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Jin P.,Shandong University | Jin P.,National University of Singapore | Andiappan A.K.,Agency for Science, Technology and Research Singapore | Andiappan A.K.,National University of Singapore | And 30 more authors.
Journal of Allergy and Clinical Immunology | Year: 2015

Background Brain-derived neurotrophic factor (BDNF) is a secretory protein that has been implicated in the pathogenesis of allergic rhinitis (AR), atopic asthma, and eczema, but it is currently unknown whether BDNF polymorphisms influence susceptibility to moderate-to-severe AR. Objective We sought to identify disease associations and the functional effect of BDNF genetic variants in patients with moderate-to-severe AR. Methods Tagging single nucleotide polymorphisms (SNPs) spanning the BDNF gene were selected from the human HapMap Han Chinese from Beijing (CHB) data set, and associations with moderate-to-severe AR were assessed in 2 independent cohorts of Chinese patients (2216 from Shandong province and 1239 living in Singapore). The functional effects of the BDNF genetic variants were determined by using both in vitro and ex vivo assays. Results The tagging SNP rs10767664 was significantly associated with the risk of moderate-to-severe AR in both Singapore Chinese (P =.0017; odds ratio, 1.324) and Shandong Chinese populations (P =.039; odds ratio, 1.180). The coding nonsynonymous SNP rs6265 was in perfect linkage with rs10767664 and conferred increased BDNF protein secretion by a human cell line in vitro. Subjects bearing the AA genotype of rs10767664 exhibited increased risk of moderate-to-severe AR and displayed increased BDNF protein and total IgE levels in plasma. Using a large-scale expression quantitative trait locus study, we demonstrated that BDNF SNPs are significantly associated with altered BDNF concentrations in peripheral blood. Conclusion A common genetic variant of the BDNF gene is associated with increased risk of moderate-to-severe AR, and the AA genotype is associated with increased BDNF mRNA levels in peripheral blood. Together, these data indicate that functional BDNF gene variants increase the risk of moderate-to-severe AR. © 2015 American Academy of Allergy, Asthma & Immunology.


Liu H.,Shandong Academy of Sciences | Liu H.,Shandong University | Liu H.,Shandong Provincial Key Laboratory for Dermatovenereology | Liu H.,Shandong Provincial Medical Center for Dermatovenereology | And 61 more authors.
American Journal of Human Genetics | Year: 2012

Of eight leprosy susceptibility loci identified by genome-wide association studies, five have been implicated in Crohn disease, suggesting a common genetic fingerprint between leprosy and inflammatory bowel disease (IBD). Here, we conducted a multiple-stage genetic association study of 133 IBD susceptibility loci in multiple leprosy samples (totaling 4,971 leprosy cases and 5,503 controls) from a Chinese population and discovered two associations at rs2058660 on 2q12.1 (p = 4.57 × 10-19; odds ratio [OR] = 1.30) and rs6871626 on 5q33.3 (p = 3.95 × 10-18; OR = 0.75), implicating IL18RAP/IL18R1 and IL12B as susceptibility genes for leprosy. Our study reveals the important role of IL12/IL18-mediated transcriptional regulation of IFN-γ production in leprosy, and together with previous findings, it demonstrates the shared genetic susceptibility between infectious and inflammatory diseases. © 2012 The American Society of Human Genetics.


Zhang F.,Shandong Academy of Sciences | Zhang F.,Shandong University | Zhang F.,Shandong Provincial Key Laboratory for Dermatovenereology | Zhang F.,Shandong Provincial Medical Center for Dermatovenereology | And 63 more authors.
Nature Genetics | Year: 2011

We performed a genome-wide association study with 706 individuals with leprosy and 5,581 control individuals and replicated the top 24 SNPs in three independent replication samples, including a total of 3,301 individuals with leprosy and 5,299 control individuals from China. Two loci not previously associated with the disease were identified with genome-wide significance: rs2275606 (combined P = 3.94 × 10 -14, OR = 1.30) on 6q24.3 and rs3762318 (combined P = 3.27 × 10 -11, OR = 0.69) on 1p31.3. These associations implicate IL23R and RAB32 as new susceptibility genes for leprosy. Furthermore, we identified evidence of interaction between the NOD2 and RIPK2 loci, which is consistent with the biological association of the proteins encoded by these genes (NOD2-RIPK2 complex) in activating the NF-κB pathway as a part of the host defense response to infection. Our findings have expanded the biological functions of IL23R by uncovering its involvement in infectious disease susceptibility and suggest a potential involvement of autophagocytosis in leprosy pathogenesis. The IL23R association supports previous observations of the marked overlap of susceptibility genes for leprosy and Crohn's disease, implying common pathogenesis mechanisms. © 2011 Nature America, Inc. All rights reserved.


Liu H.,Shandong University | Liu H.,Shandong Academy of Sciences | Liu H.,Shandong Provincial Key Laboratory for Dermatovenereology | Irwanto A.,Agency for Science, Technology and Research Singapore | And 53 more authors.
Nature Genetics | Year: 2015

Genome-wide association studies (GWAS) have led to the discovery of several susceptibility loci for leprosy with robust evidence, providing biological insight into the role of host genetic factors in mycobacterial infection. However, the identified loci only partially explain disease heritability, and additional genetic risk factors remain to be discovered. We performed a 3-stage GWAS of leprosy in the Chinese population using 8,313 cases and 16,017 controls. Besides confirming all previously published loci, we discovered six new susceptibility loci, and further gene prioritization analysis of these loci implicated BATF3, CCDC88B and CIITA-SOCS1 as new susceptibility genes for leprosy. A systematic evaluation of pleiotropic effects demonstrated a high tendency for leprosy susceptibility loci to show association with autoimmunity and inflammatory diseases. Further analysis suggests that molecular sensing of infection might have a similar pathogenic role across these diseases, whereas immune responses have discordant roles in infectious and inflammatory diseases. © 2015 Nature America, Inc. All rights reserved.


Zhang F.,Shandong Academy of Sciences | Zhang F.,Shandong Provincial Hospital for Skin Diseases | Zhang F.,Shandong Provincial Key Laboratory for Dermatovenereology | Zhang F.,Shandong Provincial Medical Center for Dermatovenereology | And 22 more authors.
Journal of the European Academy of Dermatology and Venereology | Year: 2012

Background Although dermatitis herpetiformis (DH) is a relatively common disease in Caucasian populations, it is very rare in the Far East, including China. Objectives To investigate the clinical, histological and immunopathological characteristics of Chinese patients with DH. Methods The clinical data and serum samples of patients with DH diagnosed at Shandong Provincial Institute of Dermatology and Venereology from 2006 to 2010 were collected. Anti-endomysium antibodies (EMA) and anti-tissue transglutaminase (tTG) antibodies were tested using indirect immunofluorescence and enzyme-linked immunosorbent assay respectively. Biopsies of small intestine were performed in those patients who had given informed consent. Results The study group consisted of 22 patients with DH. The male to female ratio was 2.1: 1; the average age was 44 years. Five patients reported mild gastrointestinal symptoms. Dapsone was used to treat 14 patients, who achieved rapid relief. Direct immunofluorescence showed granular IgA deposits at the papillary tips and/or basement membrane zone in 95.5% (21/22) patients. Fibrillar IgA deposition limited to the papillary tips was also seen in one patient (4.5%). IgA antibodies against EMA and tTG were found in 50% (8/16) and 62.5% (10/16) of patient sera respectively. Small-intestinal biopsies of two patients confirmed the presence of coeliac disease. Conclusions The clinical, histological and immunopathological characteristics of Chinese patients with DH are similar to those seen in Caucasian populations. The positive rates of anti-EMA and anti-tTG antibodies were lower compared with those seen in Western countries. DH is not extremely rare in China and should be actively investigated. © 2011 European Academy of Dermatology and Venereology.


Yang B.,Shandong Academy of Sciences | Yang B.,Shandong Provincial Key Laboratory for Dermatovenereology | Wang C.,Shandong Academy of Sciences | Wang C.,Shandong Provincial Key Laboratory for Dermatovenereology | And 12 more authors.
Australasian Journal of Dermatology | Year: 2014

A 22-year-old primigravida had a pruritic, erythematous, bullous eruption on the skin during the 26th week of gestation. After delivery the eruption flared up. The diagnosis of pemphigoid gestationis was confirmed based on histopathological and immunofluorescence findings. The result of immunoblotting showed IgG autoantibodies which reacted against BP230 in epidermal extracts and 290 kDa type VII collagen in dermal extracts. The BP180 antibodies were also detected by an enzyme-linked immunosorbent assay BP180NC16a diagnosis kit. Pulsed corticosteroid and cyclophosphamide resulted in a favourable response at the acute stage. The patient was cured in 2 years. The analysis of the patient's autoantibodies provides strong evidence for the involvement of epitope spreading in her autoimmune disease. © 2012 The Australasian College of Dermatologists.


Yang B.,Shandong Academy of Sciences | Yang B.,Shandong Provincial Key Laboratory for Dermatovenereology | Wang C.,Shandong Academy of Sciences | Wang C.,Shandong Provincial Key Laboratory for Dermatovenereology | And 14 more authors.
Pediatric Dermatology | Year: 2012

Epidermolysis bullosa acquisita (EBA) is a rare, acquired, subepidermal blistering disease characterized by autoantibodies directed against type VII collagen, the major component of anchoring fibrils. We report a 5-year-old Chinese boy who presented with extensive lesions consisting of disseminated pruritic vesicles and tense blisters. The diagnosis of EBA was confirmed by histopathology, immunofluorescence, and immunoblotting analysis. The disease was controlled with a combination of prednisone and dapsone. © 2012 Wiley Periodicals, Inc.


Sun Y.,Shandong Academy of Sciences | Sun Y.,Shandong Provincial Key Laboratory for Dermatovenereology | Liu H.,Shandong Academy of Sciences | Liu H.,Shandong Provincial Key Laboratory for Dermatovenereology | And 12 more authors.
Experimental Dermatology | Year: 2011

Leprosy is caused by Mycobacterium leprae, and the global registered prevalence of leprosy at the beginning of 2009 stood at 213036 cases. It has long been thought that leprosy has a strong genetic risk. Recently, we have identified significant associations (P<1.00×10-10) between SNPs in the genes CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR and RIPK2 and a trend towards an association (P=5.10×10-5) with a SNP in LRRK2. Here, we investigated the expression of these seven genes in formalin-fixed, paraffin-embedded skin tissues of leprosy and matched normal tissues using branched DNA technology. This technology allows for direct measurement of targeted mRNA within cellular lysate using a 96-well plate format in a time frame compared to a reporter gene assay. The clear upregulation of all seven genes was found in leprosy tissues compared to normal tissues, which further supports our genome-wide association study results. © 2011 John Wiley & Sons A/S.


Liu H.,Shandong Provincial Institute of Dermatology and Venereology | Liu H.,Shandong Provincial Key Laboratory for Dermatovenereology | Fu X.-A.,Shandong Provincial Institute of Dermatology and Venereology | Fu X.-A.,Shandong Provincial Key Laboratory for Dermatovenereology | And 14 more authors.
Clinical and Experimental Dermatology | Year: 2011

Dyschromatosis symmetrica hereditaria (DSH) is a rare, autosomal dominant dermatosis, characterized by a mixture of hyperpigmented and hypopigmented macules on the dorsa of the hands and feet. The DSH locus has been mapped to chromosome 1q21, and in 2003, pathogenic mutations were identified in the ADAR1 (adenosine deaminase acting on RNA1) gene. In this study, we performed mutation detection of the ADAR1 gene in two Chinese families with DSH. PCR and direct sequencing of the ADAR1 gene were used to identify and confirm the mutations in the two families. Furthermore, we analysed the RNA transcripts by reverse transcriptase (RT)-PCR. Two aberrant splice products were confirmed with RT-PCR and DNA direct sequence analysis. These novel findings further extend our understanding of the role of ADAR1 in DSH. © 2011 British Association of Dermatologists.


Li X.,Shandong Academy of Sciences | Li X.,Shandong Provincial Key Laboratory for Dermatovenereology | Li X.,University of Jinan | Chen M.,Shandong Academy of Sciences | And 25 more authors.
Journal of Dermatological Science | Year: 2014

Background: Generalized pustular psoriasis (GPP) is a rare type of psoriasis with potentially life-threatening implications. Mutations in IL36RN gene have been suggested to be causative or predisposing factors for GPP. Objective: To evaluate the genetic heterogeneity of GPP, PV and GPP alone, GPP with PV. Methods: We performed a sanger sequencing identify IL36RN mutations in 62 Chinese Han patients with sporadic GPP, including 17 GPP without psoriasis vulgaris (PV) (GPP alone) cases vs. 45 GPP with preceding, later or accompanied by PV (GPP with PV) cases; 16 patients with pediatric-onset GPP (PGPP) vs. 46 adult-onset GPP (AGPP). We included 96 healthy controls and 174 sporadic patients with PV. Resuts: We found 2 new variants and 4 known IL36RN variants in 29 GPP patients, 18 individuals carried recessive (homozygous/compound heterozygous) alleles and 11 cases harbored a single heterozygous change. Twelve PV patients and six controls harbored a single heterozygous for three out of the six variants.Significant differences were observed between GPP and PV groups, GPP alone and GPP with PV groups when compared frequencies of IL36RN variants, but we did not found association between PGPP and AGPP groups. Conclusion: Our study provided more evidence that GPP and PV are distinct subtypes of psoriasis caused by different pathogenesis, and GPP alone could be regarded as an especial entities of GPP which is different from GPP with PV on the etiology. © 2014 Japanese Society for Investigative Dermatology.

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