Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 90
Filtrar
1.
Front Immunol ; 10: 2189, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31572394

RESUMO

Talaromyces (Penicillium) marneffei is an AIDS-defining infection in Southeast Asia and is associated with high mortality. It is rare in non-immunosuppressed individuals, especially children. Little is known about host immune response and genetic susceptibility to this endemic fungus. Genetic defects in the interferon-gamma (IFN-γ)/STAT1 signaling pathway, CD40/CD40 ligand- and IL12/IL12-receptor-mediated crosstalk between phagocytes and T-cells, and STAT3-mediated Th17 differentiation have been reported in HIV-negative children with talaromycosis and other endemic mycoses such as histoplasmosis, coccidioidomycosis, and paracoccidioidomycosis. There is a need to design a diagnostic algorithm to evaluate such patients. In this article, we review a cohort of pediatric patients with disseminated talaromycosis referred to the Asian Primary Immunodeficiency Network for genetic diagnosis of PID. Using these illustrative cases, we propose a diagnostics pipeline that begins with immunoglobulin pattern (IgG, IgA, IgM, and IgE) and enumeration of lymphocyte subpopulations (T-, B-, and NK-cells). The former could provide clues for hyper-IgM syndrome and hyper-IgE syndrome. Flow cytometric evaluation of CD40L expression should be performed for patients suspected to have X-linked hyper-IgM syndrome. Defects in interferon-mediated JAK-STAT signaling are evaluated by STAT1 phosphorylation studies by flow cytometry. STAT1 hyperphosphorylation in response to IFN-α or IFN-γ and delayed dephosphorylation is diagnostic for gain-of-function STAT1 disorder, while absent STAT1 phosphorylation in response to IFN-γ but normal response to IFN-α is suggestive of IFN-γ receptor deficiency. This simple and rapid diagnostic algorithm will be useful in guiding genetic studies for patients with disseminated talaromycosis requiring immunological investigations.

2.
Eur J Pharm Sci ; : 105093, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31648049

RESUMO

Reaction phenotyping is a method commonly used for characterizing drug metabolism. It determines the drug metabolic pathways and ratios by measuring the metabolized fractions of individual enzymes. However, currently published results have focused on cytochrome P450 (CYP), while not considering phase II metabolism. Therefore, the morphinan analgesic, nalbuphine, primarily metabolized in the liver via CYPs and UDP-glucuronosyltransferases (UGTs), was selected as a model drug to establish a dual-phase platform to elucidate its comprehensive metabolic pathway. Enzyme kinetics was studied using 8 common recombinant (r)CYPs,10 rUGTs, and pooled human liver microsomes. The overall fraction of nalbuphine metabolized by each isozyme was evaluated by determining parent drug depletion. Finally, in vitro-in vivo correlation was validated in animal studies. Fluconazole, a specific UGT2B7 inhibitor, was administered orally to rats to determine the pharmacokinetic effects on nalbuphine and nalbuphine metabolites. Seventy-five percent and 25% of nalbuphine was metabolized by UGTs and CYPs, respectively. UGT2B7, UGT1A3, and UGT1A9 were primarily responsible for nalbuphine glucuronidation; only UGT2B7 produced nalbuphine-6-glucuronide. CYP2C9 and CYP2C19 were the two CYP isozymes that produced 3'-hydroxylnalbuphine and 4'-hydroxylnalbuphine. In vivo, the maximum serum concentration (Cmax) and area under the curve (AUC) of nalbuphine increased 12.4-fold and 13.2-fold, respectively, with fluconazole co-administration. A dual system platform for drug metabolism was successfully established in this study and was used to generate a complete metabolic scheme for nalbuphine. This platform has been verified by in vivo evaluations and can be utilized to study drugs that undergo multisystem metabolism.

3.
Sci Rep ; 9(1): 7879, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-31133697

RESUMO

Blood pressure (BP), especially systolic BP (SBP), is higher in adult growth hormone deficiency (AGHD) patients than in normal controls. Additionally, obesity is a known risk factor for hypertension, and growth hormone deficiency (GHD) is an important cause of short stature. For children with GHD, attention has been directed solely towards height. Few studies have assessed its potential impact on BP. Here, we investigated the effect of body mass index standard deviation score (BMISDS) on BP in children with short stature. This study included 736 children with short stature divided into two groups based on peak growth hormone (GH) level in GH provocation tests [severe GHD (SGHD) group = 212 children; non-SGHD group = 524 children]. We found that SBP was significantly higher in the SGHD group than in the non-SGHD group (p = 0.045). Additionally, there was a significant positive association between BMISDS and SBP in the SGHD group (ß = 3.12, 95% CI: 1.40-4.84, p < 0.001), but no association between these variables was observed in the non-SGHD group. Thus, SGHD patients had a higher SBP than non-SGHD patients. BMISDS is a significant factor for higher SBP in SGHD patients but not in non-SGHD patients.

4.
Am J Med Genet C Semin Med Genet ; 181(2): 262-268, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30897304

RESUMO

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with extreme clinical heterogeneity and significant differences between populations. East Asian populations are known to have higher prevalence and more severe clinical manifestations for SLE than Europeans. The difference could be the result of genetic and environmental factors, and the interactions between them. Thus, identifying genetic associations from diverse populations provides an opportunity to better understand the genetic architecture of this heterogeneous disease. It is also necessary to elucidate population differences and to apply the findings in future stratified treatment of the disease, with ethnicity likely a major factor to consider. Indeed, it has shown that there are significant differences between East Asians and European populations in several genetic loci for SLE. Genetic studies on SLE are very active in East Asian countries and there have been close collaborations among scientists in this region. Here, we document some work done in this region on SLE genetic research and discuss the aspect of population differences.

5.
Epigenetics ; 14(4): 341-351, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30806140

RESUMO

Patients with paediatric-onset systemic lupus erythematosus (SLE) often present with more severe clinical courses than adult-onset patients. Although genome-wide DNA methylation (DNAm) profiling has been performed in adult-onset SLE patients, parallel data on paediatric-onset SLE are not available. Therefore, we undertook a genome-wide DNAm study in paediatric-onset SLE patients across multiple blood cell lineages. The DNAm profiles of four purified immune cell lineages (CD4 + T cells, CD8 + T cells, B cells and neutrophils) and whole blood were compared in 16 Chinese patients with paediatric-onset SLE and 13 healthy controls using the Illumina HumanMethylationEPIC BeadChip. Comparison of DNAm in whole blood and within each independent cell lineage identified a consistent pattern of loss of DNAm at 21 CpG sites overlapping 15 genes, which represented a robust, disease-specific DNAm signature for paediatric-onset SLE in our cohort. In addition, cell lineage-specific changes, involving both loss and gain of DNAm, were observed in both novel genes and genes with well-described roles in SLE pathogenesis. This study also highlights the importance of studying DNAm changes in different immune cell lineages rather than only whole blood, since cell type-specific DNAm changes facilitated the elucidation of the cell type-specific molecular pathophysiology of SLE.

6.
Pharm Res ; 36(2): 32, 2019 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-30604282

RESUMO

PURPOSE: Various blood collection methods were developed and used in the pharmacokinetic evaluation of drugs. However, the influence of different blood sampling methods on plasma drug concentrations has not been clarified. In the present study, we aimed to determine whether the plasma concentration of a target drug changes based on the collection site and elucidate the mechanism responsible for this change. METHODS: We compared three blood sampling methods commonly used in small animals. Eight clinical drugs were selected and administered to rats simultaneously via intracardiac injection or oral gavage. Blood samples were collected from different sites at the same individual, and pharmacokinetic properties of the drugs were then evaluated. RESULTS: Study results showed that the maximum plasma concentration or area under the curve of three study drugs was significantly higher in rats when blood was sampled from the carotid artery than when it was sampled from the caudal vein or by tail snip. CONCLUSIONS: Pharmacokinetics of certain drugs may differ based on the blood sampling site. The acid-base properties of drugs may influence pharmacokinetic evaluation. The rate and extent of drug distribution may also cause such differences and have significant effects on plasma drug levels.


Assuntos
Coleta de Amostras Sanguíneas/métodos , Preparações Farmacêuticas/sangue , Animais , Área Sob a Curva , Cromatografia Líquida/métodos , Limite de Detecção , Modelos Lineares , Masculino , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem/métodos
7.
Int J Cancer ; 144(12): 3031-3042, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-30536939

RESUMO

Whether certain variants of Epstein-Barr virus (EBV) are linked to the pathogenesis of nasopharyngeal carcinoma (NPC), which shows a marked geographic restriction, remains an unresolved issue. We performed a case-control study comparing genomic sequences of EBV isolated from saliva samples of 142 population carriers with those from primary tumour biopsies derived from 62 patients with NPC of Hong Kong. Cluster analysis discovered five EBV subgroups 1A-C and 2A-B amongst the population carriers in contrast to the predominance of 1A and -B in the majority of NPC. Genome-wide association study (GWAS) identified a panel of NPC-associated single nucleotide polymorphisms (SNPs) and indels in the EBER locus. The most significant polymorphism, which can be found in 96.8% NPC cases and 40.1% population carriers of Hong Kong, is a four-base-deletion polymorphism downstream of EBER2 (EBER-del) from coordinates 7188-7191 (p = 1.91 × 10-7 ). In addition, the predicted secondary structure of EBER2 is altered with likely functional consequence in nearly all NPC cases. Using the SNPs and indels associated with NPC, genetic risk score is assigned for each EBV variant. EBV variants with high genetic risk score are found to be much more prevalent in Hong Kong Chinese than individuals of other geographic regions and in NPC than other EBV-associated cancers. We conclude that high risk EBV variants with polymorphisms in the EBER locus, designated as HKNPC-EBERvar, are strongly associated with NPC. Further investigation of the biological function and potential clinical application of these newly identified polymorphisms in NPC and other EBV-associated cancers is warranted.


Assuntos
Herpesvirus Humano 4/genética , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/virologia , RNA Viral/genética , Portador Sadio/virologia , Estudos de Casos e Controles , DNA Viral/genética , Infecções por Vírus Epstein-Barr/virologia , Loci Gênicos , Genoma Viral , Estudo de Associação Genômica Ampla , Haplótipos , Herpesvirus Humano 4/classificação , Herpesvirus Humano 4/isolamento & purificação , Hong Kong , Humanos , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Saliva/virologia
8.
BMC Med Genomics ; 11(1): 93, 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30359267

RESUMO

BACKGROUND: Whole-exome sequencing (WES) has become an invaluable tool for genetic diagnosis in paediatrics. However, it has not been widely adopted in the prenatal setting. This study evaluated the use of WES in prenatal genetic diagnosis in fetuses with structural congenital anomalies (SCAs) detected on prenatal ultrasound. METHOD: Thirty-three families with fetal SCAs on prenatal ultrasonography and normal chromosomal microarray results were recruited. Genomic DNA was extracted from various fetal samples including amniotic fluid, chorionic villi, and placental tissue. Parental DNA was extracted from peripheral blood when available. We used WES to sequence the coding regions of parental-fetal trios and to identify the causal variants based on the ultrasonographic features of the fetus. RESULTS: Pathogenic mutations were identified in three families (n = 3/33, 9.1%), including mutations in DNAH11, RAF1 and CHD7, which were associated with primary ciliary dyskinesia, Noonan syndrome, and CHARGE syndrome, respectively. In addition, variants of unknown significance (VUSs) were detected in six families (18.2%), in which genetic changes only partly explained prenatal features. CONCLUSION: WES identified pathogenic mutations in 9.1% of fetuses with SCAs and normal chromosomal microarray results. Databases for fetal genotype-phenotype correlations and standardized guidelines for variant interpretation in prenatal diagnosis need to be established to facilitate the use of WES for routine testing in prenatal diagnosis.

9.
Gastroenterology ; 155(6): 1908-1922.e5, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30217742

RESUMO

BACKGROUND & AIMS: Hirschsprung disease, or congenital aganglionosis, is believed to be oligogenic-that is, caused by multiple genetic factors. We performed whole-genome sequence analyses of patients with Hirschsprung disease to identify genetic factors that contribute to disease development and analyzed the functional effects of these variants. METHODS: We performed whole-genome sequence analyses of 443 patients with short-segment disease, recruited from hospitals in China and Vietnam, and 493 ethnically matched individuals without Hirschsprung disease (controls). We performed genome-wide association analyses and gene-based rare-variant burden tests to identify rare and common disease-associated variants and study their interactions. We obtained induced pluripotent stem cell (iPSC) lines from 4 patients with Hirschsprung disease and 2 control individuals, and we used these to generate enteric neural crest cells for transcriptomic analyses. We assessed the neuronal lineage differentiation capability of iPSC-derived enteric neural crest cells using an in vitro differentiation assay. RESULTS: We identified 4 susceptibility loci, including 1 in the phospholipase D1 gene (PLD1) (P = 7.4 × 10-7). The patients had a significant excess of rare protein-altering variants in genes previously associated with Hirschsprung disease and in the ß-secretase 2 gene (BACE2) (P = 2.9 × 10-6). The epistatic effects of common and rare variants across these loci provided a sensitized background that increased risk for the disease. In studies of the iPSCs, we observed common and distinct pathways associated with variants in RET that affect risk. In functional assays, we found variants in BACE2 to protect enteric neurons from apoptosis. We propose that alterations in BACE1 signaling via amyloid ß precursor protein and BACE2 contribute to pathogenesis of Hirschsprung disease. CONCLUSIONS: In whole-genome sequence analyses of patients with Hirschsprung disease, we identified rare and common variants associated with disease risk. Using iPSC cells, we discovered some functional effects of these variants.

10.
Bioinformatics ; 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-30169743

RESUMO

Availability: http://wyanglab.org:3838/RefPanelWebsite/. Supplementary information: Supplementary data are available at Bioinformatics online.

11.
NPJ Genom Med ; 3: 19, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30109123

RESUMO

Currently, offering whole-exome sequencing (WES) via collaboration with an external laboratory is increasingly common. However, the receipt of a WES report can be merely the beginning of a continuing exploration process rather than the end of the diagnostic odyssey. The laboratory often does not have the information the physician has, and any discrepancies in variant interpretation must be addressed by a medical geneticist. In this study, we performed diagnostic WES of 104 patients with paediatric-onset genetic diseases. The post-exome review of WES reports by the clinical geneticist led to a more comprehensive assessment of variant pathogenicity in 16 cases. The overall diagnostic yield was 41% (n = 43). Among these 43 diagnoses, 51% (22/43) of the pathogenic variants were nucleotide changes that have not been previously reported. The time required for the post-exome review of the WES reports varied, and 26% (n = 27) of the reports required an extensive amount of time (>3 h) for the geneticist to review. In this predominantly Chinese cohort, we highlight the importance of discrepancies between global and ethnic-specific frequencies of a genetic variant that complicate variant interpretation and the significance of post-exome diagnostic modalities in genetic diagnosis using WES. The challenges faced by geneticists in interpreting WES reports are also discussed.

12.
EMBO Rep ; 19(10)2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30104205

RESUMO

Mouse p202 is a disease locus for lupus and a dominant-negative inhibitor of AIM2 inflammasome activation. A human homolog of p202 has not been identified so far. Here, we report a novel transcript isoform of human IFI16-designated IFI16-ß, which has a domain architecture similar to that of mouse p202. Like p202, IFI16-ß contains two HIN domains, but lacks the pyrin domain. IFI16-ß is ubiquitously expressed in various human tissues and cells. Its mRNA levels are also elevated in leukocytes of patients with lupus, virus-infected cells, and cells treated with interferon-ß or phorbol ester. IFI16-ß co-localizes with AIM2 in the cytoplasm, whereas IFI16-α is predominantly found in the nucleus. IFI16-ß interacts with AIM2 to impede the formation of a functional AIM2-ASC complex. In addition, IFI16-ß sequesters cytoplasmic dsDNA and renders it unavailable for AIM2 sensing. Enforced expression of IFI16-ß inhibits the activation of AIM2 inflammasome, whereas knockdown of IFI16-ß augments interleukin-1ß secretion triggered by dsDNA but not dsRNA Thus, cytoplasm-localized IFI16-ß is functionally equivalent to mouse p202 that exerts an inhibitory effect on AIM2 inflammasome.

13.
Mol Cancer ; 17(1): 98, 2018 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-30001707

RESUMO

BACKGROUND: Defective autophagy is thought to contribute to the pathogenesis of many diseases, including cancer. Human plasmacytoma variant translocation 1 (PVT1) is an oncogenic long non-coding RNA that has been identified as a prognostic biomarker in pancreatic ductal adenocarcinoma, but how PVT1 operates in the regulation of autophagy in pancreatic ductal adenocarcinoma (PDA) is unclear. METHODS: PVT1 expression level was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and hybridization in situ (ISH). Western blot or qRT-PCR was performed to assess the ULK1 protein or mRNA level. Autophagy was explored via autophagic flux detection under a confocal microscope and autophagic vacuoles investigation under a transmission electron microscopy (TEM). The biological role of PVT1 in autophagy and PDA development was determined by gain-of-function and loss-of-function assays. RESULTS: We found that PVT1 levels paralleled those of ULK1 protein in PDA cancer tissues. PVT1 promoted cyto-protective autophagy and cell growth by targeting ULK1 both in vitro and in vivo. Moreover, high PVT1 expression was associated with poor prognosis. Furthermore, we found that PVT1 acted as sponge to regulate miR-20a-5p and thus affected ULK1 expression and the development of pancreatic ductal adenocarcinoma. CONCLUSIONS: The present study demonstrates that the "PVT1/miR-20a-5p/ULK1/autophagy" pathway modulates the development of pancreatic ductal adenocarcinoma and may be a novel target for developing therapeutic strategies for pancreatic ductal adenocarcinoma.

14.
Methods Mol Biol ; 1833: 107-114, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30039367

RESUMO

Rapid development of next generation sequencing (NGS) technology has substantially improved our ability to detect genomic variations. However, unlike other variations, such as point mutations, insertions, and deletions, which can be identified in high sensitivities and specificities based on NGS reads, most of inversions, especially those shorter than 1 kb, remain difficult to detect. Here we introduce a new framework, SRinversion, which was developed specifically for detection of inversions shorter than 1 kb by splitting and realigning poorly mapped or unmapped reads of the NGS data.

15.
Arthritis Res Ther ; 20(1): 92, 2018 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-29724251

RESUMO

BACKGROUND: Systemic lupus erythematous (SLE) is a complex autoimmune disease with female predominance, particularly affecting those of childbearing age. We performed analysis of three genome-wide genotyping datasets of populations of both Chinese and European origin. METHODS: This study involved 5695 cases and 10,357 controls in the discovery stage. The lead signal on chromosome X was followed by replication in three additional Asian cohorts, with 2300 cases and 4244 controls in total. Conditional analysis of the known associated loci on chromosome X was also performed to further explore independent signals. RESULTS: Single-nucleotide polymorphism rs13440883 in GPR173 was found to be significantly associated with SLE (Pmeta = 7.53 × 10- 9, ORmeta= 1.16), whereas conditional analysis provided evidence of a potential independent signal in the L1CAM-IRAK1-MECP2 region in Asian populations (rs5987175 [LCA10]). CONCLUSIONS: We identified a novel SLE susceptibility locus on the X chromosome. This finding emphasizes the importance of the X chromosome in disease pathogenesis and highlights the role of sex chromosomes in the female bias of SLE.

16.
Artigo em Inglês | MEDLINE | ID: mdl-29676044

RESUMO

BACKGROUND: Several susceptibility loci have been identified associated with Chinese Han systemic lupus erythematosus (SLE). METHODS: We carried out imputation of classical HLA alleles, amino acids and Single Nucleotide Polymorphisms (SNPs) across the MHC region in Chinese Han SLE genome-wide association study (GWAS) of mainland and Hong Kong populations for the first time using newly constructed Han-MHC reference panel followed by stepwise conditional analysis. RESULTS: We mapped the most significant independent association to HLA-DQß1 at amino acid position (Phe87, p = 7.807 × 10-17 ) and an independent association at HLA-DQB1*0301 (Pcondiational  = 1.43 × 10-7 ). CONCLUSION: Our study illustrates the value of population-specific HLA reference panel for fine-mapping causal variants in the MHC.

17.
Neurobiol Aging ; 68: 160.e1-160.e7, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29656768

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disorders in the elderly. To identify rare genetic factors other than apolipoprotein E ɛ4 allele (ApoE ɛ4) contributing to the pathogenesis of late-onset AD (LOAD), we conducted a whole-exome analysis of 246 ApoE ɛ4-negative LOAD cases and 172 matched controls in Hong Kong Chinese population. LOAD patients showed a significantly higher burden of rare loss-of-function variants in genes related to immune function than healthy controls. Among the genes involved in immune function, we identified a rare stop-gain variant (p.Q48X) in mixed lineage kinase domain like pseudokinase (MLKL) gene present exclusively in 6 LOAD cases. MLKL is expressed in neurons, and the its expression levels in the p.Q48X carriers were significantly lower than that in age-matched wild-type controls. The ratio of Aß42 to Aß40 significantly increased in MLKL knockdown cells compared to scramble controls. MLKL loss-of-function mutation might contribute to late-onset ApoE ɛ4-negative AD in the Hong Kong Chinese population.


Assuntos
Doença de Alzheimer/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Mutação com Perda de Função , Proteínas Quinases/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Apolipoproteínas E/genética , Grupo com Ancestrais do Continente Asiático/genética , Células Cultivadas , Feminino , Células HEK293 , Células HeLa , Hong Kong , Humanos , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade
18.
Hum Immunol ; 79(7): 539-544, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29660452

RESUMO

In Cord blood transplantation (CBT), the non-inherited maternal antigen (NIMA) virtual six HLA matched CB is found to have similar outcomes to six HLA inherited matched CB. Such virtual HLA matched CB units can be generated by substituting the inherited alleles with one to three NIMAs. In Hong Kong Cord Blood Bank, CB units have no NIMA defined. 100 CB samples were collected with NIMA defined. Retrospective searches of Hong Kong patients (n = 520) were matched against the inherited and virtual HLA phenotypes of NIMA CB file. One to three NIMA matches was analyzed, virtual six HLA matches were identified for 31.7% patients, 29.4% from CB units with 5/6 HLA match with 1 NIMA match and 1.7% CB units with a 4/6 HLA match and 2 NIMA matches. However, searches in the 167,201 Bone Marrow Donors Worldwide CB units with defined NIMA did not yield similar increases, possibly due to the ethnicity differences between populations. The match performance rises from 26% to 60% after including the NIMA match. Comparing the match performance of 32% in a previous Dutch study, we calculated with 60% matching in this smaller size study. This provides a solid ground to considering NIMA in stem cell donor selection which was adopted in some centers, to be extended to Asian and local CB registries to increase the chance for matches and also to improve patient outcomes, increase the utilization of CB units, enhance clinical flexibility and signify economic intelligence.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Rejeição de Enxerto/imunologia , Antígenos HLA/genética , Adulto , Simulação por Computador , Grupos Étnicos , Feminino , Genótipo , Histocompatibilidade , Teste de Histocompatibilidade , Hong Kong , Humanos , Tolerância Imunológica , Isoantígenos/imunologia , Masculino , Mães , Estudos Retrospectivos , Resultado do Tratamento
19.
Ann Rheum Dis ; 77(7): 1078-1084, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29625966

RESUMO

OBJECTIVES: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component in its pathogenesis. Through genome-wide association studies (GWAS), we recently identified 10 novel loci associated with SLE and uncovered a number of suggestive loci requiring further validation. This study aimed to validate those loci in independent cohorts and evaluate the role of SLE genetics in drug repositioning. METHODS: We conducted GWAS and replication studies involving 12 280 SLE cases and 18 828 controls, and performed fine-mapping analyses to identify likely causal variants within the newly identified loci. We further scanned drug target databases to evaluate the role of SLE genetics in drug repositioning. RESULTS: We identified three novel loci that surpassed genome-wide significance, including ST3AGL4 (rs13238909, pmeta=4.40E-08), MFHAS1 (rs2428, pmeta=1.17E-08) and CSNK2A2 (rs2731783, pmeta=1.08E-09). We also confirmed the association of CD226 locus with SLE (rs763361, pmeta=2.45E-08). Fine-mapping and functional analyses indicated that the putative causal variants in CSNK2A2 locus reside in an enhancer and are associated with expression of CSNK2A2 in B-lymphocytes, suggesting a potential mechanism of association. In addition, we demonstrated that SLE risk genes were more likely to be interacting proteins with targets of approved SLE drugs (OR=2.41, p=1.50E-03) which supports the role of genetic studies to repurpose drugs approved for other diseases for the treatment of SLE. CONCLUSION: This study identified three novel loci associated with SLE and demonstrated the role of SLE GWAS findings in drug repositioning.

20.
Nucleic Acids Res ; 46(8): 4054-4071, 2018 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-29547894

RESUMO

STING is a core adaptor in innate nucleic acid sensing in mammalian cells, on which different sensing pathways converge to induce type I interferon (IFN) production. Particularly, STING is activated by 2'3'-cGAMP, a cyclic dinucleotide containing mixed phosphodiester linkages and produced by cytoplasmic DNA sensor cGAS. Here, we reported on a novel transcript isoform of STING designated STING-ß that dominantly inhibits innate nucleic acid sensing. STING-ß without transmembrane domains was widely expressed at low levels in various human tissues and viral induction of STING-ß correlated inversely with IFN-ß production. The expression of STING-ß declined in patients with lupus, in which type I IFNs are commonly overproduced. STING-ß suppressed the induction of IFNs, IFN-stimulated genes and other cytokines by various immunostimulatory agents including cyclic dinucleotides, DNA, RNA and viruses, whereas depletion of STING-ß showed the opposite effect. STING-ß interacted with STING-α and antagonized its antiviral function. STING-ß also interacted with TBK1 and prevented it from binding with STING-α, TRIF or other transducers. In addition, STING-ß bound to 2'3'-cGAMP and impeded its binding with and activation of STING-α, leading to suppression of IFN-ß production. Taken together, STING-ß sequesters 2'3'-cGAMP second messenger and other transducer molecules to inhibit innate nucleic acid sensing dominantly.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA