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2.
Transl Psychiatry ; 11(1): 343, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083506

RESUMO

BACKGROUND: Clozapine is considered to be the most effective antipsychotic medication for schizophrenia. However, it is associated with several adverse effects such as leukopenia, and the underlying mechanism has not yet been fully elucidated. The authors performed a genome-wide association study (GWAS) in a Chinese population to identify genetic markers for clozapine-induced leukopenia (CIL) and clozapine-induced neutropenia (CIN). METHODS: A total of 1879 patients (225 CIL cases, including 43 CIN cases, and 1,654 controls) of Chinese descent were included. Data from common and rare single nucleotide polymorphisms (SNPs) were tested for association. The authors also performed a trans-ancestry meta-analysis with GWAS results of European individuals from the Clozapine-Induced Agranulocytosis Consortium (CIAC). RESULTS: The authors identified several novel loci reaching the threshold of genome-wide significance level (P < 5 × 10-8). Three novel loci were associated with CIL while six were associated with CIN, and two T cell related genes (TRAC and TRAT1) were implicated. The authors also observed that one locus with evidence close to genome-wide significance (P = 5.08 × 10-8) was near the HLA-B gene in the major histocompatibility complex region in the trans-ancestry meta-analysis. CONCLUSIONS: The associations provide novel and valuable understanding of the genetic and immune causes of CIL and CIN, which is useful for improving clinical management of clozapine related treatment for schizophrenia. Causal variants and related underlying molecular mechanisms need to be understood in future developments.


Assuntos
Antipsicóticos , Clozapina , Neutropenia , Esquizofrenia , Antipsicóticos/efeitos adversos , Clozapina/efeitos adversos , Estudo de Associação Genômica Ampla , Humanos , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Neutropenia/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética
3.
Hereditas ; 158(1): 10, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33597004

RESUMO

BACKGROUND: Next-generation sequencing technology is developing rapidly and target capture sequencing has become an important technique. Several different platforms for library preparation and target capture with different bait types respectively are commercially available. Here we compare the performance of the four platforms with different bait types to find out their advantages and limitations. The purpose of this study is to help investigators and clinicians select the appropriate platform for their particular application and lay the foundation for the development of a better target capture platform for next-generation sequencing. RESULTS: We formulate capture efficiency as a novel parameter that can be used to better evaluations of specificity and coverage depth among the different capture platforms. Target coverage, capture efficiency, GC bias, AT Dropout, sensitivity in single nucleotide polymorphisms, small insertions and deletions detection, and the feature of each platform were compared for low input samples. In general, all platforms perform well and small differences among them are revealed. In our results, RNA baits have stronger binding power than DNA baits, and with ultra deep sequencing, double stranded RNA baits perform better than single stranded RNA baits in all aspects. DNA baits got better performance in the region with high GC content and RNA baits got lower AT dropout suggesting that the binding power is different between DNA and RNA baits to genome regions with different characteristics. CONCLUSIONS: The platforms with double stranded RNA baits have the most balanced capture performance. Our results show the key differences in performance among the four updated platforms with four different bait types. The better performance of double stranded RNA bait with ultra deep sequencing suggests that it may improve the sensitivity of ultra low frequent mutation detection. In addition, we further propose that the mixed baits of double stranded RNA and single stranded DNA may improve target capture performance.


Assuntos
DNA/genética , Exoma , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento Completo do Exoma/métodos , Composição de Bases , Humanos , Mutação INDEL , Polimorfismo de Nucleotídeo Único
4.
World J Biol Psychiatry ; 22(7): 526-534, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33143498

RESUMO

OBJECTIVES: Environmental and genetic factors play important roles in the development of schizophrenia (SCZ), bipolar disorder (BPD) or major depressive disorder (MDD). Some risk loci are identified with shared genetic effects on major psychiatric disorders. To investigate whether SNX29 gene played a significant role in these psychiatric disorders in the Han Chinese population. METHODS: We focussed on 11 single-nucleotide polymorphisms (SNPs) harbouring SNX29 gene and carried out case-control studies in patients with SCZ (n = 1248), BPD (n = 1344), or MDD (n = 1056), and 1248 healthy controls (HC) recruited from the Han Chinese population. We constructed weighted gene co-expression network analysis (WGCNA) and extracted significant modules by R package. RESULTS: We found that rs3743592 was significantly associated with MDD and rs6498263 with BPD in both allele and genotype distributions. Before correction, rs3743592 showed allelic and genotypic significance with SCZ, rs6498263 showed allelic significance with SCZ. WGCNA identified top 10 modules of co-expressed genes. Gene Ontology (GO) and pathway analysis were used to examine the functions of SNX29, which revealed that SNX29 was involved in the regulation of a number of biological processes, such as TGF-beta, ErbB, and Wnt signalling pathway, etc. CONCLUSIONS: Our results supported common risk factors in SNX29 might share among these three mental disorders in the Han Chinese population.


Assuntos
Transtorno Bipolar , Transtorno Depressivo Maior , Transtornos Mentais , Nexinas de Classificação/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Transtorno Depressivo Maior/genética , Predisposição Genética para Doença/genética , Humanos , Polimorfismo de Nucleotídeo Único
5.
J Autoimmun ; 116: 102562, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33168359

RESUMO

Adult-onset Still's disease (AOSD) is a rare autoinflammatory disease with systemic involvement, and its pathophysiology remains unclear. Genome-wide association studies (GWAS) in the Chinese population have revealed an association between AOSD and the major histocompatibility complex (MHC) locus; however, causal variants in the MHC remain undetermined. In the present study, we identified independent amino-acid polymorphisms in human leukocyte antigen (HLA) molecules that are associated with Han Chinese patients with AOSD by fine-mapping the MHC locus. Through conditional analyses, we identified position 34 in HLA-DQα1 (p = 1.44 × 10-14) and Asn in HLA-DRß1 position 37 (p = 5.12 × 10-11) as the major determinants for AOSD. Moreover, we identified the associations for three main HLA class II alleles: HLA-DQB1*06:02 (OR = 2.70, p = 3.02 × 10-14), HLA-DRB1*15:01 (OR = 2.44, p = 3.66 × 10-13), and HLA-DQA1*01:02 (OR = 1.97, p = 1.09 × 10-9). This study reveals the relationship between functional variations in the class II HLA region and AOSD, implicating the MHC locus in the pathogenesis of AOSD.

6.
World J Biol Psychiatry ; 22(1): 27-33, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32129128

RESUMO

OBJECTIVES: Chromosome 8p12 was first identified as a schizophrenia (SCZ) risk locus in Chinese populations and replicated in European populations. However, the underlying functional variants still need to be further explored. In this study, we sought to identify plausible causal variants within this locus. METHODS: A total of 386 potentially functional variants from 29 genes within the 8p12 locus were analysed in 2403 SCZ cases and 2594 control subjects in the Han Chinese population using Affymetrix customised genotyping assays. SHEsisplus was used for association analysis. A multiple testing corrected p value (false discovery rate (FDR)) < .05 was considered significant, and an unadjusted p value < .05 was considered nominal evidence of an association. RESULTS: We did not find significant associations between the tested variants and SCZ. However, nominal associations were found for rs201292574 (unadjusted p = .033, FDR p = .571; 95% confidence interval (CI): 0.265-0.945; TACC1, NP_006274.2:p.Ala211Thr) and rs45563241 (unadjusted p = .039, FDR p = .571; 95% CI: 1.023-1.866; a synonymous mutation in ADRB3). CONCLUSIONS: Our results provide limited evidence for the associations between variants from protein coding regions in 8p12 and SCZ in the Chinese population. Analyses of both coding and regulatory variants in larger sample sizes are required to further clarify the causal variants for SCZ with this risk locus.


Assuntos
Esquizofrenia , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Receptores Adrenérgicos beta 3 , Esquizofrenia/genética
7.
Artigo em Inglês | MEDLINE | ID: mdl-32450113

RESUMO

Multiple genetic risk factors have been associated with psychiatric disorders which provides the genetic insight to these disorders; however, the etiology of these disorders is still elusive. 15q13.3 was previously associated with schizophrenia, bipolar and other neurodevelopmental disorders. Whereas, the FAN1 which encodes the Fanconi anemia associated nuclease 1 was suggested to be causal gene for 15q13.3 related psychiatric disorders. This study aimed to investigate the association of FAN1 with three major psychiatric disorders. Herein, we conducted a case-control study with the Chinese Han population. Three single nucleotide polymorphisms (SNPs) of FAN1 were genotyped in 1248 schizophrenia cases, 1344 bipolar disorder cases, 1056 major depressive disorder cases and 1248 normal controls. We found that SNPs rs7171212 was associated with bipolar (pallele = 0.023, pgenotype = 0.022, OR = 0.658) and schizophrenia (pallele = 0.021, pgenotype = 0.019, OR = 0.645). Whereas, rs4779796 was associated with schizophrenia (pgenotype = 0.001, adjusted pgenotype = 0.003, OR = 1.089). In addition, rs7171212 (adjusted pallele = 0.018, adjusted pgenotype = 0.018, OR = 0.652) and rs4779796 (adjusted pgenotype = 0.024, OR = 1.12) showed significantly associated with combined cases of schizophrenia and bipolar disorder. Further, meta-analysis was performed with the case-control data and dataset extracted from previously reported genome-wide association study to validate the promising SNPs. Our results provide the new evidence that FAN1 may be a common susceptibility gene for schizophrenia and bipolar disorder in Han Chinese. These novel findings need further validation with larger sample size and functional characterization to understand the underlying pathogenic mechanism behind FAN1 in the prevalence of schizophrenia and bipolar disorders.


Assuntos
Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Cromossomos Humanos Par 15/genética , Endodesoxirribonucleases/genética , Exodesoxirribonucleases/genética , Enzimas Multifuncionais/genética , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Adulto , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , China/epidemiologia , Bases de Dados Factuais , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
8.
Hereditas ; 157(1): 8, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32172688

RESUMO

BACKGROUND: Short tandem repeats (STRs) are important polymorphism makers for human identification and kinship analyses in forensic science. With the continuous development of massively parallel sequencing (MPS), more laboratories have utilized this technology for forensic applications. Existing STR genotyping tools, mostly developed for whole-genome sequencing data, are not effective for MPS data. More importantly, their backward compatibility with the conventional capillary electrophoresis (CE) technology has not been evaluated and guaranteed. RESULTS: In this study, we developed a new end-to-end pipeline called STRsearch for STR-MPS data analysis. The STRsearch can not only determine the allele by counting repeat patterns and INDELs that are actually in the STR region, but it also translates MPS results into standard STR nomenclature (numbers and letters). We evaluated the performance of STRsearch in two forensic sequencing datasets, and the concordance with CE genotypes was 75.73 and 75.75%, increasing 12.32 and 9.05% than the existing tool named STRScan, respectively. Additionally, we trained a base classifier using sequence properties and used it to predict the probability of correct genotyping at a given locus, resulting in the highest accuracy of 96.13%. CONCLUSIONS: All these results demonstrated that STRsearch was a better tool to protect the backward compatibility with CE for the targeted STR profiling in MPS data. STRsearch is available as open-source software at https://github.com/AnJingwd/STRsearch.


Assuntos
Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Repetições de Microssatélites , DNA/genética , Conjuntos de Dados como Assunto , Eletroforese Capilar/métodos , Reação em Cadeia da Polimerase/métodos , Reprodutibilidade dos Testes
9.
J Clin Endocrinol Metab ; 105(6)2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32163573

RESUMO

BACKGROUND: Observational studies have shown a link between elevated body mass index (BMI) and the risk of polycystic ovary syndrome (PCOS). While Mendelian randomization (MR) studies in Europeans have suggested a causal role of increased BMI in PCOS, whether the same role is suggested in Asians has yet to be investigated. We used MR studies to infer causal effects using genetic data from East Asian populations. METHODS AND FINDINGS: We performed a 2-sample bidirectional MR analysis using summary statistics from genome-wide association studies (GWAS) of BMI (with up to 173 430 individuals) and PCOS (4386 cases and 8017 controls) in East Asian populations. Seventy-eight single nucleotide polymorphisms (SNPs) correlated with BMI were selected as genetic instrumental variables to estimate the causal effect of BMI on PCOS using the inverse-variance weighted (IVW) method. To test the reliability of the results, further sensitivity analyses included MR-Egger regression, weighted median estimates, and leave-one-out analysis. The IVW analysis indicated a significant association between high BMI and the risk of PCOS (odds ratio per standard deviation higher BMI, 2.208; 95% confidence interval 1.537 to 3.168, P = 1.77 × 10-5). In contrast, the genetic risk of PCOS had no significant effect on BMI. CONCLUSIONS: The results of our bidirectional MR study showed that an increase in BMI causes PCOS, while PCOS does not cause an increased BMI. This study provides further genetic support for a link between BMI and PCOS. Further research is needed to interpret the potential mechanisms of this association.


Assuntos
Biomarcadores/análise , Índice de Massa Corporal , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana/estatística & dados numéricos , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/patologia , Polimorfismo de Nucleotídeo Único , Feminino , Humanos , Prognóstico
11.
Hereditas ; 156: 15, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31148953

RESUMO

Background: Athletic performances are complex traits with heritability of ~66%. Dynamic balance is one of the most important athletic performances, and there has been little studies for it in sports genomics. The candidate PPARD gene was reported to be able to affect muscle development for balance predisposition and influence the athletic performance including skiing triumph in the Caucasian population. This study aims to investigate whether the PPARD gene is a susceptibility gene for dynamic balance performance in Han Chinese children. Results: A total 2244 children were recruited and their balance beam performances were measured. Five polymorphisms in the PPARD gene were genotyped through the MassARRAY Sequenom platform. Rs2016520 exerted significant association with dynamic balance performance (minor allele C, P = 0.015, Pcorrected < 0.05) and was affirmed in a meta-analysis by combining previously reported Caucasian cohorts (OR = 1.57, 95% CI = [1.30, 1.91], P < 10 -5) . Another polymorphism, rs2267668, was also significantly associated with dynamic balance performance (minor allele G, P = 0.015, Pcorrected < 0.05). In the dichotomous study, 321 cases (61% boys and 39% girls) and 370 controls (49% boys and 51% girls) in our samples were selected as representatives, and the thresholds were the mean velocity (0.737 m/s) ± standard deviation (0.264 m/s), in which rs2016520-C and rs2267668-G still remained significant (CI =1.41 [1.11~1.79], P = 0.004, Pcorrected < 0.016; CI =1.45 [1.14~1.86], P = 0.002, Pcorrected < 0.016). In different genders, consistent OR direction was observed for each variant. Conclusions: Our results suggested that the PPARD gene is associated with dynamic balance performance of human being, and further studies to reveal its etiology is strongly suggested.


Assuntos
Genótipo , PPAR delta/genética , Polimorfismo de Nucleotídeo Único , Equilíbrio Postural/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Criança , China , Feminino , Frequência do Gene , Estudos de Associação Genética , Ligação Genética , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Masculino , Razão de Chances , Locos de Características Quantitativas
12.
Psychiatr Genet ; 29(4): 120-126, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31162297

RESUMO

OBJECTIVE: Schizophrenia is one of the most severe mental disorders and its etiology is supposed to be an interaction between genes and environmental factors. Previous genome-wide association studies of schizophrenia have reported multiple susceptibility loci including rs6704641 in the SATB2 gene. Recently, this locus was further confirmed as a genome-wide significant locus for association with schizophrenia by trans-ancestry meta-analysis of Han Chinese and Caucasian samples. However, there is no report of genetic analysis in Uygur Chinese population, which is considered to have a combined genetic background between eastern Asia and Caucasian. This study is aimed to explore whether SATB2 gene is significantly associated with schizophrenia in Uygur Chinese population, thus providing additional evidence for elucidating the role of SATB2 gene in schizophrenia. PARTICIPANTS AND METHODS: In this study, we performed a case-control analysis focusing on seven tag single nucleotide polymorphisms located in SATB2 gene among 985 patients with schizophrenia and 1218 healthy controls recruited from the Xinjiang Province of China. RESULTS: We found that rs6704641 was significantly associated with schizophrenia in both allelic and genotypic distributions (Pallele = 0.008, Pgenotype = 0.028 after correction). In addition, rs16831466 is significantly associated with schizophrenia in allelic distributions (corrected Pallele = 0.041). Besides, several haplotypes of single nucleotide polymorphism are significantly associated with schizophrenia too. CONCLUSION: Our results suggest that SATB2 is also a susceptibility gene for schizophrenia in Uygur Chinese population, and subsequent functional experiments are necessary to reveal its role in the pathogenesis.


Assuntos
Grupos Étnicos/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas de Ligação à Região de Interação com a Matriz/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino
13.
Mol Genet Genomic Med ; 7(7): e00722, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31131560

RESUMO

BACKGROUND: To identify potential causative mutations in SLC2A9 and SLC22A12 that lead to hypouricemia or hyperuricemia (HUA). METHODS: Targeted resequencing of whole exon regions of SLC2A9 and SLC22A12 was performed in three cohorts of 31 hypouricemia, 288 HUA and 280 normal controls. RESULTS: A total of 84 high-quality variants were identified in these three cohorts. Eighteen variants were nonsynonymous or in splicing region, and then included in the following association analysis. For common variants, no significant effects on hypouricemia or HUA were identified. For rare variants, six single nucleotide variations (SNVs) p.T21I and p.G13D in SLC2A9, p.W50fs, p.Q382L, p.V547L and p.E458K in SLC22A12, occurred in totally six hypouricemia subjects and were absent in HUA and normal controls. Allelic and genotypic frequency distributions of the six SNVs differed significantly between the hypouricemia and normal controls even after multiple testing correction, and p.G13D in SLC2A9 and p.V547L in SLC22A12 were newly reported. All these mutations had no significant effects on HUA susceptibility, while the gene-based analyses substantiated the significant results on hypouricemia. CONCLUSION: Our study first presents a comprehensive mutation spectrum of hypouricemia in a large Chinese cohort.


Assuntos
Proteínas Facilitadoras de Transporte de Glucose/genética , Hiperuricemia/genética , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Erros Inatos do Transporte Tubular Renal/genética , Cálculos Urinários/genética , Adulto , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Suscetibilidade a Doenças , Feminino , Frequência do Gene , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hiperuricemia/patologia , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Erros Inatos do Transporte Tubular Renal/patologia , Cálculos Urinários/patologia
14.
Nanoscale ; 11(13): 6263-6269, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30882811

RESUMO

Tetrahedral DNA nanostructures (TDNs) are programmable DNA nanostructures that have great potential in bio-sensing, cell imaging and therapeutic applications. In this study, we investigate the translocation behavior of individual TDNs through solid-state nanopores. Pronounced translocation signals for TDNs are observed that are sensitive to the size of the nanostructures. TDNs bound to linear DNA molecules produce an extra signal in the ionic current traces. Statistical analysis of its relative temporal position reveals distinct features between TDNs bound to the end and those bound to the middle of the linear DNA molecules. A featured current trace for two TDNs bound to the same linear DNA molecule has also been observed. Our study demonstrates the potential of using TDNs as sensitive bio-sensors to detect specific segments of a single DNA molecule in real time, based on solid-state nanopore devices.


Assuntos
DNA/química , Nanoporos , Nanoestruturas/química , Bacteriófago M13/genética , DNA/metabolismo , DNA Viral/química , DNA Viral/metabolismo , Microscopia de Força Atômica , Razão Sinal-Ruído
15.
Ann Transl Med ; 7(23): 745, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32042761

RESUMO

Background: The present study aimed to identify key differentially expressed genes (DEGs) and miRNAs (DEmiRNAs) in gastric adenocarcinoma. Methods: We performed integrated analysis to determine DEGs and DEmiRNAs of gastric adenocarcinoma based on the GEO database. A DEmiRNA-target interaction network was established. GO and KEGG pathway enrichment analyses were utilized. Then, MKN45 cells were transfected with shRNA-RAB23 to knock down the expression of RAB23. CCK-8, transwell and flow cytometry assays were utilized to measure the capacities for cell proliferation, migration and apoptosis, and the apoptosis-related gene and protein levels were measured by using polymerase chain reaction (PCR) and Western blot, respectively. Colocalization analysis of Snc1 with the vesicular protein VAMP3 and the endoplasmic reticulum protein Calnexin was performed to assess the influence of RAB23 on vesicle transport. Finally, we performed metabolomic analysis by using gas chromatography mass spectrometry (GC-MS). Results: We performed MMIA of gastric adenocarcinoma based on two miRNA datasets and two mRNA datasets. A total of 4,586 DEmRNAs and 30 DEmiRNAs were obtained. The DEmRNAs of gastric adenocarcinoma were significantly enriched in PI3K/Akt signaling. We identified three interactions, hsa-miR-23a-3p-PTPN4, hsa-miR-20b-5p (hsa-miR-130a-3p)-TNFRSF10B, and hsa-miR-130a-3p (hsa-miR-363-3p)-RAB23, that may be related to the pathogenesis of gastric adenocarcinoma. The growth of MKN45 cells was inhibited by RAB23 knockdown via shRNA-RAB23 transfection. Metabolic analysis of three groups revealed a number of significantly altered metabolites, including glycerol, niacinamide, and nonadecanoic acid methylester. Conclusions: RAB23 might be a target gene of hsa-miR-130a-3p and hsa-miR-363-3p. In gastric adenocarcinoma cells, knockdown of RAB23 inhibited cell proliferation, migration, and invasion and increased apoptosis by downregulating the PI3K/Akt pathway.

16.
Mol Genet Genomics ; 294(1): 47-56, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30167790

RESUMO

The ACTN3 gene locates on 11q13-q14 and encodes the α-actinin-3 protein, which is only expressed in human skeletal muscle and influenced muscle function and metabolism. The previous studies reported that SNP rs1815739 is associated with elite power athletes' performance. In this study, we investigated the association between five SNPs within the ACTN3 gene and Chinese children physical fitness. We recruited 2244 Han Chinese children participants, and measured their 25-m run, stand broad jump, 10-m shuttle run, handgrip, BMI (calculated by weight and height) data. SNPs rs1671064, rs2275998, rs2290463, rs10791881, and rs1815739 of ACTN3 gene were genotyped and analyzed in five physical fitness data. QTL analysis on genotype and physical fitness data was carried out in all samples. Furthermore, a dichotomous division of samples into an overweight group (543) and a normal group (1701) was used for an association study of overweight. In the QTL analysis, we found rs2290463 was significantly associated with stand broad jump (corrected P value = 0.009, beta = 2.692). After added age and gender as covariates in the regression test, the association became more significant (P value = 5.80 × 10- 5, corrected P value = 4.06 × 10- 4); when we used BMI as a covariate, the association still existed (P value = 4.65 × 10- 4, corrected P value = 0.001). In the association study of overweight, rs2275998 was found to be significant (OR, 95% CI = 0.733 [0.6-0.895]; Pallele = 0.011, Pgenotype = 0.024) after the Bonferroni correction, and the association did not change much after a further correction for gender, age, and stand broad jump performance. Our results showed that common variants in ACTN3 are significantly associated with both stand broad jump performance and overweight in Han Chinese children.


Assuntos
Actinina/genética , Grupo com Ancestrais do Continente Asiático/etnologia , Sobrepeso/genética , Aptidão Física , Polimorfismo de Nucleotídeo Único , Grupo com Ancestrais do Continente Asiático/genética , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Genótipo , Força da Mão , Humanos , Masculino , Locos de Características Quantitativas
17.
Onco Targets Ther ; 11: 6111-6118, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30275715

RESUMO

Purpose: NVP-BEZ235 is a recently developed dual inhibitor of PI3K and mTOR and shows good inhibitory effects on several types of tumors. However, the efficacy of NVP-BEZ235 on gastric cancer therapy remains unclear. This study aimed to investigate the potential of NVP-BEZ235 as a new agent to enhance chemotherapy for gastric cancer. Methods: Human gastric cancer MKN-45 cells or nude mice xenografted with MKN-45 cells were treated by NVP-BEZ235 and fluorouracil (5-FU) alone or in combination. The proliferation, invasion, apoptosis, and chemoresistance of gastric cancer cells were examined in vivo and in vitro. Results: In vitro, combined treatment with NVP-BEZ235 and 5-FU showed synergistic inhibitory effects on proliferation, migration, and invasion and synergistic stimulating effects on apoptosis of MKN-45 cells. In vivo, NVP-BEZ235 and 5-FU synergistically inhibited the growth and induced apoptosis of MKN-45 xenografts. Mechanistically, NVP-BEZ235 inhibited PI3K/Akt/mTOR signaling; decreased the levels of Bcl-2, MMP9, and VEGF; but increased the levels of Bax and cleaved caspase-3 in MKN-45 xenografts. Conclusion: NVP-BEZ235 enhances the antitumor efficacy of 5-FU. Therefore, NVP-BEZ235 is a promising agent to enhance chemotherapy for gastric cancer.

18.
BMC Med Genet ; 19(1): 142, 2018 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-30097038

RESUMO

BACKGROUND: Renal hypouricemia (RHUC) is a heterogeneous genetic disorder that is characterized by decreased serum uric acid concentration and increased fractional excretion of uric acid. Previous reports have revealed many functional mutations in two urate transporter genes, SLC22A12 and/or SLC2A9, to be the causative genetic factors of this disorder. However, there are still unresolved patients, suggesting the existence of other causal genes or new mutations. Here, we report an RHUC patient with novel compound heterozygous mutations in the SLC22A12 gene. CASE PRESENTATION: A 27-year-old female presenting with recurrent hypouricemia during routine checkups was referred to our hospital. After obtaining the patient's consent, both the patient and her healthy parents were analyzed using whole-exome sequencing (WES) and Sanger sequencing to discover and validate causal mutations, respectively. The prioritization protocol of WES screened out two mutations of c.269G > A/p.R90H and c.1289_1290insGG/p.M430fsX466, which are both located in the SLC22A12 gene, in the patient. Sanger sequencing further confirmed that the patient's heterozygous c.269G > A/p.R90H mutation, which has been reported previously, derived from her mother, and the heterozygous c.1289_1290insGG/p.M430fsX466 mutation, which was found for the first time, derived from her father. p.R90H, which is highly conserved among different species, may decrease the stability of this domain and was considered to be almost damaging in silicon analysis. p.M430fsX466 lacks the last three transmembrane domains, including the tripeptide motif (S/T)XΦ (X = any amino acid and Φ = hydrophobic residue), at the C-terminal, which interact with scaffolding protein PDZK1 and thus will possibly lead to weak functioning of urate transport through the disruption of the "transporter complex" that is formed by URAT1 and PDZK1. CONCLUSIONS: We report a Chinese patient with RHUC, which was caused by compound heterozygous mutations of the SLC22A12 gene, using WES and Sanger sequencing for the first time. Mutation-induced structural instability or malfunction of the urate transporter complex may be the main mechanisms for this hereditary disorder.


Assuntos
Mutação/genética , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Erros Inatos do Transporte Tubular Renal/genética , Cálculos Urinários/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Heterozigoto , Humanos , Masculino , Erros Inatos do Transporte Tubular Renal/metabolismo , Ácido Úrico/metabolismo , Cálculos Urinários/metabolismo
19.
Cell Physiol Biochem ; 47(4): 1533-1545, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29940566

RESUMO

BACKGROUND/AIMS: Gastric cancer (GC) is the most common gastrointestinal malignancy, causing cancer-related deaths in East Asia. MicroRNAs (miRNAs) are small non-coding RNAs aberrantly expressed in human tumors. In this study, we aim to investigate the roles of miR-204 in the epithelial to mesenchymal transition (EMT)-associated chemosensitivity. METHODS: The expression of miR-204 was detected in clinical tumor samples and GC cell lines by real time PCR. Tumor cell's growth, invasion, and migration were measured by MTT assay, wound healing assay, and transwell invasion assay, respectively. Western blot method was used to detect the protein levels of indicated genes. Luciferase reporter assay was performed to validate the target gene of miR-204. The in vivo role of miR-204 was measured using a xenograft mouse model of GC. RESULTS: By comparing the expressions of miR-204 in human gastric tumors and their adjacent normal tissues, it was disclosed that miR-204 was significantly downregulated in gastric tumors. Moreover, miR-204 was downregulated in multiple GC cell lines compared with normal gastric epithelial cells. Overexpression of miR-204 suppressed GC cells' proliferation, invasion, and migration. It is noteworthy that 5-FU treatments induced miR-204 expression and suppressed TGF-ß pathway. By establishment of 5-FU resistant GC cell line, it was revealed that miR-204 was significantly downregulated in 5-FU resistant GC cells, representing mesenchymal features with downregulation of epithelial marker, while mesenchymal markers were upregulated. We identified TGFBR2 as a direct target of miR-204 by Western blot method and luciferase assay in GC cells and tumor samples as well. In addition, overexpression of miR-204 sensitized GC cells to 5-FU in vitro. Xenograft experiments demonstrated that the combination of miR-204 and 5-FU efficiently inhibited tumor growth and improved survival rate of mice as well. Eventually, we illustrated the restoration of TGFBR2 in miR-204 overexpression GC cells, which recovered resistance to 5-FU treatments compared with miR-204 overexpression GC cells. CONCLUSION: This study describes a miRNA-based therapeutic strategy against 5-FU resistance in GC, contributing to the development of anti-chemoresistance therapeutic agents.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Fluoruracila/farmacologia , MicroRNAs , Proteínas de Neoplasias , Proteínas Serina-Treonina Quinases , RNA Neoplásico , Receptores de Fatores de Crescimento Transformadores beta , Neoplasias Gástricas , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Humanos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Small ; 14(6)2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29283218

RESUMO

The hepatitis B virus (HBV) genotyping may profoundly affect the accurate diagnosis and antiviral treatment of viral hepatitis. Existing genotyping methods such as serological, immunological, or molecular testing are still suffered from substandard specificity and low sensitivity in laboratory or clinical application. In a previous study, a set of high-efficiency hybridizable DNA origami-based shape ID probes to target the templates through which genetic variation could be determined in an ultrahigh resolution of atomic force microscopy (AFM) nanomechanical imaging are established. Here, as a further confirmatory research to explore the sensitivity and applicability of this assay, differentially predesigned DNA origami shape ID probes are also developed for precisely HBV genotyping. Through the specific identification of visualized DNA origami nanostructure with clinical HBV DNA samples, the genetic variation information of genotypes can be directly identified under AFM. As a proof-of-concept, five genotype B and six genotype C are detected in 11 HBV-infected patients' blood DNA samples of Han Chinese population in the single-blinded test. The AFM image-based DNA origami shape ID genotyping approach shows high specificity and sensitivity, which could be promising for virus infection diagnosis and precision medicine in the future.


Assuntos
DNA Viral/sangue , DNA Viral/genética , Genes Virais , Genótipo , Vírus da Hepatite B/genética , China , DNA Viral/química , Grupos Étnicos , Humanos , Microscopia de Força Atômica , Conformação de Ácido Nucleico , Estudo de Prova de Conceito
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