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Zha X.,Peking Union Medical College | Zha X.,Anhui Medical University | Zha X.,State Key Laboratory Incubation Base of Dermatology | Hu Z.,Peking Union Medical College | And 4 more authors.
Cancer Letters | Year: 2011

Aberrant activation of mammalian target of rapamycin complex 1 (mTORC1), caused by loss or inactivation of TSC1/TSC2 protein complex, leads to negative feedback inhibition of Akt. The exact mechanisms of this process are still not fully understood. Here we present evidence for the involvement of STAT3, a known mTORC1 regulated transcription factor, in this process. We demonstrate that STAT3 promotes the transcription of PTEN by directly binding on the PTEN promoter. Elevated PTEN then inhibits the proliferation of Tsc1 -/- or Tsc2 -/- cells through down-regulation of Akt signaling. Activation of PTEN in this pathway may thus serve as a protective mechanism against hyper-activated mTORC1 mediated tumorigenesis and contribute to the benign nature of tumors caused by loss of either TSC1 or TSC2. © 2011 Elsevier Ireland Ltd. Source


Zhang X.,Anhui Medical University | Zhang X.,State Key Laboratory Incubation Base of Dermatology
Frontiers of Medicine in China | Year: 2014

The advent of whole-exome sequencing (WES) has facilitated the discovery of rare structure and functional genetic variants. Combining exome sequencing with linkage studies is one of the most efficient strategies in searching disease genes for Mendelian diseases. WES has achieved great success in the past three years for Mendelian disease genetics and has identified over 150 new Mendelian disease genes. We illustrate the workflow of exome capture and sequencing to highlight the advantages of WES. We also indicate the progress and limitations of WES that can potentially result in failure to identify disease-causing mutations in part of patients. With an affordable cost, WES is expected to become the most commonly used tool for Mendelian disease gene identification. The variants detected cumulatively from previous WES studies will be widely used in future clinical services. © 2014 Higher Education Press and Springer-Verlag Berlin Heidelberg. Source


Liu J.L.,Hainan Nongken General Hospital | Zhang S.Q.,Anhui Medical University | Zhang S.Q.,State Key Laboratory Incubation Base of Dermatology | Zeng H.M.,Hainan Medical College
Journal of the European Academy of Dermatology and Venereology | Year: 2013

Objectives To determine whether ApaI, BsmI, FokI or TaqI polymorphisms in vitamin D receptor (VDR) gene confer susceptibility to psoriasis. Methods All related association studies published before January 2012 were retrieved and eligible ones were included in our meta-analysis. For each of the four polymorphisms, we explored the significance of the associations for the allele contrast as well as the recessive and dominant models in overall samples, Caucasians and East Asians. Heterogeneity was identified by sensitivity analysis and publication bias was examined by funnel plot and Egger's test. Results 12 studies that met our selection criteria were included. For ApaI polymorphism, the dominant model for allele a in Caucasians produced a significant result [heterogeneity χ2=3.46, P = 0.177, I2=42.2%; OR fixed-effect model = 1.398 (1.011-1.934), z = 2.03, P = 0.043]. While in East Asians, pooling analysis under any genetic model acquired no-significant result. Significant heterogeneity was identified among East Asian studies and a Korean study accounted mostly for the heterogeneity detected. The heterogeneities were no longer statistically significant after removing this study, and the results of re-analyses in remaining studies have not been affected. Regarding TaqI polymorphism, the allele contrast discovered significant association between allele T and psoriasis susceptibility in Caucasians [heterogeneity χ2 = 4.35, P = 0.226, I2 = 31.1%; ORfixed-effect model = 1.287 (1.067-1.551), z = 2.64, P = 0.008]. As for the BsmI and FokI polymorphisms, allele contrast, recessive and dominant models produced non-significant results in either Caucasians or East Asians. The funnel plots and Egger's tests found no publication bias presenting in the studies analyzed. Conclusions This meta-analysis showed that ApaI, TaqI polymorphisms in VDR gene correlate with psoriasis in Caucasians. © 2012 The Authors. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology. Source


Wu L.-S.,Central South University | Li F.-F.,Central South University | Sun L.-D.,State Key Laboratory Incubation Base of Dermatology | Li D.,Central South University | And 5 more authors.
Human Genetics | Year: 2011

Psoriasis (PS; MIM#177900) is a chronic inflammatory immune-mediated skin disorder. Although the disease is believed to be caused by a combination of genetic, immunologic and environmental factors, its complete etiology has not been fully understood. Here, we focused on the BSG (MIM#109480), a member of the immunoglobulin superfamily expressed ubiquitously in circulating immune cell populations. We observed that the expression level of BSG in PBMCs was elevated in psoriasis patients. To understand the underlying mechanism for this change, we genotyped the rs8259 T>A SNP located in the 3′UTR of the BSG gene from 668 psoriasis patients and 1,143 healthy controls. The rs8259 T allele was associated with significantly decreased psoriasis susceptibility (OR = 0.758, 95% CI 0.638-0.901, p = 0.002). Interestingly, the rs8259 polymorphism was located in a seed region for miR-492 binding. The miR-492 was able to bind to the BSG 3′UTR sequence bearing the rs8259 T allele as assayed by luciferase reporter gene assay. The substitution of T with A abolished miR-492 binding. BSG protein expression in PBMCs from patients carrying the rs8259 AA genotype was significantly higher than in those from patients carrying the rs8259 TT genotype. Our study suggests that miR-492 may physiologically suppress BSG expression and the BSG rs8259 polymorphism is associated with decreased psoriasis susceptibility through affecting miR-492 binding. © 2011 Springer-Verlag. Source


Coin L.J.M.,BGI Shenzhen | Coin L.J.M.,Imperial College London | Cao D.,BGI Shenzhen | Ren J.,BGI Shenzhen | And 14 more authors.
Bioinformatics | Year: 2012

Motivation: Despite the prevalence of copy number variation (CNV) in the human genome, only a handful of confirmed associations have been reported between common CNVs and complex disease. This may be partially attributed to the difficulty in accurately genotyping CNVs in large cohorts using array-based technologies. Exome sequencing is now widely being applied to case-control cohorts and presents an exciting opportunity to look for common CNVs associated with disease. Results: We developed ExoCNVTest: an exome sequencing analysis pipeline to identify disease-associated CNVs and to generate absolute copy number genotypes at putatively associated loci. Our method re-discovered the LCE3B_LCE3C CNV association with psoriasis (P-value = 5 × 10e-6) while controlling inflation of test statistics (λ<1). ExoCNVTest-derived absolute CNV genotypes were 97.4% concordant with PCR-derived genotypes at this locus. © The Author(s) 2012. Published by Oxford University Press. Source

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