RESUMO
The aim of the study is to explore additional susceptibility factors for systemic lupus erythematosus (SLE) in Chinese Hans. Based on our previous GWAS of SLE, we performed a multistage replication study involving 3,152 cases and 7,050 controls from China to identify additional susceptibility loci for SLE by using the Sequenom MassArray system. All Chinese Han samples used in this study were obtained from doctors through collaboration with multiple hospitals in two geographic regions (central and southern China). Single-marker association analyses were performed using logistic regression with gender as a covariate in each case-control cohort. The joint analysis of all combined samples was performed using logistic regression with gender and sample cohorts as covariates. The significant association evidence for rs906868 (OR = 1.14, 95% CI 1.08-1.20, P combined = 7.71 × 10(-10)) and rs7579944 (OR = 1.13, 95% CI 1.07-1.19, P combined = 5.55 × 10(-9)) was observed, which located at 2p23.1. In this region, limb bud and heart development homolog (LBH) was the only gene indicated, suggesting LBH might be a susceptibility gene for SLE, although its function was still unknown. The results indicated that the SNP rs7579944, rs906868 at 2p23.1 showed significant association with SLE. The genes LBH which located in this loci might be the predisposing genes of SLE.
Assuntos
Povo Asiático/genética , Loci Gênicos , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Adulto , China , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: We have performed a large-scale replication study based on our previous genome-wide association study (GWAS) of SLE in the Chinese Han population to further explore additional genetic variants affecting susceptibility to SLE. METHODS: Thirty-eight single nucleotide polymorphisms from our GWAS were genotyped in two additional Chinese Han cohorts (total 3152 cases and 7050 controls) using the Sequenom Massarray system. Association analyses were performed using logistic regression with gender or sample cohorts as a covariate. RESULTS: Association evidence for rs16972959 (PRKCB at 16p11.2) and rs12676482 (8p11.21) with SLE was replicated independently in both replication cohorts (P < 0.05), showing high significance for SLE in combined all 4199 cases and 8255 controls of Chinese Han [rs16972959: odds ratio (OR) = 0.81; 95% CI 0.76, 0.87; P(combined) = 1.35 × 10(-9); rs12676482: OR = 1.26; 95% CI 1.15, 1.38; P(combined) = 6.68 × 10(-7)). PRKCB is related to the established SLE immune-related pathway (NF-κB) and 8p11.21 contains important candidate genes such as IKBKB and DKK4. IKBKB is a critical component of NF-κB and DKK4 is an inhibitor of canonical Wnt signalling pathway. Interestingly, PRKCB is required for recruiting IKBKB into lipid rafts, up-regulating NF-κB-dependent survival signal. CONCLUSIONS: Our findings provided novel insights into the genetic architecture of SLE and emphasized the contribution of multiple variants of modest effect. Further study focused on PRKCB, 8p11.21, should advance our understanding on the pathogenesis of SLE.
Assuntos
Povo Asiático/genética , Cromossomos Humanos Par 8/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único/genética , Proteína Quinase C/genética , Adulto , Povo Asiático/etnologia , Estudos de Casos e Controles , China , Feminino , Seguimentos , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Quinase I-kappa B/genética , Quinase I-kappa B/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Pessoa de Meia-Idade , NF-kappa B/fisiologia , Proteína Quinase C beta , Transdução de Sinais/genética , Proteínas Wnt/fisiologiaRESUMO
Leishmania spp. are able to survive and proliferate inside mammals' mononuclear phagocytes, causing Leishmaniasis. Previous studies have noted that the regulation of apoptosis in host cells by these parasites may contribute to their ability to evade the immune system. However, current results remain unclear about whether the parasites can promote or delay the apoptotic process in host cells, because the regulatory effect of Leishmania was assumed to be strain-, species- and even infection time-dependent. The aim of this study was to investigate whether the Sichuan isolates of Chinese Leishmania (SC10H2) can alter the process of intrinsic apoptosis induced by cycloheximide in different types of macrophage cell lines and to determine in which steps of the signaling pathway the parasites were involved. Human THP-1 and mouse RAW264.7 macrophages were infected by SC10H2 promastigotes followed by cycloheximide stimulation to assess the alteration of intrinsic apoptosis in these cells. The results indicated that SC10H2 infection of human THP-1 macrophages could promote the initiation of intrinsic apoptosis, but completely opposite results were found in mouse RAW264.7 macrophages. Nevertheless, the expression of Bcl-2 and the DNA fragmentation rates were not altered by SC10H2 infection in the cell lines used in the experiments. This study suggests that SC10H2 promastigote infection is able to promote and delay the transduction of early apoptotic signals induced by cycloheximide in THP-1 and RAW264.7 macrophages, revealing that the regulation of intrinsic apoptosis in host cells by SC10H2 in vitro occurs in a host cell-dependent manner. The data from this study might play a significant role in further understanding the relationship between Leishmania and different host cells.