RESUMEN
A recent genome-wide association study revealed a variant (rs2431697) in an intergenic region, between the pituitary tumor-transforming 1 (PTTG1) and microRNA (miR-146a) genes, associated with systemic lupus erythematosus (SLE) susceptibility. Here, we analyzed with a case-control design this variant and other candidate polymorphisms in this region together with expression analysis in order to clarify to which gene this association is related. The single-nucleotide polymorphisms (SNPs) rs2431697, rs2910164 and rs2277920 were genotyped by TaqMan assays in 1324 SLE patients and 1453 healthy controls of European ancestry. Genetic association was statistically analyzed using Unphased. Gene expression of PTTG1, the miRNAs miR-3142 and primary and mature forms of miR-146a in peripheral blood mononuclear cells (PBMCs) were assessed by quantitative real-time PCR. Of the three variants analyzed, only rs2431697 was genetically associated with SLE in Europeans. Gene expression analysis revealed that this SNP was not associated with PTTG1 expression levels, but with the microRNA-146a, where the risk allele correlates with lower expression of the miRNA. We replicated the genetic association of rs2341697 with SLE in a case-control study in Europeans and demonstrated that the risk allele of this SNP correlates with a downregulation of the miRNA 146a, potentially important in SLE etiology.
Asunto(s)
Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico/genética , MicroARNs/genética , Proteínas de Neoplasias/genética , Población Blanca/genética , Alelos , Estudios de Casos y Controles , Europa (Continente) , Orden Génico , Estudio de Asociación del Genoma Completo , Humanos , Lupus Eritematoso Sistémico/etnología , Polimorfismo de Nucleótido Simple , SecurinaRESUMEN
Previous studies of multiple sclerosis patients showed the existence of a positive association between multiple sclerosis and HLA--A3 and --B7, as well as a negative association with B12. These observations have been confirmed. In addition, a more marked association has been observed with two recently identified B-cell antigens, DRw2 and DRw3, closely related to the HLA--D locus. The presence of cold lymphocytotoxic antibodies was found to bear no relationship with those two specificities. These results suggest that two genes of the HLA--DR region may play a role in the pathogenesis of multiple sclerosis.
Asunto(s)
Antígenos HLA , Esclerosis Múltiple/inmunología , Epítopos , Frecuencia de los Genes , Humanos , Esclerosis Múltiple/genéticaRESUMEN
Previous studies of multiple sclerosis patients showed the existence of a positive association between multiple sclerosis and HLA-A3 and B7, as well as a negative association with B12, These observations have been confirmed. In addition, a more marked association has been observed with two recently identified B-cell antigens, DRW2 and DRW3, closely related to HLA-D locus. The presence of cold lymphocytotoxic antibodies was found to bear no relationship with those two specificities. These results suggest that two genes of the HLA-DR region may play a role in the pathogenesis of multiple sclerosis.