Subtype-specific inherited predisposition to pemphigus in the Chinese population.

BACKGROUND: Pemphigus is a group of rare life-threatening mucocutaneous autoimmune diseases, presenting mainly as two subtypes: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Inherited predispositions to pemphigus have long been speculated but they remain poorly understood. OBJECTIVES: To identify common and specific nongenetic and genetic factors associated with pemphigus and its subtypes in the Chinese population. METHODS: A genome-wide association study (GWAS) was performed in 496 unrelated patients with pemphigus (including 365 with PV and 104 with PF) and 1105 controls without pemphigus. RESULTS: A sex preference was observed only in PV (57·5% female) and not in PF (47·1% female). For male patients only, the mean age at diagnosis was significantly lower for PV than for PF (P < 0·001). The strongest associated single-nucleotide polymorphisms are in the human leucocyte antigen (HLA) region: rs70993900 (PV; P = 1·5 × 10-45 ) and rs9469220 (PF; P = 1·1 × 10-8 ). HLA-DQB1*05:03 ranks at the top (P = 4·7 × 10-40 ; odds ratio 12·4) in both subtypes, with significantly different risk allele frequency (RAFPV = 34·2% vs. RAFPF = 18·8% vs. RAFcontrol = 4·4%), whereas HLA-DRB1*14:01 and HLA-DRB1*04:06 are PV specific. HLA-DQB1*03:03 and HLA-DQB1*03:02 show significant subtype specificity in opposite directions. All of these associations were validated in the replication series with 147 cases of pemphigus and 604 controls. Multiple novel non-HLA susceptibility loci were also identified in the GWAS. CONCLUSIONS: This study represents the largest GWAS on pemphigus in the Chinese population published to date, and has allowed us to identify HLA haplotypes significantly shared between or specific to the two main subtypes of pemphigus.

The use of lncRNA analysis for stratification management of prognostic risk in patients with NSCLC.

OBJECTIVE: Lung cancer is the most frequent cancer in China and worldwide. Long noncoding RNAs (lncRNAs) have been shown to play important regulatory roles in human cancer biology. The aim of the present study was to investigate the relationship between genomics and prognosis among lung cancer patients. PATIENTS AND METHODS: We collected specimens from non-small cell lung cancer (NSCLC) patients after surgery. Q-PCR was performed to investigate the expression level of lncRNAs in cancerous and adjacent normal tissue. Patients were divided into different risk groups according to lncRNA expression levels and then follow-up. RESULTS: The lncRNAs HOTAIR, H19 and MALAT1 were up-regulated, while PANDAR and TUG1 were down-regulated in NSCLC cancer tissues compared with the corresponding adjacent normal tissue. After two years of follow-up time, the disease-free survival time (DFS) curves were significantly different between the high-risk, moderate-risk and low-risk patient groups. CONCLUSIONS: Our results suggest that lncRNAs are involved in the process of NSCLC and that the use of genetic analysis for stratification management of prognostic risk could help us to implement individualized treatment for patients with NSCLC and ultimately to improve the patient prognosis.

Low expression of long noncoding RNA PANDAR predicts a poor prognosis of non-small cell lung cancer and affects cell apoptosis by regulating Bcl-2.

Recently, a novel class of transcripts, long noncoding RNAs (lncRNAs), is involved in diseases including cancer. Here, we investigated the the role of lncRNA PANDAR in the progression of non-small cell lung carcinoma (NSCLC). PANDAR, interacting with NF-YA, was generally downregulated in NSCLC tissues. In a cohort of 140 NSCLC patients, decreased PANDAR expression was negatively correlated with greater tumor size (P<0.001) and advanced TNM stage (P=0.002). Moreover, PANDAR could serve as an independent predictor for overall survival in NSCLC (P=0.015). Further experiments demonstrated that PANDAR expression was induced by p53, and chromatin immunoprecipitation (ChIP) assays confirmed that PANDAR was a direct transcriptional target of p53 in NSCLC cells. PANDAR overexpression significantly repressed the proliferation in vitro and in vivo. We also showed that PANDAR-mediated growth regulation is in part due to the transcriptional modulation of Bcl-2 by interacting with NF-YA, thus affecting NSCLC cell apoptosis. To our knowledge, this is the first report which showed the role of PANDAR in the progression of NSCLC. The p53/PANDAR/NF-YA/Bcl-2 interaction might serve as targets for NSCLC diagnosis and therapy.

P53-regulated long non-coding RNA TUG1 affects cell proliferation in human non-small cell lung cancer, partly through epigenetically regulating HOXB7 expression.

Recently, a novel class of transcripts, long non-coding RNAs (lncRNAs), is being identified at a rapid pace. These RNAs have critical roles in diverse biological processes, including tumorigenesis. Here we report that taurine-upregulated gene 1 (TUG1), a 7.1-kb lncRNA, recruiting and binding to polycomb repressive complex 2 (PRC2), is generally downregulated in non-small cell lung carcinoma (NSCLC) tissues. In a cohort of 192 NSCLC patients, the lower expression of TUG1 was associated with a higher TNM stage and tumor size, as well as poorer overall survival (P<0.001). Univariate and multivariate analyses revealed that TUG1 expression serves as an independent predictor for overall survival (P<0.001). Further experiments revealed that TUG1 expression was induced by p53, and luciferase and chromatin immunoprecipitation (ChIP) assays confirmed that TUG1 was a direct transcriptional target of p53. TUG1 knockdown significantly promoted the proliferation in vitro and in vivo. Moreover, the lncRNA-mediated regulation of the expression of HOX genes in tumorigenesis and development has been recently receiving increased attention. Interestingly, inhibition of TUG1 could upregulate homeobox B7 (HOXB7) expression; ChIP assays demonstrated that the promoter of HOXB7 locus was bound by EZH2 (enhancer of zeste homolog 2), a key component of PRC2, and was H3K27 trimethylated. This TUG1-mediated growth regulation is in part due to specific modulation of HOXB7, thus participating in AKT and MAPK pathways. Together, these results suggest that p53-regulated TUG1 is a growth regulator, which acts in part through control of HOXB7. The p53/TUG1/PRC2/HOXB7 interaction might serve as targets for NSCLC diagnosis and therapy.

End-stage renal disease risk equations for Hong Kong Chinese patients with type 2 diabetes: Hong Kong Diabetes Registry.

AIMS/HYPOTHESIS: The objective of the study was to investigate risk factors and develop risk equations for end-stage renal disease (ESRD) in Chinese patients with type 2 diabetes. SUBJECTS AND METHODS: A prospective cohort of 4,438 patients with type 2 diabetes mellitus and without ESRD (median observation period 2.9 years, interquartile range 1.6-4.1 years) was included in the analysis. The end-point (ESRD) was defined by: (1) death due to diabetes with renal manifestations or renal failure; (2) hospitalisation due to renal failure; (3) estimated GFR (eGFR) <15 ml min(-1) 1.73 m(-2). Cox proportional hazards regression was used to develop risk equations. The data were randomly and evenly divided into the training data for development of the risk equations and the test data for validation. The validation was performed using the area under the receiver operating characteristic curve (aROC), which takes into account follow-up time and censoring. RESULTS: During the observation period, 159 patients or 12.45 per 1,000 person-years (95% CI 10.52-14.37 per 1,000 person-years) developed ESRD. Known duration of diabetes, systolic blood pressure, log(10) total cholesterol:HDL cholesterol ratio and retinopathy were significant predictors of ESRD. After further adjusting for eGFR, log(10) spot albumin:creatinine ratio (ACR) and haematocrit, only eGFR, haematocrit and log(10) ACR remained as independent predictors of ESRD. The risk equation derived from these three independent predictors had good discrimination, with an aROC of 0.97. CONCLUSIONS/INTERPRETATION: Estimated GFR, haematocrit and ACR were independent predictors of ESRD and the derived risk equation performed well in Chinese patients with type 2 diabetes.