RESUMEN
OBJECTIVE: Although the number of convincingly established genetic associations with systemic lupus erythematosus (SLE) has increased sharply over the last few years, refinement of these associations is required, and their potential roles in gene-gene interactions need to be further investigated. Recent genome-wide association studies (GWAS) in SLE have produced renewed interest in B cell/T cell responses and the NF-κB signaling pathway. The aim of this study was to search for possible gene-gene interactions based on identified single-nucleotide polymorphisms (SNPs), in using an approach based on the role of signaling pathways. METHODS: The SNPs in BLK, TNFSF4, TRAF1, TNFAIP3, and REL were replicated in order to evaluate genetic associations with SLE. TaqMan genotyping was conducted in 804 Chinese patients with SLE and 722 matched control subjects. A multiple logistic regression model was used to estimate the multiplicative interaction effect of the SNPs, and additive interactions were analyzed by 2×2 factorial designs. Data from a previously published GWAS conducted by the International Consortium on the Genetics of Systemic Lupus Erythematosus were derived for comparison and validation. RESULTS: Single-marker analysis validated the association of BLK rs2736340 (P=4.25×10(-6)) as well as TNFSF4 rs2205960 (P=2.82×10(-5)) and TNFAIP3 rs5029939 (P=1.92×10(-3)) with SLE susceptibility in Chinese. Multiplicative interaction analysis indicated that BLK had an interactive effect with TNFSF4 in Chinese patients with SLE (P=6.57×10(-4)). Additive interaction analysis revealed interactions between TRAF1 and TNFAIP3 in both Chinese (P=2.18×10(-3)) and Caucasians (P=2.86×10(-4)). In addition, multiple tendencies toward interactions were observed, and an additive effect was observed as the number of risk genotypes increased. CONCLUSION: The results of this study provide evidence of the possible gene-gene interactions of BLK, TNFSF4, TRAF1, TNFAIP3, and REL in SLE, which may represent a synergic effect of T cells and B cells through the NF-κB pathway in determining immunologic aberration.
Asunto(s)
Epistasis Genética/fisiología , Predisposición Genética a la Enfermedad/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Lupus Eritematoso Sistémico/genética , Adulto , Pueblo Asiatico/genética , Proteínas de Unión al ADN , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Proteínas Nucleares/genética , Ligando OX40/genética , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas c-rel/genética , Transducción de Señal , Factor 1 Asociado a Receptor de TNF/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa , Familia-src Quinasas/genéticaRESUMEN
OBJECTIVE: Recent genome-wide association studies suggested the PRDM1-ATG5 gene region as a systemic lupus erythematosus (SLE)-associated locus both in Caucasian and Chinese populations; however, the candidate gene was still obscure and the possible functional significance needed to be determined. METHODS: In this study, by a multistage integrative strategy, the authors first performed a case-control association study involving 1745 individuals in the Chinese population by genotyping nine single nucleotide polymorphisms within this region, and a meta-analysis was conducted. Correlation between associated genotypes and expression levels of messenger RNA in B-cell lines from 210 unrelated HapMap data was examined, and was validated in vitro. To determine the biological significance, a genetic association study was also checked in a pathway-based manner and the significant associations were validated in a second 844 Chinese cohort. RESULTS: A peak of association was found in the intergenic region (p=0.036-3.26×10(-4)). Meta-analysis consolidated the association between rs548234 and SLE (OR 1.254, p=1.28×10(-16)). Significant positive correlations with ATG5 expression were identified, suggesting ATG5 as a candidate gene in the region. Epstein-Barr virus B-cell-based downstream gene expression analysis supported a functional effect of rs548234 and rs6937876, and in-vitro experiments confirmed the regulatory effect of rs6937876 in B-cell populations. Finally, an autophagy pathway-based genetic association study identified ATG7 (p=1.12×10(-4)) and IRGM (p=0.015) as novel candidate genes, and gene-gene interactions were observed between ATG5, ATG7 and IRGM. CONCLUSION: These data may demonstrate that autophagy is involved in the pathogenesis of SLE and imply a common biological pathway in autoimmunity.