Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Hum Mol Genet ; 28(8): 1369-1380, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30541027

RESUMO

The role of somatic variants in diseases beyond cancer is increasingly being recognized, with potential roles in autoinflammatory and autoimmune diseases. However, as mutation rates and allele fractions are lower, studies in these diseases are substantially less tolerant of false positives, and bio-informatics algorithms require high replication rates. We developed a pipeline combining two variant callers, MuTect2 and VarScan2, with technical filtering and prioritization. Our pipeline detects somatic variants with allele fractions as low as 0.5% and achieves a replication rate of >55%. Validation in an independent data set demonstrates excellent performance (sensitivity > 57%, specificity > 98%, replication rate > 80%). We applied this pipeline to the autoimmune disease multiple sclerosis (MS) as a proof-of-principle. We demonstrate that 60% of MS patients carry 2-10 exonic somatic variants in their peripheral blood T and B cells, with the vast majority (80%) occurring in T cells and variants persisting over time. Synonymous variants significantly co-occur with non-synonymous variants. Systematic characterization indicates somatic variants are enriched for being novel or very rare in public databases of germline variants and trend towards being more damaging and conserved, as reflected by higher phred-scaled combined annotation-dependent depletion (CADD) and genomic evolutionary rate profiling (GERP) scores. Our pipeline and proof-of-principle now warrant further investigation of common somatic genetic variation on top of inherited genetic variation in the context of autoimmune disease, where it may offer subtle survival advantages to immune cells and contribute to the capacity of these cells to participate in the autoimmune reaction.


Assuntos
Doenças Autoimunes/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Análise de Sequência de DNA/métodos , Imunidade Adaptativa/genética , Adulto , Algoritmos , Alelos , Biologia Computacional/métodos , Análise Mutacional de DNA , Feminino , Variação Genética/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único/genética , Reprodutibilidade dos Testes , Software
2.
Mult Scler ; 24(13): 1773-1775, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29303040

RESUMO

BACKGROUND: In contrast to successes for multiple sclerosis (MS) susceptibility, the genetic basis for clinical heterogeneity remains largely unresolved. OBJECTIVES: We investigate the first reported genetic association with relapse rate. METHODS: We genotyped variant rs12988804 in LRP2 in a homogeneous study population of 527 Belgian MS patients with 970 documented relapses. RESULTS: The rs12988804*T allele is associated with a 1.16-fold increased hazard rate for a relapse occurring ( P = 0.0078) and a higher baseline relapse rate prior to immunomodulatory treatment ( P = 0.044). CONCLUSION: Variant rs12988804 in LRP2, the first example of a genome-wide significant association with relapse rate in MS, is replicated in an independent study.


Assuntos
Predisposição Genética para Doença/genética , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Alelos , Bélgica , Doença Crônica , Feminino , Genótipo , Humanos , Masculino , Recidiva
3.
Eur J Nucl Med Mol Imaging ; 43(1): 142-151, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26260650

RESUMO

PURPOSE: Preclinical, or asymptomatic, Alzheimer's disease (AD) refers to the presence of positive AD biomarkers in the absence of cognitive deficits. This research concept is being applied to define target populations for clinical drug development. In a prospective community-recruited cohort of cognitively intact older adults, we compared two amyloid imaging markers within subjects: (18)F-flutemetamol and (11)C-Pittsburgh compound B (PIB). METHODS: In 32 community-recruited cognitively intact older adults aged between 65 and 80 years, we determined the concordance between binary classification based on (18)F-flutemetamol versus (11)C-PIB according to semiquantitative assessment (standardized uptake value ratio in composite cortical volume, SUVRcomp) and, alternatively, according to visual reads. We also determined the correlation between (18)F-flutemetamol and (11)C-PIB SUVR and evaluated how this was affected by the reference region chosen (cerebellar grey matter versus pons) and the use of partial volume correction (PVC) in this population. RESULTS: Binary classification based on semiquantitative assessment was concordant between (18)F-flutemetamol and (11)C-PIB in 94 % of cases. Concordance of blinded binary visual reads between tracers was 84 %. The Spearman correlation between (18)F-flutemetamol and (11)C-PIB SUVRcomp with cerebellar grey matter as reference region was 0.84, with a slope of 0.98. Correlations in neocortical regions were significantly lower with the pons as reference region. PVC improved the correlation in striatum and medial temporal cortex. CONCLUSION: For the definition of preclinical AD based on (18)F-flutemetamol, concordance with (11)C-PIB was highest using semiquantitative assessment with cerebellar grey matter as reference region.


Assuntos
Amiloide/metabolismo , Compostos de Anilina , Benzotiazóis , Cognição , Tomografia por Emissão de Pósitrons/métodos , Tiazóis , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino
4.
Brain ; 138(Pt 3): 632-43, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25616667

RESUMO

Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10(-16)). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10(-7)). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10(-37)). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10(-22)), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10(-6)). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.


Assuntos
Variação Genética , Imunoglobulina G/líquido cefalorraquidiano , Complexo Principal de Histocompatibilidade/genética , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Europa (Continente) , Feminino , Estudos de Associação Genética , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Bandas Oligoclonais/sangue , Bandas Oligoclonais/líquido cefalorraquidiano , Índice de Gravidade de Doença , Proteína Smad4/genética , Proteínas Supressoras de Tumor/genética , Adulto Jovem
5.
Mult Scler ; 21(13): 1670-80, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25948629

RESUMO

BACKGROUND: More than 100 common variants underlying multiple sclerosis (MS) susceptibility have been identified, but their effect on disease phenotype is still largely unknown. OBJECTIVE: The objective of this paper is to assess whether the cumulative genetic risk score of currently known susceptibility variants affects clinical presentation. METHODS: A cumulative genetic risk score was based on four human leukocyte antigen (HLA) and 106 non-HLA risk loci genotyped or imputed in 842 Belgian MS patients and 321 controls. Non-parametric analyses were applied. RESULTS: An increased genetic risk is observed for MS patients, including subsets such as oligoclonal band-negative and primary progressive MS patients, compared to controls. Within the patient group, a stronger association between HLA risk variants and the presence of oligoclonal bands, an increased immunoglobulin G (IgG) index and female gender was apparent. Results suggest an association between a higher accumulation of non-HLA risk variants and increased relapse rate as well as shorter relapse-free intervals after disease onset. CONCLUSION: MS patients display a significantly increased genetic risk compared to controls, irrespective of disease course or presence of oligoclonal bands. Whereas the cumulative burden of non-HLA risk variants appears to be reflected in the relapses of MS patients, the HLA region influences intrathecal IgG levels.


Assuntos
Predisposição Genética para Doença , Antígenos HLA/genética , Imunoglobulina G/líquido cefalorraquidiano , Esclerose Múltipla Crônica Progressiva/epidemiologia , Esclerose Múltipla Crônica Progressiva/genética , Bandas Oligoclonais/genética , Adulto , Alelos , Bélgica/epidemiologia , Feminino , Genótipo , Humanos , Imunoglobulina G/sangue , Masculino , Bandas Oligoclonais/líquido cefalorraquidiano , Fenótipo , Polimorfismo de Nucleotídeo Único , Recidiva , Fatores de Risco
6.
Ann Neurol ; 73(3): 433-7, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23483640

RESUMO

Association studies have implicated common variants in the 12q14.1 region containing CYP27B1 in multiple sclerosis (MS). Rare CYP27B1 mutations cause autosomal recessive vitamin D-dependent rickets type 1, and it has recently been reported that heterozygous CYP27B1 mutations are associated with increased MS susceptibility and lower active vitamin D levels. By sequencing CYP27B1 in 134 multiplex families and genotyping the most common variant R389H in 2,608 MS patients and 1,987 controls from Italy and Belgium (a total of 4,729 individuals), we were unable to replicate these observations. These results provide evidence against a major role for CYP27B1 mutations in MS.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Esclerose Múltipla/genética , Mutação/genética , Adulto , Bélgica , Estudos de Casos e Controles , Biologia Computacional , Feminino , Genótipo , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Radioimunoensaio , Vitamina D/análogos & derivados , Vitamina D/sangue , Adulto Jovem
8.
Cell Rep ; 25(3): 798-810.e6, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30332657

RESUMO

The immune system is highly diverse, but characterization of its genetic architecture has lagged behind the vast progress made by genome-wide association studies (GWASs) of emergent diseases. Our GWAS for 54 functionally relevant phenotypes of the adaptive immune system in 489 healthy individuals identifies eight genome-wide significant associations explaining 6%-20% of variance. Coding and splicing variants in PTPRC and COMMD10 are involved in memory T cell differentiation. Genetic variation controlling disease-relevant T helper cell subsets includes RICTOR and STON2 associated with Th2 and Th17, respectively, and the interferon-lambda locus controlling regulatory T cell proliferation. Early and memory B cell differentiation stages are associated with variation in LARP1B and SP4. Finally, the latrophilin family member ADGRL2 correlates with baseline pro-inflammatory interleukin-6 levels. Suggestive associations reveal mechanisms of autoimmune disease associations, in particular related to pro-inflammatory cytokine production. Pinpointing these key human immune regulators offers attractive therapeutic perspectives.


Assuntos
Doenças Autoimunes/genética , Regulação da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Fatores Imunológicos/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Feminino , Perfilação da Expressão Gênica , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Adulto Jovem
9.
Neurol Neuroimmunol Neuroinflamm ; 3(4): e240, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27231713

RESUMO

OBJECTIVE: We undertook a systems immunology approach of the adaptive immune system in multiple sclerosis (MS), overcoming tradeoffs between scale and level of detail, in order to identify the immunologic signature of MS and the changes wrought by current immunomodulatory treatments. METHODS: We developed a comprehensive flow cytometry platform measuring 38 immunologic cell types in the peripheral blood of 245 individuals in a routine clinical setting. These include patients with MS, untreated or receiving any of 4 current immunomodulatory treatments (interferon-ß, glatiramer acetate, natalizumab, or fingolimod), patients with autoimmune thyroid disease, and healthy controls. RESULTS: An increase in memory CD8(+) T cells and B cells was observed in untreated patients with MS. Interferon-ß and fingolimod induce significant changes upon multiple aspects of the peripheral immune system, with an unexpectedly prominent alteration of B cells. Overall, both treatments push the immune system in different directions, with only 2 significant effects shared across these treatments-an increase in transitional B cells and a decrease in class-switched B cells. We further identified heightened B cell-activating factor (BAFF) levels as regulating this shared B cell pathway. CONCLUSIONS: A systems immunology approach established different immunologic profiles induced by current immunomodulatory MS treatments, offering perspectives for personalized medicine. Pathways shared between the immunologic architecture of existing efficacious treatments identify targets for future treatment design.

10.
G3 (Bethesda) ; 6(7): 2073-9, 2016 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-27194806

RESUMO

Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93-1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.


Assuntos
Cromossomos Humanos Par 6/química , Esclerose Múltipla/genética , Plasminogênio/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Sequência de Aminoácidos , Estudos de Casos e Controles , Cromossomos Humanos Par 6/metabolismo , Exoma , Feminino , Expressão Gênica , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Linhagem , Fatores de Risco , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos
11.
Alzheimers Res Ther ; 7(1): 75, 2015 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-26677842

RESUMO

INTRODUCTION: In this study of preclinical Alzheimer's disease (AD) we assessed the added diagnostic value of using cerebrospinal fluid (CSF) Aß ratios rather than Aß42 in isolation for detecting individuals who are positive on amyloid positron emission tomography (PET). METHODS: Thirty-eight community-recruited cognitively intact older adults (mean age 73, range 65-80 years) underwent (18)F-flutemetamol PET and CSF measurement of Aß1-42, Aß1-40, Aß1-38, and total tau (ttau). (18)F-flutemetamol retention was quantified using standardized uptake value ratios in a composite cortical region (SUVRcomp) with reference to cerebellar grey matter. Based on a prior autopsy validation study, the SUVRcomp cut-off was 1.57. Sensitivities, specificities and cut-offs were defined based on receiver operating characteristic analysis with CSF analytes as variables of interest and (18)F-flutemetamol positivity as the classifier. We also determined sensitivities and CSF cut-off values at fixed specificities of 90 % and 95 %. RESULTS: Seven out of 38 subjects (18 %) were positive on amyloid PET. Aß42/ttau, Aß42/Aß40, Aß42/Aß38, and Aß42 had the highest accuracy to identify amyloid-positive subjects (area under the curve (AUC) ≥ 0.908). Aß40 and Aß38 had significantly lower discriminative power (AUC = 0.571). When specificity was fixed at 90 % and 95 %, Aß42/ttau had the highest sensitivity among the different CSF markers (85.71 % and 71.43 %, respectively). Sensitivity of Aß42 alone was significantly lower under these conditions (57.14 % and 42.86 %, respectively). CONCLUSION: For the CSF-based definition of preclinical AD, if a high specificity is required, our data support the use of Aß42/ttau rather than using Aß42 in isolation.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/diagnóstico por imagem , Compostos de Anilina , Área Sob a Curva , Benzotiazóis , Biomarcadores/líquido cefalorraquidiano , Estudos de Coortes , Feminino , Humanos , Masculino , Fosforilação , Tomografia por Emissão de Pósitrons , Curva ROC , Compostos Radiofarmacêuticos , Sensibilidade e Especificidade , Punção Espinal , Proteínas tau/líquido cefalorraquidiano
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA