Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Genome Res ; 27(11): 1807-1815, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29025893

RESUMO

Genome-wide association studies (GWAS) have identified multiple, shared allelic associations with many autoimmune diseases. However, the pathogenic contributions of variants residing in risk loci remain unresolved. The location of the majority of shared disease-associated variants in noncoding regions suggests they contribute to risk of autoimmunity through effects on gene expression in the immune system. In the current study, we test this hypothesis by applying RNA sequencing to CD4+, CD8+, and CD19+ lymphocyte populations isolated from 81 subjects with type 1 diabetes (T1D). We characterize and compare the expression patterns across these cell types for three gene sets: all genes, the set of genes implicated in autoimmune disease risk by GWAS, and the subset of these genes specifically implicated in T1D. We performed RNA sequencing and aligned the reads to both the human reference genome and a catalog of all possible splicing events developed from the genome, thereby providing a comprehensive evaluation of the roles of gene expression and alternative splicing (AS) in autoimmunity. Autoimmune candidate genes displayed greater expression specificity in the three lymphocyte populations relative to other genes, with significantly increased levels of splicing events, particularly those predicted to have substantial effects on protein isoform structure and function (e.g., intron retention, exon skipping). The majority of single-nucleotide polymorphisms within T1D-associated loci were also associated with one or more cis-expression quantitative trait loci (cis-eQTLs) and/or splicing eQTLs. Our findings highlight a substantial, and previously underrecognized, role for AS in the pathogenesis of autoimmune disorders and particularly for T1D.


Assuntos
Processamento Alternativo , Diabetes Mellitus Tipo 1/genética , Perfilação da Expressão Gênica/métodos , Linfócitos/química , Análise de Sequência de RNA/métodos , Adulto , Linfócitos T CD4-Positivos/química , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/química , Linfócitos T CD8-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Feminino , Redes Reguladoras de Genes , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Linfócitos/imunologia , Masculino , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Locos de Características Quantitativas , Receptores CCR1/metabolismo
2.
Diabetes ; 63(12): 4360-8, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25008175

RESUMO

Single nucleotide polymorphisms (SNPs) located in the chromosomal region 16p13.13 have been previously associated with risk for several autoimmune diseases, including type 1 diabetes. To identify and localize specific risk variants for type 1 diabetes in this region and understand the mechanism of their action, we resequenced a 455-kb region in type 1 diabetic patients and unaffected control subjects, identifying 93 novel variants. A panel of 939 SNPs that included 46 of these novel variants was genotyped in 3,070 multiplex families with type 1 diabetes. Forty-eight SNPs, all located in CLEC16A, provided a statistically significant association (P < 5.32 × 10(-5)) with disease, with rs34306440 being most significantly associated (P = 5.74 × 10(-6)). The panel of SNPs used for fine mapping was also tested for association with transcript levels for each of the four genes in the region in B lymphoblastoid cell lines. Significant associations were observed only for transcript levels of DEXI, a gene with unknown function. We examined the relationship between the odds ratio for type 1 diabetes and the magnitude of the effect of DEXI transcript levels for each SNP in the region. Among SNPs significantly associated with type 1 diabetes, the common allele conferred an increased risk for disease and corresponded to lower DEXI expression. Our results suggest that the primary mechanism by which genetic variation at CLEC16A contributes to the risk for type 1 diabetes is through reduced expression of DEXI.


Assuntos
Cromossomos Humanos Par 16/genética , Proteínas de Ligação a DNA/genética , Diabetes Mellitus Tipo 1/genética , Lectinas Tipo C/genética , Proteínas de Membrana/genética , Proteínas de Transporte de Monossacarídeos/genética , RNA Mensageiro/análise , Estudos de Casos e Controles , Mapeamento Cromossômico , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase Reversa
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...