RESUMEN
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.
Asunto(s)
Pueblo Asiatico/genética , Cromosomas Humanos Par 8/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Lupus Eritematoso Sistémico/genética , Polimorfismo de Nucleótido Simple/genética , Proteína Quinasa C/genética , Adulto , Pueblo Asiatico/etnología , Estudios de Casos y Controles , China , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad/etnología , Genotipo , Humanos , Quinasa I-kappa B/genética , Quinasa I-kappa B/fisiología , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/fisiología , Lupus Eritematoso Sistémico/etnología , Masculino , Persona de Mediana Edad , FN-kappa B/fisiología , Proteína Quinasa C beta , Transducción de Señal/genética , Proteínas Wnt/fisiologíaRESUMEN
We extended our previous genome-wide association study for psoriasis with a multistage replication study including 8,312 individuals with psoriasis (cases) and 12,919 controls from China as well as 3,293 cases and 4,188 controls from Germany and the United States and 254 nuclear families from the United States. We identified six new susceptibility loci associated with psoriasis in the Chinese study containing the candidate genes ERAP1, PTTG1, CSMD1, GJB2, SERPINB8 and ZNF816A (combined P < 5 × 10â»8) and replicated one locus, 5q33.1 (TNIP1-ANXA6), previously reported (combined P = 3.8 × 10⻲¹) in the European studies. Two of these loci showed evidence for association in the German study at ZNF816A and GJB2 with P = 3.6 × 10⻳ and P = 7.9 × 10⻳, respectively. ERAP1 and ZNF816A were associated with type 1 (early onset) psoriasis in the Chinese Han population (test for heterogeneity P = 6.5 × 10⻳ and P = 1.5 × 10⻳, respectively). Comparisons with the results of previous GWAS of psoriasis highlight the heterogeneity of disease susceptibility between the Chinese and European populations. Our study identifies new genetic susceptibility factors and suggests new biological pathways in psoriasis.
Asunto(s)
Pueblo Asiatico/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Psoriasis/genética , Aminopeptidasas/genética , Conexina 26 , Conexinas/genética , Replicación del ADN , Alemania/epidemiología , Humanos , Proteínas de la Membrana/genética , Antígenos de Histocompatibilidad Menor , Proteínas de Neoplasias/genética , Securina , Serpinas/genética , Proteínas Supresoras de Tumor , Estados Unidos/epidemiologíaRESUMEN
Patients with advanced hepatocellular carcinoma (HCC) have shown to benefit from tamoxifen treatment. The mechanisms of tamoxifen effects in HCC, however, are not yet clearly understood. The PI3K/Akt/mTOR signal pathway is involved in cell proliferation, tumorigenesis, and apoptosis. Over-expression of survivin has played an important role in leading to antiapoptosis. The current study investigated changes in mTOR pathway and survivin expression in hepatocarcinoma cell line HepG2 treated with tamoxifen. We detected apoptosis of hepatocarcinoma cells by flow cytometry assay. Survivin transcription level and p70S6k was demonstrated by PCR, dual-luciferase reporter assay and western blot analysis respectively. Our results are showed as follows: tamoxifen leads to apoptosis of the cells, and reduction in survivin expression, as well as a dramatic reduction in the activated form of p70S6 kinase. Twenty micromoles tamoxifen treatment significantly depresses transcription of survivin mRNA. Treating HepG2 cells with rapamycin, a specific mTOR inhibitor, significantly reduce survivin protein level but did not affect survivin transcription, which indicated that tamoxifen and rapamycin were synergistic in regards to down-regulation of survivin expression in hepatocellular carcinoma cells. Our results suggest that tamoxifen down-regulate survivin expression in HepG2 cells is mediated by transcriptional and posttranscriptional level via PI3K/Akt/mTOR pathway to induce apoptosis.
Asunto(s)
Antineoplásicos Hormonales/farmacología , Péptidos y Proteínas de Señalización Intracelular/efectos de los fármacos , Proteínas Asociadas a Microtúbulos/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/efectos de los fármacos , Tamoxifeno/farmacología , Apoptosis/efectos de los fármacos , Western Blotting , Regulación hacia Abajo/efectos de los fármacos , Sinergismo Farmacológico , Citometría de Flujo , Genes Reporteros , Células Hep G2 , Hepatoblastoma/tratamiento farmacológico , Hepatoblastoma/patología , Humanos , Proteínas Inhibidoras de la Apoptosis , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Luciferasas , Proteínas Asociadas a Microtúbulos/genética , Reacción en Cadena de la Polimerasa , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología , Survivin , Serina-Treonina Quinasas TORRESUMEN
OBJECTIVE: The aim of this study was to detect the expression of livin in human gastric carcinoma and analyze the relationship between livin expression and cliniopathologic features. To explore the feasibility of small interference RNA (siRNA) in inhibition of livin gene expression and to investigate the apoptosis susceptibility of SGC-7901 cells by siRNA-mediated silencing of the livin gene. METHODS: The expression of livin at mRNA and protein levels were determined by RT-PCR and Western blot assay, respectively. The relationship between livin expression and clinicopathologic features was analyzed. Two siRNAs specifically targeting livin gene were designed and synthesized in vitro, and were transfected into the gastric cancer SGC-7901 cells. The expression of livin mRNA was assayed by RT-PCR. Cell growth state and 50% inhibition concentration (IC50) of 5-Fu and cisplatin on SGC-7901 cells were determined by MTT method. Cell apoptosis was assessed by flow cytometry (FCM). RESULTS: The expressions of livin mRNA and protein were detected in 19 of 40 gastric carcinoma cases (47.5%). No expression of livin was detected in tumor-adjacent tissues and benign gastric lesion. A positive correlation was found between livin expression and poor differentiation as well as lymph node metastases (P < 0.05). The level of livin mRNA was decreased in the SGC-7901 cells transfected by si-livin1 for 48 hours, with inhibition of cell growth. IC50 of si-livin-treated SGC-7901 cells to 5-Fu and cisplatin was decreased (P < 0.05) and the cells were more susceptible to proapoptotic stimuli (5-Fu and cisplatin) than control groups (P < 0.05). CONCLUSION: Livin is overexpressed in gastric carcinoma with a correlation to tumor differentiation and lymph node metastasis, suggesting that it may be as one of molecular prognostic factors for some cases of gastric cancer. SiRNA can inhibit livin expression of SGC-7901 cells and induce cell apoptosis. Livin might serve as a new target for apoptosis-inducing therapy of gastric cancer. Livin;