RESUMO
The objective of this study was to identify additional diabetes susceptibility markers in the MHC that could be responsible for the differential diabetogenicity of different HLA-DR3 CEHs. High-resolution SNP genotyping of the MHC was carried out in 15 type 1 diabetes (T1D) patients and 39 non-diabetic controls, homozygous for DR3-DQ2 and with one copy of the A(*)30-B(*)18-MICA(*)4-F1C30-DRB1(*)0301-DQB1(*)0201-DPB1(*)0202 HLA haplotype. Significantly associated SNPs were replicated in an independent sample of 554 T1D patients and 841 controls without HLA matching. Electrophoretic mobility shift assay was used to show a functional effect of an associated SNP. Seven SNPs showed evidence of association in the initial discovery experiment. Upon replication, only rs419434 (upstream HLA-DOA gene) remained significant. A functional variant (rs432375) in complete LD with rs419434 was shown to affect USF-1 binding and could be responsible for the association signal in the region. We have identified a new susceptibility locus within the MHC with a modest contribution to T1D (OR=1.93; CI: 1.52-2.44; P=10(-8)) that is independent of HLA-DRB1 locus.
Assuntos
Diabetes Mellitus Tipo 1/genética , Antígenos HLA-B/genética , Antígenos HLA-D/genética , Antígeno HLA-DR3/genética , Haplótipos/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/imunologia , Ensaio de Desvio de Mobilidade Eletroforética , Genótipo , Antígeno HLA-B18 , Humanos , Repetições de Microssatélites/genética , Prognóstico , Espanha/epidemiologiaRESUMO
The functional (R620W) variant of human PTPN22 (protein tyrosine phosphatase non-receptor 22) gene has been implicated in the risk to several autoimmune disorders, including type 1 diabetes, Graves' disease, rheumatoid arthritis and systemic lupus erythematosus. In an association study of this single nucleotide polymorphism with celiac disease (CD), comparison of 262 young diagnosis patients and 214 adult controls from Spain showed a higher frequency of the minor allele in the CD group (9.7% vs 5.6% in controls; P = 0.018), suggestive of an increased genetic risk to the disease (odds ratio = 1.82; 95% confidence interval 1.1-3.0). These results support the role of PTPN22 as a general autoimmunity locus involved in tolerance induction in the thymus.
Assuntos
Doença Celíaca/genética , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Adolescente , Adulto , Substituição de Aminoácidos , Estudos de Casos e Controles , Doença Celíaca/enzimologia , Doença Celíaca/imunologia , Criança , Pré-Escolar , Feminino , Frequência do Gene , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Tolerância Imunológica/genética , Lactente , Masculino , Proteína Tirosina Fosfatase não Receptora Tipo 22/imunologia , Fatores de Risco , EspanhaRESUMO
Genome-wide scans have detected linkage to celiac disease (CD) in several genomic locations, including 19q13.4. Killer immunoglobulin-like receptor (KIR) genes map to the region and encode receptors of natural killer (NK) cells and certain T cells that modulate cytolitic activity through interactions with HLA class I ligands, participating in the innate immune response. We performed KIR genotyping in a group of 70 CD patients of Basque origin and compared gene content, genotype and haplotype frequencies to ethnically matched blood-donors. The frequency of gene combination KIR2DL5B(+)/KIR2DL5A(-) was significantly higher in the disease group, and this result was confirmed in a second group of 343 CD patients and 160 controls of Spanish origin, suggesting an implication of this 'unexpressed' gene with increased susceptibility to CD (combined OR of 3.63 (95% CI: 1.76-7.51; P=0.0004)), possibly due to the lack of an efficient inhibitory signal. Our results support the role of the KIR gene cluster in celiac disease and replicate the CD-susceptibility locus at 19q13.4.
Assuntos
Doença Celíaca/genética , Cromossomos Humanos Par 19/genética , Etnicidade/genética , Predisposição Genética para Doença/genética , Receptores Imunológicos/genética , Genótipo , Haplótipos/genética , Humanos , Receptores KIR , Receptores KIR2DL5 , EspanhaRESUMO
Toll-like receptors (TLRs) participate in the first line of immune defense through antigen pattern recognition, and ligands include exogenous and host-derived molecules. Coding variants in TLR4 have been associated with autoimmune diseases like ulcerative colitis, Crohn's disease, and rheumatoid arthritis. Our aim was to determine whether these polymorphisms are associated with celiac disease (CD). Two coding single nucleotide polymorphisms of TLR4 (Asp299Gly and Thr399Ile) were genotyped in 95 family trios with CD as well as in 186 patients and 186 unrelated controls. There were no differences in allele, genotype or haplotype distribution, or transmission between patient and control groups. Our results do not support association of these TLR4 variants with CD.