RESUMEN
OBJECTIVE: Bcl-2 antagonist killer 1 (BAK1) is a Bcl-2 family proapoptotic member suggested as a candidate gene for autoimmune diseases. The influence of BAK1 polymorphisms on the risk of developing autoimmune rheumatic diseases (AIRDs) in women was investigated. METHODS: A total of 719 Colombian women were included in the present study: 209 had systemic lupus erythematosus, 99 primary Sjögren syndrome, 159 rheumatoid arthritis and 252 were healthy matched controls. Tag single nucleotide polymorphisms (SNPs) and potentially functional variants were typed by TaqMan allele discrimination assays. HLA-DRB1 and HLA-DQB1 typing was performed by reverse dot-blot hybridisation and linkage disequilibrium (LD) with BAK1 SNPs was assessed. RESULTS: SNPs rs513349 (odds ratio (OR) 0.57, 95% CI 0.46 to 0.72, p = <0.001) and rs5745582 (OR 1.61, 95% CI 1.26 to 2.04, p = <0.001) were associated with the AIRDs included in this study. There was a significant increase of the rs513349G-rs561276C-rs5745582A (GCA) haplotype in each patient cohort as compared to controls (OR 1.95, 95% CI 1.50 to 2.54, p = <0.001). These SNPs were not in LD with HLA-DRB1 or HLA-DQB1 genes. CONCLUSIONS: The results indicate that the BAK1 polymorphisms influence the risk of acquiring AIRDs in the population studied and are consistent with the paradigm that autoimmune diseases are likely to share common susceptibility variants.
Asunto(s)
Enfermedades Autoinmunes/genética , Enfermedades Reumáticas/genética , Proteína Destructora del Antagonista Homólogo bcl-2/genética , Artritis Reumatoide/genética , Estudios de Casos y Controles , Colombia , Femenino , Predisposición Genética a la Enfermedad , Antígenos HLA-DQ/genética , Cadenas beta de HLA-DQ , Antígenos HLA-DR/genética , Cadenas HLA-DRB1 , Prueba de Histocompatibilidad/métodos , Humanos , Desequilibrio de Ligamiento , Lupus Eritematoso Sistémico/genética , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo de Nucleótido Simple , Polimorfismo Conformacional Retorcido-Simple , Síndrome de Sjögren/genéticaRESUMEN
We targeted LYN, a src-tyosine kinase involved in B-cell activation, in case-control association studies using populations of European-American, African-American and Korean subjects. Our combined European-derived population, consisting of 2463 independent cases and 3131 unrelated controls, shows significant association with rs6983130 in a female-only analysis with 2254 cases and 2228 controls (P=1.1 x 10(-4), odds ratio (OR)=0.81 (95% confidence interval: 0.73-0.90)). This single nucleotide polymorphism (SNP) is located in the 5' untranslated region within the first intron near the transcription initiation site of LYN. In addition, SNPs upstream of the first exon also show weak and sporadic association in subsets of the total European-American population. Multivariate logistic regression analysis implicates rs6983130 as a protective factor for systemic lupus erythematosus (SLE) susceptibility when anti-dsDNA, anti-chromatin, anti-52 kDa Ro or anti-Sm autoantibody status were used as covariates. Subset analysis of the European-American female cases by American College of Rheumatology classification criteria shows a reduction in the risk of hematological disorder with rs6983130 compared with cases without hematological disorders (P=1.5 x 10(-3), OR=0.75 (95% CI: 0.62-0.89)). None of the 90 SNPs tested show significant association with SLE in the African American or Korean populations. These results support an association of LYN with European-derived individuals with SLE, especially within autoantibody or clinical subsets.
Asunto(s)
Lupus Eritematoso Sistémico/genética , Polimorfismo de Nucleótido Simple , Familia-src Quinasas/genética , Factores de Edad , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Lupus Eritematoso Sistémico/epidemiología , Lupus Eritematoso Sistémico/inmunologíaRESUMEN
OBJECTIVES: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus (SLE), investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5. METHODS: 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in five new sets of cases and controls for replication. STAT4 cDNA was analysed by 5'-RACE PCR and sequencing. Expression levels were measured by quantitative PCR. RESULTS: In the fine mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals, represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. Transcription of alternative tissue-specific exons 1, indicating the presence of tissue-specific promoters of potential importance in the expression of STAT4, was also detected. No interaction with associated SNPs of IRF5 was observed using regression analysis. CONCLUSIONS: These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. The results also indicate that the genes STAT4 and IRF5 act additively to increase the risk for SLE.