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Li M.,Shanghai JiaoTong University | Cheng R.,Shanghai JiaoTong University | Shi M.,Shanghai JiaoTong University | Liu J.,Baoan Maternal and Child Health Hospital | And 4 more authors.
British Journal of Dermatology | Year: 2013

Background Ichthyosis vulgaris (IV; OMIM 146700) is a very common inherited skin disorder. Loss-of-function mutations in the filaggrin gene (FLG) have been identified as the cause of IV. In a previous study, we found that the percentage of FLG null mutations was lower in IV associated with atopic dermatitis (AD) than in IV not associated with AD (isolated IV). We speculated that some clinical manifestations of IV in patients with AD are not induced by FLG mutations. Objectives In order to clarify this issue, we collected 21 IV pedigrees, 33 patients with sporadic isolated IV and 116 patients with AD-associated IV to analyse FLG mutation frequency and filaggrin expression in isolated IV and AD-associated IV. Methods A comprehensive sequencing of the FLG gene in all patients was performed using an overlapping polymerase chain reaction (PCR) strategy. We also studied the immunohistochemistry of profilaggrin/filaggrin protein expression in the skin and measured the mRNA expression using real-time PCR in seven patients, including one patient with IV harbouring the mutation c.3321delA, two patients with AD-associated IV harbouring c.3321delA and c.6834del5, and four patients with AD-associated IV without FLG mutations. Results The percentage of mutations in the FLG gene was 74% and 43% in patients with isolated IV and patients with AD-associated IV, respectively. Immunohistochemical staining revealed that profilaggrin/filaggrin peptides were remarkably reduced in the epidermis of all the patients. All the patients with either AD or IV showed lower FLG mRNA expression compared with the normal control. Conclusions These results indicate that factors other than FLG gene mutations can downregulate profilaggrin/filaggrin expression, leading to the ichthyosiform phenotype in the context of AD. What's already known about this topic? FLG mutations are the cause of ichthyosis vulgaris (IV) and the strongest genetic risk for atopic dermatitis (AD). T helper 2 cytokines and tumour necrosis factor-α may reduce filaggrin expression. What does this study add? The frequency of FLG mutations in isolated IV is much higher than in AD-associated IV. Factors other than FLG gene mutations can downregulate profilaggrin/filaggrin expression, leading to the ichthyosiform phenotype in the context of AD. © 2013 The Authors. BJD © 2013 British Association of Dermatologists. Source

Li M.,Shanghai JiaoTong University | Liu Q.,Shanxi Provincial Childrens Hospital | Liu J.,Baoan Maternal and Child Health Hospital | Cheng R.,Shanghai JiaoTong University | And 4 more authors.
Journal of the European Academy of Dermatology and Venereology | Year: 2013

Background Recently, we have reported filaggrin mutations (FLG) of atopic dermatitis in southern China. However, there have been few detailed reports of FLG mutations of patients with AD in northern China by now. Objectives The present aim was to establish the mutation spectrum of FLG gene in AD patients in northern China. Methods A total of 339 cases met Hanifin and Rajka diagnostic criteria of AD were recruited. A comprehensive sequencing of the entire FLG coding region in these patients was conducted. All detected FLG null mutations were screened in a cohort of 301 normal controls. Results Seven novel mutations (478insA, Q1070X, 4026delT, Q1712X, Q2397X, 7145del4 and 8001del4) and eleven reported mutations (3222del4, 3321delA, 4271delAA, S1515X, Q1790X, 5757del4, 6834del5, Q2417X, E2422X, 7945delA and K4671X) in AD were identified. Mutations 3321delA and K4671X were two of the most common mutations in AD. FLG null mutations were present in 26.0% of AD patients. FLG null alleles (compound genotypes) were significantly higher in AD (P < 0.001) than in the controls. The compound genotypes for all FLG variants were significantly associated with IV (P < 0.001) and palmar hyperlinearity (P < 0.001). The common mutation, K4671X, was significantly associated with AD-coexistent allergic rhinitis (P = 0.005). Conclusions Our study increases the total number of FLG mutations. We clearly demonstrated that FLG loss-of-function mutations were significantly associated with AD in northern China. The FLG null mutations in the Chinese population differed not only from that in the European population but also from that in sub-populations of Asians outside of the Chinese mainland. © 2012 The Authors. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology. Source

Li S.-Y.,Baoan Maternal and Child Health Hospital | Li S.-Y.,Southern Medical University | Li R.,Southern Medical University | Chen Y.-L.,Baoan Maternal and Child Health Hospital | And 4 more authors.
BMC Genetics | Year: 2014

Background: Aberrant hypermethylation of gene promoter regions is a primary mechanism by which tumor suppressor genes become inactivated in breast cancer. Epigenetic inactivation of the protein tyrosine phosphatase receptor-type O gene (PTPRO) has been described in several types of cancer.Results: We screened primary breast cancer tissues for PTPRO promoter hypermethylation and assessed potential associations with pathological features and patient outcome. We also evaluated its potential as a breast cancer biomarker. PTPRO methylation was observed in 53 of 98 (54%) breast cancer tissues but not in adjacent normal tissue. Among matched peripheral blood samples from breast cancer patients, 33 of 98 (34%) exhibited methylated PTPRO in plasma. In contrast, no methylated PTPRO was observed in normal peripheral blood from 30 healthy individuals. PTPRO methylation was positively associated with lymph node involvement (P = 0.014), poorly differentiated histology (P = 0.037), depth of invasion (P = 0.004), and HER2 amplification (P = 0.001). Multivariate analysis indicated that aberrant PTPRO methylation could serve as an independent predictor for overall survival hazard ratio (HR): 2.7; 95% CI: 1.1-6.2; P = 0.023), especially for patients with HER2-positive (hazard ratio (HR): 7.5; 95% CI: 1.8-31.3; P = 0.006), but not in ER + and PR + subpopulation. In addition, demethylation induced by 5-azacytidine led to gene reactivation in PTPRO-methylated and -silenced breast cancer cell lines.Conclusions: Here, we report that tumor PTPRO methylation is a strong prognostic factor in breast cancer. Methylation of PTPRO silences its expression and plays an important role in breast carcinogenesis. The data we present here may provide insight into the development of novel therapies for breast cancer treatment. Additionally, detection of PTPRO methylation in peripheral blood of breast cancer patients may provide a noninvasive means to diagnose and monitor the disease. © 2014 Li et al.; licensee BioMed Central Ltd. Source

Luo Y.L.,Southern Medical University | Cheng Y.L.,Baoan Maternal and Child Health Hospital | Ye P.,Southern Medical University | Wang W.,Baoan Maternal and Child Health Hospital | And 2 more authors.
Birth Defects Research Part A - Clinical and Molecular Teratology | Year: 2012

Background The roles of C677T and A1298C polymorphisms in methylenetetrahydrofolate reductase (MTHFR) gene in orofacial clefts (OFCs) risk have been substantially explored, but the results remain conflicting. To address this gap, we conducted a meta-analysis involving all eligible studies. METHODS: Electronic literature searches of the PubMed, EmBase, and Medline databases were performed up to October 31, 2011. Fixed-effects or random-effects models were used to calculate the pooled odds ratios (ORs) for two genetic comparisons (heterozygous mutation vs. wild type, homozygous mutation vs. wild type). Results A total of 18 studies were ultimately identified. The pooled results revealed no statistical association between infant and maternal C677T and A1298C variants and risk of cleft lip with or without palate (CL/P) or cleft palate only (CPO), except for the maternal 677TT genotype for CL/P, the OR was 1.32 (95% confidence interval [CI], 1.06-1.63) as compared to the normal 677CC genotype. In the subgroup analyses on CL/P data based on ethnicity and source of control subjects, almost all of the results were replicated as nonsignificant associations in both examined polymorphisms, whereas the pooled risk estimate calculated for maternal 677TT genotype in the white population remained statistically significant, with an OR of 1.36 (95% CI, 1.05-1.76). Conclusions This meta-analysis suggests that maternal MTHFR 677TT genotype might increase the risk of having a CL/P offspring in the white population. However, these findings remain to be confirmed by additional investigations. © 2012 Wiley Periodicals, Inc. Source

Luo Y.L.,Southern Medical University | Cheng Y.L.,Baoan Maternal and Child Health Hospital | Gao X.H.,Shenzhen Maternal and Child Health Hospital | Tan S.Q.,Southern Medical University | And 2 more authors.
PLoS ONE | Year: 2013

Background: The etiology of birth defects has been widely studied but is not yet fully clarified, previously published data had suggested that maternal age or parity maybe involved, but without consistent conclusions. Methods: A population-based, case-control study was nested in a cohort of perinatal infants born from 2010 to 2012 in Baoan District, Shenzhen. Four categories of isolated birth defects were defined as cases: congenital heart defects (CHD, n = 693), polydactyly (n = 352), cleft lip with or without palate (CL/P, n = 159) and equinovarus (n = 119). Controls were non-malformed infants (n = 11,307) randomly selected from the same area and period. Odds ratios (ORs) and the 95% confidence intervals (CIs) were computed by multivariable unconditional logistic regression analysis. Results: Young maternal age (<25 years old) was associated with a reduced risk of CHD (adjusted OR = 0.73, 95% CI 0.59- 0.90), while with an elevated risk of polydactyly (adjusted OR = 1.42, 95% CI 1.09-1.84). Increased risk of CL/P-affected pregnancy was observed in mothers older than 35 years old (adjusted OR = 2.12, 95% CI 1.26-3.57). Compared to primipara, those having their second, and third or more delivery were less likely to have infants with equinovarus, with significant adjusted ORs of 0.59 (0.40-0.89) and 0.42 (0.19-0.93), respectively. Conclusion: Maternal age was significantly associated with CHD, polydactyly and CL/P relevant pregnancy. Mothers with higher parity might have lower risk of equinovarus occurrence in offsprings. © 2013 Luo et al. Source

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