Controles , Proteínas de Ciclo Celular , Mapeo Cromosómico , Proteínas del Citoesqueleto , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Desequilibrio de LigamientoRESUMEN
The human leukocyte antigen (HLA)-DRB1*1501 allele has long been established as the main genetic risk factor for multiple sclerosis (MS), and it therefore follows that stratification of study populations for this allele could aid in the identification of novel susceptibility genes and/or in establishing interactions. To this end, we have developed a simple Taqman-based assay allowing cost-efficient medium-throughput HLA-DRB1*1501 genotyping. We have validated this assay in 444 trio families with MS and 1066 individuals from the UK 1958 birth cohort (3908 independent chromosomes). In this validation cohort, the correlation coefficient (r(2)) between rs3135388*A and HLA-DRB1*1501 was >0.94. Subsequently, applying the assay to a group of MS patients and controls from Belgium confirmed the association of HLA-DRB1*1501 and MS in this population (P = 5 x 10(-21)).
Asunto(s)
Frecuencia de los Genes/genética , Antígenos HLA-DR/genética , Esclerosis Múltiple/genética , Análisis de Secuencia de ADN/métodos , Alelos , Estudios de Cohortes , Predisposición Genética a la Enfermedad , Genotipo , Cadenas HLA-DRB1 , Humanos , Sensibilidad y EspecificidadRESUMEN
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system with a strong genetic component. Variation in the major histocompatibility complex on chromosome 6p21, specifically the HLA-DRB1*15 haplotype, is the strongest genetic factor for MS, yet it is estimated to account for only a portion of risk for the disease. Previous evidence has implicated the nitric oxide synthase gene (NOS2A) encoding inducible NOS on chromosome 17q11 as a potential MS susceptibility gene. To determine whether variation in the NOS2A gene contributes to MS risk, we investigated a total of 50 polymorphisms within or flanking the locus for evidence of association using a comprehensive analytical strategy. A total of 6265 members from 1858 well-characterized MS families were utilized. No evidence for overtransmission of any individual single-nucleotide polymorphism allele or haplotype to the MS-affected individuals was observed. Furthermore, different transmission rates were not observed in either DRB1*15-positive or DRB1*15-negative family subgroups, or when extreme clinical outcomes characterizing disease progression were examined. The very largest study of NOS2A variation in MS, to date, excludes even a modest role for this locus in susceptibility.
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Predisposición Genética a la Enfermedad , Esclerosis Múltiple/genética , Óxido Nítrico Sintasa de Tipo II/genética , Estudios de Casos y Controles , Antígenos HLA-DR/genética , Cadenas HLA-DRB1 , Esclerosis Múltiple/inmunología , Polimorfismo Genético , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: By comparison with the neighboring island of Sicily, the frequency of multiple sclerosis (MS) in Malta is remarkably low. METHODS: To explore whether the relative rarity of MS in Malta might be the result of lower population frequencies of major histocompatibility complex susceptibility alleles, we genotyped the HLA-DRB1 locus in 77 Maltese-born patients (97% of the prevalent unrelated native cases) and 206 Maltese controls. We made comparisons with previously published data for Sicily and other European countries. RESULTS: The anticipated association with HLA-DRB1*15, the main susceptibility allele in most other populations, was confirmed (p(c) = 0.009) but, in addition, we also observed an equally strong, and apparently protective, effect of the HLA-DRB1*11 allele (p(c) = 0.016). In comparison with previously published data from Sicily, we found that all HLA-DRB1 risk alleles were more common in Malta, whereas HLA-DRB1*11 was slightly less common. CONCLUSIONS: The difference in prevalence seen between the neighboring islands of Malta and Sicily cannot be explained by differences in background HLA-DRB1 population allele frequencies, which if anything would predict a higher rate of disease in Malta than in Sicily.
Asunto(s)
Predisposición Genética a la Enfermedad , Antígenos HLA-DR/genética , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/genética , Frecuencia de los Genes , Genotipo , Antígenos HLA-DR/metabolismo , Cadenas HLA-DRB1 , Malta/epidemiología , Malta/etnologíaAsunto(s)
Degeneración Nerviosa/genética , Degeneración Nerviosa/fisiopatología , Atrofia Óptica Hereditaria de Leber/complicaciones , Enfermedades de la Médula Espinal/genética , Enfermedades de la Médula Espinal/fisiopatología , Médula Espinal/fisiopatología , Adulto , Tronco Encefálico/patología , Tronco Encefálico/fisiopatología , Progresión de la Enfermedad , Resultado Fatal , Femenino , Humanos , Imagen por Resonancia Magnética , Degeneración Nerviosa/patología , Fibras Nerviosas Mielínicas/patología , Vías Nerviosas/patología , Vías Nerviosas/fisiopatología , Paraparesia/etiología , Médula Espinal/patología , Enfermedades de la Médula Espinal/diagnósticoRESUMEN
Given the known roles of TGFbeta2 in both regulating the immune system and promoting the survival of dopaminergic neurons, it is feasible that genetic variations in TGFB2 might play an aetiological role in neurological diseases such as Multiple Sclerosis (MS) and Parkinson's disease (PD). Hence we performed an indirect association analysis of TGFB2 using 8 haplotype-tagging SNPs in a population of 937 MS patients, 538 PD cases and 2022 controls. We found no evidence for association with susceptibility or progression of MS, but have demonstrated a trend towards association of the 5' region of the gene with susceptibility to PD. Further analysis of TGFB2 is warranted in other PD cohorts.
Asunto(s)
Esclerosis Múltiple/genética , Enfermedad de Parkinson/genética , Factor de Crecimiento Transformador beta2/genética , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Familial factors influence susceptibility to multiple sclerosis (MS) but it is unknown whether there are additional effects on the natural history of the disease. METHOD: We evaluated 1,083 families with > or =2 first-degree relatives with MS for concordance of age at onset, clinical course, and disease severity and investigated transmission patterns of these clinical features in affected parent-child pairs. RESULTS: There is concordance for age at onset for all families (correlation coefficient 0.14; p < 0.001), as well as for affected siblings (correlation coefficient 0.15; p < 0.001), and affected parent-child pairs (correlation coefficient 0.12; p = 0.03) when each is evaluated separately. Concordance for year of onset is present among affected siblings (correlation coefficient 0.18; p < 0.001) but not the parent-child group (correlation coefficient 0.08; p = 0.15). The clinical course is similar between siblings (kappa 0.12; p < 0.001) but not affected parents and their children (kappa -0.04; p = 0.09). This influence on the natural history is present in all clinical subgroups of relapsing-remitting, and primary and secondary progressive MS, reflecting a familial effect on episodic and progressive phases of the disease. There is no concordance for disease severity within any of the considered family groups (correlation coefficients: all families analyzed together, 0.02, p = 0.53; affected sibling group, 0.02, p = 0.61; affected parent-child group, 0.02, p = 0.69). Furthermore, there are no apparent transmission patterns of any of the investigated clinical features in affected parent-child pairs and no evidence for anticipation or effects of genetic loading. CONCLUSION: Familial factors do not significantly affect eventual disease severity. However, they increase the probability of a progressive clinical course, either from onset or after a phase of relapsing remitting disease. The familial effect is more likely to reflect genetic than environmental conditions. The results are relevant for counseling patients and have implications for the design of studies seeking to identify factors that influence the natural history of the disease.
Asunto(s)
Familia , Heterocigoto , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/genética , Medición de Riesgo/métodos , Adulto , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Humanos , Internacionalidad , Masculino , Persona de Mediana Edad , Linaje , Prevalencia , Factores de RiesgoAsunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Predisposición Genética a la Enfermedad , Esclerosis Múltiple/genética , Proteínas del Tejido Nervioso/genética , Adulto , Femenino , Variación Genética , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Repeticiones de TrinucleótidosRESUMEN
Discrepant findings have been reported regarding an association of the apolipoprotein E (APOE) gene with the clinical course of multiple sclerosis (MS). To resolve these discrepancies, we examined common sequence variation in six candidate genes residing in a 380-kb genomic region surrounding and including the APOE locus for an association with MS severity. We genotyped at least three polymorphisms in each of six candidate genes in 1,540 Caucasian MS families (729 single-case and multiple-case families from the United States, 811 single-case families from the UK). By applying the quantitative transmission/disequilibrium test to a recently proposed MS severity score, the only statistically significant (P=0.003) association with MS severity was found for an intronic variant in the Herpes Virus Entry Mediator-B Gene PVRL2. Additional genotyping extended the association to a 16.6 kb block spanning intron 1 to intron 2 of the gene. Sequencing of PVRL2 failed to identify variants with an obvious functional role. In conclusion, the analysis of a very large data set suggests that genetic polymorphisms in PVRL2 may influence MS severity and supports the possibility that viral factors may contribute to the clinical course of MS, consistent with previous reports.
Asunto(s)
Alelos , Variación Genética , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Receptores del Factor de Necrosis Tumoral/genética , Receptores Virales/genética , Regiones no Traducidas 3' , Regiones no Traducidas 5' , Adulto , Distribución por Edad , Edad de Inicio , Exones , Femenino , Humanos , Intrones , Desequilibrio de Ligamiento , Masculino , Esclerosis Múltiple/epidemiología , Polimorfismo de Nucleótido Simple , Miembro 14 de Receptores del Factor de Necrosis Tumoral , Índice de Severidad de la Enfermedad , Reino Unido/epidemiología , Estados Unidos/epidemiología , Población BlancaRESUMEN
BACKGROUND: Previous studies have examined the role of APOE variation in multiple sclerosis (MS), but have lacked the statistical power to detect modest genetic influences on risk and disease severity. The meta- and pooled analyses presented here utilize the largest collection, to date, of MS cases, controls, and families genotyped for the APOE epsilon polymorphism. METHODS: Studies of MS and APOE were identified by searches of PubMed, Biosis, Web of Science, Cochrane Review, and Embase. When possible, authors were contacted for individual genotype data. Meta-analyses of MS case-control data and family-based analyses were performed to assess the association of APOE epsilon genotype with disease risk. Pooled analyses of MS cases were also performed to assess the influence of APOE epsilon genotype on disease severity. RESULTS: A total of 22 studies (3,299 MS cases and 2,532 controls) were available for meta-analysis. No effect of epsilon2 or epsilon4 status on MS risk was observed (summary OR 1.14, 95% CI 0.96-1.34 and OR 0.89, 95% CI 0.78-1.01). Results obtained from analyses of APOE genotypes in 1,279 MS families were also negative (p = 0.61). Finally, results from pooled analyses of 4,048 MS cases also argue strongly that APOE epsilon status does not distinguish a relapsing-remitting from primary progressive disease course, or influence disease severity, as measured by the Expanded Disability Status Scale and disease duration. CONCLUSION: Overall, these findings do not support a role for APOE in multiple sclerosis, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.
Asunto(s)
Apolipoproteínas E/genética , Esclerosis Múltiple/genética , Alelos , Apolipoproteína E2 , Apolipoproteína E4 , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Desequilibrio de Ligamiento , Esclerosis Múltiple/epidemiología , Linaje , Fenotipo , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , Riesgo , Índice de Severidad de la EnfermedadRESUMEN
The LRRK2 G2019S mutation is the commonest genetic cause of Parkinson's disease (PD) identified to date, although estimates of its prevalence in idiopathic disease vary considerably. Our objectives were to determine G2019S mutation frequency in an unselected, community based cohort of idiopathic PD cases from the UK and to describe phenotypic characteristics among carriers. The mutation was present in two of 519 cases (0.4%) and none of 887 control individuals. The true prevalence of the mutation in idiopathic disease, its penetrance, and the phenotypic heterogeneity of associated cases have important implications for genetic screening in the clinical field.
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Sustitución de Aminoácidos/genética , Análisis Mutacional de ADN , Exones , Glicina/genética , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Serina/genética , Adulto , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Estudios de Cohortes , Inglaterra , Femenino , Frecuencia de los Genes , Genes Dominantes , Tamización de Portadores Genéticos , Pruebas Genéticas , Genotipo , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico , FenotipoRESUMEN
To date, three loci have been validated to confer susceptibility to inflammatory bowel disease (IBD): the CARD15/NOD2 gene, the discs large homolog 5 gene (DLG5), and the IBD5 locus on 5q31 (IBD5). We have explored the possibility that these loci may also be associated with susceptibility to two other chronic inflammatory diseases, multiple sclerosis (MS) and systemic lupus erythematosus (SLE). As the CARD15 risk alleles had previously been assessed in our collection of 496 MS trios, we focused our efforts on the DLG5 risk allele and the IBD5(risk) haplotype (IBD5(risk)) for MS. While there is no evidence of association within our MS sample with either of these polymorphisms, screening of 1027 subjects with SLE suggests that IBD5(risk) may have a modest contribution to disease risk in the subset of SLE subjects without lupus nephritis. In addition, a pooled analysis of existing published and unpublished data in 1305 cases of SLE genotyped for the CARD15 risk alleles suggests that only the CARD15(908R) IBD risk allele may have a strong effect on risk of SLE. Our data, therefore, suggest that both the CARD15 gene and the IBD5 locus may have a role as general susceptibility loci for certain common, genetically complex inflammatory diseases.
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Cromosomas Humanos Par 5/genética , Enfermedades Inflamatorias del Intestino/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Lupus Eritematoso Sistémico/genética , Proteínas de la Membrana/genética , Esclerosis Múltiple/genética , Proteínas Supresoras de Tumor/genética , Exones/genética , Predisposición Genética a la Enfermedad , Humanos , Proteína Adaptadora de Señalización NOD2 , Polimorfismo de Nucleótido SimpleRESUMEN
Neurodegeneration following inflammatory injury is considered to be a pathological correlate of irreversible disability in patients with multiple sclerosis. The availability of neurotrophins could influence the probability or rate of disease progression and the time of onset. The BDNF-Val66Met-polymorphism leads to altered intracellular transport and secretion of BDNF, and is thus a logical candidate for a gene that influences susceptibility and, more specifically, the clinical course of multiple sclerosis. In order to test this hypothesis we genotyped the polymorphism in 951 UK multiple sclerosis trio families, but found no evidence for association before (p=0.63) or after stratification for clinical course (p=0.73).
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Predisposición Genética a la Enfermedad , Esclerosis Múltiple/genética , Polimorfismo Genético , Salud de la Familia , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Metionina/genética , Valina/genéticaRESUMEN
BACKGROUND: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. METHODS: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. RESULTS: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. CONCLUSION: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.
Asunto(s)
Evaluación de la Discapacidad , Esclerosis Múltiple/diagnóstico , Índice de Severidad de la Enfermedad , Adulto , Edad de Inicio , Estudios de Cohortes , Estudios Transversales , Bases de Datos Factuales , Progresión de la Enfermedad , Femenino , Francia/epidemiología , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Modelos Neurológicos , Modelos Estadísticos , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/fisiopatología , Valor Predictivo de las Pruebas , Pronóstico , Recurrencia , Reproducibilidad de los ResultadosRESUMEN
AIMS: The Type 1 diabetes susceptibility locus, IDDM2, has been mapped to a variable number of tandem repeats (VNTR) region 5' upstream of the insulin (INS) and insulin-like growth factor (IGF2) genes on chromosome 11p15. The function of the VNTR is uncertain; however, it may influence the thymic expression of the insulin gene and affect the development of immune self-tolerance. The aim of this study was to investigate whether the INS VNTR region is a Type 1 diabetes-specific locus or acting as a general autoimmunity gene. METHODS: We genotyped the INS-IGF2 VNTR [using the surrogate INS-23 HphI single nucleotide polymorphism (SNP)] in 823 Graves' disease (GD)/multiple sclerosis (MS) families, 1433 GD/MS patients and 837 healthy control subjects. RESULTS: We found no evidence of excess transmission of the allele associated with Type 1 diabetes to individuals affected by GD or MS within the families. Analysis of the case-control dataset showed no genotypic or allelic difference between the two populations. CONCLUSIONS: These data suggest that the INS-IGF2 VNTR is acting as a Type 1 diabetes-specific susceptibility gene rather than as an influence on general autoimmunity.
Asunto(s)
Enfermedades Autoinmunes/genética , Diabetes Mellitus Tipo 1/genética , Factor II del Crecimiento Similar a la Insulina/genética , Insulina/genética , Alelos , Cromosomas Humanos Par 11/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Enfermedad de Graves/genética , Humanos , Masculino , Repeticiones de Minisatélite/genética , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
In order to analyze whether loci in the human leukocyte antigen (HLA) class I region may contribute to the HLA class II-associated genetic susceptibility to multiple sclerosis (MS), we examined selected microsatellite markers in 177 Nordic sib-pair families, 222 British sib-pair families, 323 sporadic Norwegian MS patients and 386 Norwegian controls. All samples were, in addition, genotyped for the HLA-DR DQ haplotype, and the Norwegian case-control samples were also typed for HLA-A and -B loci. In the Norwegian sporadic MS patients association was seen with HLA-A, HLA-B, and with the D6S265 marker, located 100 kb centromeric to HLA-A. Associations with HLA-A and D6S265 loci were also suggested when restricting the analysis to HLA-DR15 haplotypes. In the sib-pair data a similar trend was seen with marker D6S265. Higher genotypic relative risk (GRR) was found for individuals who carry both HLA-DR15 and -A3 (GRR = 15), compared to those who carry only HLA-DR15 (GRR = 7), only HLA-A3 (GRR = 3) or none of these alleles (GRR = 1). The highest risk was conferred by a combination of HLA-DR15 and -A3 (odds ratio (OR) = 5.2). These results suggest that HLA-A or a gene in linkage disequilibrium with it may contribute to the HLA class II-associated genetic susceptibility to MS.