RESUMEN
BACKGROUND: Electronic medical records (EMR) data are increasingly used in research, but no studies have yet evaluated similarity between EMR and research-quality data and between characteristics of an EMR multiple sclerosis (MS) population and known natural MS history. OBJECTIVES: To (1) identify MS patients in an EMR system and extract clinical data, (2) compare EMR-extracted data with gold-standard research data, and (3) compare EMR MS population characteristics to expected MS natural history. METHODS: Algorithms were implemented to identify MS patients from the University of California San Francisco EMR, de-identify the data and extract clinical variables. EMR-extracted data were compared to research cohort data in a subset of patients. RESULTS: We identified 4142 MS patients via search of the EMR and extracted their clinical data with good accuracy. EMR and research values showed good concordance for Expanded Disability Status Scale (EDSS), timed-25-foot walk, and subtype. We replicated several expected MS epidemiological features from MS natural history including higher EDSS for progressive versus relapsing-remitting patients and for male versus female patients and increased EDSS with age at examination and disease duration. CONCLUSION: Large real-world cohorts algorithmically extracted from the EMR can expand opportunities for MS clinical research.
Asunto(s)
Investigación Biomédica , Registros Electrónicos de Salud , Almacenamiento y Recuperación de la Información , Esclerosis Múltiple , Procesamiento de Lenguaje Natural , Centros Médicos Académicos , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/fisiopatología , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: To characterize the accrual of long-term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and magnetic resonance imaging (MRI) data used in clinical trials have long-term prognostic value. METHODS: This is a prospective study of 517 actively managed MS patients enrolled at a single center. RESULTS: More than 91% of patients were retained, with data ascertained up to 10 years after the baseline visit. At this last assessment, neurologic disability as measured by the Expanded Disability Status Scale (EDSS) was stable or improved compared to baseline in 41% of patients. Subjects with no evidence of disease activity (NEDA) by clinical and MRI criteria during the first 2 years had long-term outcomes that were no different from those of the cohort as a whole. 25-OH vitamin D serum levels were inversely associated with short-term MS disease activity; however, these levels had no association with long-term disability. At a median time of 16.8 years after disease onset, 10.7% (95% confidence interval [CI] = 7.2-14%) of patients reached an EDSS ≥ 6, and 18.1% (95% CI = 13.5-22.5%) evolved from relapsing MS to secondary progressive MS (SPMS). INTERPRETATION: Rates of worsening and evolution to SPMS were substantially lower when compared to earlier natural history studies. Notably, the NEDA 2-year endpoint was not a predictor of long-term stability. Finally, the data call into question the utility of annual MRI assessments as a treat-to-target approach for MS care. Ann Neurol 2016;80:499-510.
Asunto(s)
Progresión de la Enfermedad , Esclerosis Múltiple Crónica Progresiva/diagnóstico por imagen , Esclerosis Múltiple Crónica Progresiva/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Evaluación de Resultado en la Atención de Salud , Índice de Severidad de la Enfermedad , Adulto , Personas con Discapacidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , PronósticoRESUMEN
Multiple sclerosis is a demyelinating neurodegenerative disease with a strong genetic component. Previous genetic risk studies have failed to identify consistently linked regions or genes outside of the major histocompatibility complex on chromosome 6p. We describe allelic association of a polymorphism in the gene encoding the interleukin 7 receptor alpha chain (IL7R) as a significant risk factor for multiple sclerosis in four independent family-based or case-control data sets (overall P = 2.9 x 10(-7)). Further, the likely causal SNP, rs6897932, located within the alternatively spliced exon 6 of IL7R, has a functional effect on gene expression. The SNP influences the amount of soluble and membrane-bound isoforms of the protein by putatively disrupting an exonic splicing silencer.
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Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple , Receptores de Interleucina-7/genética , Adulto , Empalme Alternativo , Animales , Estudios de Casos y Controles , Línea Celular Tumoral , Mapeo Cromosómico , Europa (Continente) , Salud de la Familia , Femenino , Expresión Génica , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Células HeLa , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Transfección , Estados UnidosRESUMEN
Multiple sclerosis is a common disease with proven heritability, but, despite large-scale attempts, no underlying risk genes have been identified. Traditional linkage scans have so far identified only one risk haplotype for multiple sclerosis (at HLA on chromosome 6), which explains only a fraction of the increased risk to siblings. Association scans such as admixture mapping have much more power, in principle, to find the weak factors that must explain most of the disease risk. We describe here the first high-powered admixture scan, focusing on 605 African American cases and 1,043 African American controls, and report a locus on chromosome 1 that is significantly associated with multiple sclerosis.
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Cromosomas Humanos Par 1/genética , Predisposición Genética a la Enfermedad , Esclerosis Múltiple/genética , Negro o Afroamericano/genética , Mapeo Cromosómico/métodos , Genoma Humano , Humanos , Esclerosis Múltiple/etnologíaRESUMEN
OBJECTIVE: We sought to determine whether vitamin D status is associated with developing new T2 lesions or contrast-enhancing lesions on brain magnetic resonance imaging (MRI) in relapsing multiple sclerosis (MS). METHODS: EPIC is a 5-year longitudinal MS cohort study at the University of California at San Francisco. Participants had clinical evaluations, brain MRI, and blood draws annually. From the overall cohort, we evaluated patients with clinically isolated syndrome or relapsing-remitting MS at baseline. In univariate and multivariate (adjusted for age, sex, ethnicity, smoking, and MS treatments) repeated measures analyses, annual 25-hydroxyvitamin D levels were evaluated for their association with subsequent new T2-weighted and gadolinium-enhancing T1-weighted lesions on brain MRI, clinical relapses, and disability (Expanded Disability Status Scale [EDSS]). RESULTS: A total of 2,362 3T brain MRI scans were acquired from 469 subjects. In multivariate analyses, each 10ng/ml higher 25-hydroxyvitamin D level was associated with a 15% lower risk of a new T2 lesion (incidence rate ratio [IRR], 0.85; 95% confidence interval [CI], 0.76-0.95; p = 0.004) and a 32% lower risk of a gadolinium-enhancing lesion (IRR, 0.68; 95% CI, 0.53-0.87; p = 0.002). Each 10ng/ml higher vitamin D level was associated with lower subsequent disability (-0.047; 95% CI, -0.091 to -0.003; p = 0.037). Higher vitamin D levels were associated with lower, but not statistically significant, relapse risk. Except for the EDSS model, all associations were stronger when the within-person change in vitamin D level was the predictor. INTERPRETATION: Vitamin D levels are inversely associated with MS activity on brain MRI. These results provide further support for a randomized trial of vitamin D supplementation.
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Encéfalo/patología , Hidroxicolecalciferoles/sangre , Imagen por Resonancia Magnética , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Adolescente , Adulto , Anciano , Estudios de Cohortes , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Valor Predictivo de las Pruebas , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: Prospective, deeply phenotyped research cohorts monitoring individuals with chronic neurologic conditions, such as multiple sclerosis (MS), depend on continued participant engagement. The COVID-19 pandemic restricted in-clinic research activities, threatening this longitudinal engagement, but also forced adoption of televideo-enabled care. This offered a natural experiment in which to analyze key dimensions of remote research: (1) comparison of remote vs in-clinic visit costs from multiple perspectives and (2) comparison of the remote with in-clinic measures in cross-sectional and longitudinal disability evaluations. METHODS: Between March 2020 and December 2021, 207 MS cohort participants underwent hybrid in-clinic and virtual research visits; 96 contributed 100 "matched visits," that is, in-clinic (Neurostatus-Expanded Disability Status Scale [NS-EDSS]) and remote (televideo-enabled EDSS [tele-EDSS]; electronic patient-reported EDSS [ePR-EDSS]) evaluations. Clinical, demographic, and socioeconomic characteristics of participants were collected. RESULTS: The costs of remote visits were lower than in-clinic visits for research investigators (facilities, personnel, parking, participant compensation) but also for participants (travel, caregiver time) and carbon footprint (p < 0.05 for each). Median cohort EDSS was similar between the 3 modalities (NS-EDSS: 2, tele-EDSS: 1.5, ePR-EDSS: 2, range 0.6.5); the remote evaluations were each noninferior to the NS-EDSS within ±0.5 EDSS point (TOST for noninferiority, p < 0.01 for each). Furthermore, year to year, the % of participants with worsening/stable/improved EDSS scores was similar, whether each annual evaluation used NS-EDSS or whether it switched from NS-EDSS to tele-EDSS. DISCUSSION: Altogether, the current findings suggest that remote evaluations can reduce the costs of research participation for patients, while providing a reasonable evaluation of disability trajectory longitudinally. This could inform the design of remote research that is more inclusive of diverse participants.
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COVID-19 , Esclerosis Múltiple , Humanos , Estudios Prospectivos , Estudios Transversales , PandemiasRESUMEN
Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotype.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Glipicanos/genética , Esclerosis Múltiple/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Población Blanca/genética , Adulto JovenRESUMEN
OBJECTIVE: To determine whether body mass index (BMI) or vitamin D status is associated with MRI measures of neurodegeneration in a cohort of individuals with relapsing-remitting multiple sclerosis (RRMS) or clinically isolated syndrome (CIS). METHODS: Expression, Proteomics, Imaging, Clinical (EPIC) is a longitudinal multiple sclerosis (MS) cohort study at the University of California, San Francisco. Participants had clinical evaluations, brain MRI, and blood draws annually. We evaluated patients with CIS or RRMS at baseline. In multivariate repeated-measures analyses adjusted for age, sex, ethnicity, smoking status, and use of MS treatments, annual 25-hydroxyvitamin D levels and BMI were evaluated for their association with subsequent brain volumes (normalized gray matter [nGMV], brain parenchymal [nBPV], and white matter volumes, as determined by Structural Image Evaluation using Normalization of Atrophy-X). RESULTS: Among 469 participants, each 1-kg/m2 higher BMI was independently associated with reduced nGMV in multivariate models (-1.1 mL, 95% confidence interval [CI] -1.8 to -0.5, p = 0.001). BMI was likewise independently associated with nBPV (nBPV per 1-kg/m2 greater BMI: -1.1 mL, 95% CI -2.1 to -0.05, p = 0.039). Vitamin D levels did not appear to be meaningfully associated with brain volumes. CONCLUSIONS: Higher BMI appears to be associated with greater reductions in nGMV and nBPV, which is relevant because, in particular, nGMV loss portends greater longer-term disability. Because obesity is modifiable, further studies should explore these relationships in detail, and evaluating the effect of reducing BMI on imaging and clinical outcomes in MS may be warranted.
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Encéfalo/patología , Esclerosis Múltiple/sangre , Esclerosis Múltiple/patología , Vitamina D/sangre , Adulto , Índice de Masa Corporal , Encéfalo/diagnóstico por imagen , Femenino , Sustancia Gris/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico por imagen , Sustancia Blanca/patologíaRESUMEN
BACKGROUND: Autoimmune mechanisms are thought to have a major role in the pathogenesis of multiple sclerosis. We aimed to identify coexisting autoimmune phenotypes in patients with multiple sclerosis from families with several members with the disease and in their first-degree relatives. METHODS: A total of 176 families (386 individuals and 1107 first-degree relatives) were characterised for a history of other autoimmune disorders. Family-based or case-control analyses were done to assess the association of cytotoxic T-lymphocyte-antigen 4 (CTLA4) and protein tyrosine phosphatase (PTPN22) variants with susceptibility to multiple sclerosis. FINDINGS: 46 (26%) index cases reported at least one coexisting autoimmune disorder. The most common were Hashimoto thyroiditis (10%), psoriasis (6%), inflammatory bowel disease (3%), and rheumatoid arthritis (2%). 112 (64%) families with a history of multiple sclerosis reported autoimmune disorders (excluding multiple sclerosis) in one or more first-degree relatives, whereas 64 (36%) families reported no history of autoimmunity. Similar to index cases, Hashimoto thyroiditis, psoriasis, and inflammatory bowel disease were also the most common disorders occurring in family members. A common variant within CTLA4 was strongly associated with multiple sclerosis in families who had other autoimmune diseases (p=0.009) but not in families without a history of other autoimmune disorders (p=0.90). INTERPRETATION: The presence of various immune disorders in families with several members with multiple sclerosis suggests that the disease might arise on a background of a generalised susceptibility to autoimmunity. This distinct multiple-sclerosis phenotype, defined by its association with other autoimmune diseases, segregates with specific genotypes that could underlie the common susceptibility.
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Enfermedades Autoinmunes/genética , Análisis por Conglomerados , Salud de la Familia , Esclerosis Múltiple/genética , Riesgo , Alelos , Antígenos CD/genética , Antígenos de Diferenciación/genética , Enfermedades Autoinmunes/epidemiología , Antígeno CTLA-4 , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/epidemiología , Proteína Tirosina Fosfatasa no Receptora Tipo 22 , Proteínas Tirosina Fosfatasas/genética , Factores SexualesRESUMEN
Variation in major histocompatibility complex genes on chromosome 6p21.3, specifically the human leukocyte antigen HLA-DR2 or DRB1*1501-DQB1*0602 extended haplotype, confers risk for multiple sclerosis (MS). Previous studies of DRB1 variation and both MS susceptibility and phenotypic expression have lacked statistical power to detect modest genotypic influences, and have demonstrated conflicting results. Results derived from analyses of 1339 MS families indicate DRB1 variation influences MS susceptibility in a complex manner. DRB1*15 was strongly associated in families (P=7.8x10(-31)), and a dominant DRB1*15 dose effect was confirmed (OR=7.5, 95% CI=4.4-13.0, P<0.0001). A modest dose effect was also detected for DRB1*03; however, in contrast to DRB1*15, this risk was recessive (OR=1.8, 95% CI=1.1-2.9, P=0.03). Strong evidence for under-transmission of DRB1*14 (P=5.7x10(-6)) even after accounting for DRB1*15 (P=0.03) was present, confirming a protective effect. In addition, a high risk DRB1*15 genotype bearing DRB1*08 was identified (OR=7.7, 95% CI=4.1-14.4, P<0.0001), providing additional evidence for trans DRB1 allelic interactions in MS. Further, a significant DRB1*15 association observed in primary progressive MS families (P=0.0004), similar to relapsing-remitting MS families, suggests that DRB1-related mechanisms are contributing to both phenotypes. In contrast, results obtained from 2201 MS cases argue convincingly that DRB1*15 genotypes do not modulate age of onset, or significantly influence disease severity measured using expanded disease disability score and disease duration. These results contribute substantially to our understanding of the DRB1 locus and MS, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.
Asunto(s)
Antígenos HLA-DR/genética , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Adulto , Alelos , Secuencia de Aminoácidos , Bases de Datos Genéticas , Femenino , Variación Genética , Genotipo , Antígenos HLA-DR/química , Cadenas HLA-DRB1 , Humanos , Masculino , Persona de Mediana Edad , Modelos Moleculares , Datos de Secuencia Molecular , Esclerosis Múltiple Crónica Progresiva/genética , Esclerosis Múltiple Crónica Progresiva/inmunología , Fenotipo , Factores de Riesgo , Homología de Secuencia de AminoácidoRESUMEN
To provide a definitive linkage map for multiple sclerosis, we have genotyped the Illumina BeadArray linkage mapping panel (version 4) in a data set of 730 multiplex families of Northern European descent. After the application of stringent quality thresholds, data from 4,506 markers in 2,692 individuals were included in the analysis. Multipoint nonparametric linkage analysis revealed highly significant linkage in the major histocompatibility complex (MHC) on chromosome 6p21 (maximum LOD score [MLS] 11.66) and suggestive linkage on chromosomes 17q23 (MLS 2.45) and 5q33 (MLS 2.18). This set of markers achieved a mean information extraction of 79.3% across the genome, with a Mendelian inconsistency rate of only 0.002%. Stratification based on carriage of the multiple sclerosis-associated DRB1*1501 allele failed to identify any other region of linkage with genomewide significance. However, ordered-subset analysis suggested that there may be an additional locus on chromosome 19p13 that acts independent of the main MHC locus. These data illustrate the substantial increase in power that can be achieved with use of the latest tools emerging from the Human Genome Project and indicate that future attempts to systematically identify susceptibility genes for multiple sclerosis will have to involve large sample sizes and an association-based methodology.
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Cromosomas Humanos/genética , Ligamiento Genético , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/métodos , Esclerosis Múltiple/genética , Australia , Mapeo Cromosómico , Europa (Continente) , Familia , Marcadores Genéticos/genética , Genómica/métodos , Humanos , Persona de Mediana Edad , Estados UnidosRESUMEN
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, with a complex etiology that includes a strong genetic component. The contribution of the major histocompatibility complex (MHC) has been established in numerous genetic linkage and association studies. In addition to the MHC, the chromosome 19q13 region surrounding the apolipoprotein E (APOE) gene has shown consistent evidence of involvement in MS when family-based analyses were conducted. Furthermore, several clinical reports have suggested that the APOE-4 allele may be associated with more-severe disease and faster progression of disability. To thoroughly examine the role of APOE in MS, we genotyped its functional alleles, as well as seven single-nucleotide polymorphisms (SNPs) located primarily within 13 kb of APOE, in a data set of 398 families. Using family-based association analysis, we found statistically significant evidence that an SNP haplotype near APOE is associated with MS susceptibility (P=.005). An analysis of disease progression in 614 patients with MS from 379 families indicated that APOE-4 carriers are more likely to be affected with severe disease (P=.03), whereas a higher proportion of APOE-2 carriers exhibit a mild disease course (P=.02).
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Apolipoproteínas E/genética , Predisposición Genética a la Enfermedad , Esclerosis Múltiple/genética , Esclerosis Múltiple/fisiopatología , Polimorfismo Genético/genética , Adolescente , Adulto , Edad de Inicio , Alelos , Niño , Progresión de la Enfermedad , Femenino , Haplotipos/genética , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Esclerosis Múltiple/patología , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Probabilidad , Análisis de SupervivenciaRESUMEN
Multiple sclerosis (MS) is a common and frequently disabling autoimmune disorder mediated by autoaggressive T cells and autoantibodies that target central nervous system myelin. While numerous studies have demonstrated a strong genetic component to MS, it has been difficult to identify the specific genes involved. Several genomic screens have been undertaken to locate such genes, but have not provided consistent gene localization, except for the MHC on chromosome 6p21 and a locus on chromosome 19q13. To determine which of the original genomic locations presented in the US genome screen could be replicated, a more detailed analysis of additional families was performed. The results, derived from a population of 266 affected individuals belonging to 98 multiplex families, continue to support linkage to chromosomes 6p21, 6q27, and 19q13 with LOD scores>3.0, and suggest that regions on chromosomes 12q23-24 and 16p13 may also harbor susceptibility loci for MS. Analysis taking into account the known HLA-DR2 association identified two additional potential linkage regions on chromosomes 7q21-22 and 13q33-34. These regions can now be targeted for detailed study to identify the underlying MS susceptibility genes.
Asunto(s)
Ligamiento Genético , Predisposición Genética a la Enfermedad , Esclerosis Múltiple/genética , Cromosomas Humanos Par 13 , Cromosomas Humanos Par 6 , Cromosomas Humanos Par 7 , Heterogeneidad Genética , Antígeno HLA-DR2/genética , Humanos , Escala de Lod , Esclerosis Múltiple/etiologíaRESUMEN
A large body of research supports a multifactorial cause in multiple sclerosis (MS), with an underlying genetic susceptibility likely acting in concert with undefined environmental exposures. Here, we used a highly efficient multilocus genotyping assay to study single nucleotide polymorphisms representing variation in 34 genes from inflammatory pathways in a well-characterized MS familial data set. Evidence of transmission distortion was present for several polymorphisms. Results for the NOS2A locus (exon 10 C/T, D346D) on chromosome 17q11 remained significant after correction for multiple testing and were reproduced in a second independent African American MS data set. In addition, linkage to a NOS2A promoter region polymorphism, (CCTTT)(n), was present in a third data set of multicase MS families. Our results provide strong evidence for linkage and association to a new candidate disease gene on chromosome 17q11 in MS and suggest that variation within NOS2A or a nearby locus contributes to disease susceptibility.
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Cromosomas Humanos Par 17 , Predisposición Genética a la Enfermedad , Esclerosis Múltiple/genética , Óxido Nítrico Sintasa/genética , Adulto , Negro o Afroamericano , Estudios de Casos y Controles , Exones/genética , Salud de la Familia , Femenino , Frecuencia de los Genes , Variación Genética , Antígeno HLA-DR2 , Haplotipos , Humanos , Desequilibrio de Ligamiento , Masculino , Esclerosis Múltiple/epidemiología , Polimorfismo de Nucleótido SimpleRESUMEN
An underlying complex genetic susceptibility exists in multiple sclerosis (MS), and an association with the HLA-DRB1*1501-DQB1*0602 haplotype has been repeatedly demonstrated in high-risk (northern European) populations. It is unknown whether the effect is explained by the HLA-DRB1 or the HLA-DQB1 gene within the susceptibility haplotype, which are in strong linkage disequilibrium (LD). African populations are characterized by greater haplotypic diversity and distinct patterns of LD compared with northern Europeans. To better localize the HLA gene responsible for MS susceptibility, case-control and family-based association studies were performed for DRB1 and DQB1 loci in a large and well-characterized African American data set. A selective association with HLA-DRB1*15 was revealed, indicating a primary role for the DRB1 locus in MS independent of DQB1*0602. This finding is unlikely to be solely explained by admixture, since a substantial proportion of the susceptibility chromosomes from African American patients with MS displayed haplotypes consistent with an African origin.
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Población Negra/genética , Predisposición Genética a la Enfermedad/genética , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Complejo Mayor de Histocompatibilidad/genética , Esclerosis Múltiple/genética , Alelos , Mapeo Cromosómico , Familia , Cadenas beta de HLA-DQ , Cadenas HLA-DRB1 , Humanos , Estados UnidosRESUMEN
Multiple sclerosis (MS) is a demyelinating autoimmune disease with a strong yet complex genetic component. To date only the HLA-DR locus, and specifically the HLA-DR15 allele, has been identified and confirmed as influencing the risk of developing MS. Genomic screens on several datasets have been performed and have identified several chromosomal regions with interesting results, but none have yet been confirmed. We tested seven of the most-promising regions (on chromosomes 1p, 2p, 3p, 3q, 5q, 19q, and Xp) identified from several genomic screens in a dataset of 98 multiplex MS families from the United States and 90 multiplex MS families from France. The results did not confirm linkage to 2p, 3q, 5q, or Xp in the overall dataset, or in subsets defined by geographic origin or HLA-DR15 status. Regions on 1p34, 3p14, and 19q13 produced lod scores >0.90 in at least one subset of the data, suggesting that these regions should be examined in more detail.