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1.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072463

RESUMO

The NBN gene has been included in breast cancer (BC) multigene panels based on early studies suggesting an increased BC risk for carriers, though not confirmed by recent research. To evaluate the impact of NBN analysis, we assessed the results of NBN sequencing in 116 BRCA-negative BC patients and reviewed the literature. Three patients (2.6%) carried potentially relevant variants: two, apparently unrelated, carried the frameshift variant c.156_157delTT and another one the c.628G>T variant. The latter was subsequently found in 4/1390 (0.3%) BC cases and 8/1580 (0.5%) controls in an independent sample, which, together with in silico predictions, provided evidence against its pathogenicity. Conversely, the rare c.156_157delTT variant was absent in the case-control set; moreover, a 50% reduction of NBN expression was demonstrated in one carrier. However, in one family it failed to co-segregate with BC, while the other carrier was found to harbor also a probably pathogenic TP53 variant that may explain her phenotype. Therefore, the c.156_157delTT, although functionally deleterious, was not supported as a cancer-predisposing defect. Pathogenic/likely pathogenic NBN variants were detected by multigene panels in 31/12314 (0.25%) patients included in 15 studies. The risk of misinterpretation of such findings is substantial and supports the exclusion of NBN from multigene panels.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Proteínas de Ciclo Celular/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Proteínas Nucleares/genética , Adulto , Alelos , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética/métodos , Testes Genéticos , Genótipo , Haplótipos , Humanos , Linhagem
2.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072601

RESUMO

The high mortality rate in septic shock patients is likely due to environmental and genetic factors, which influence the host response to infection. Two genome-wide association studies (GWAS) on 832 septic shock patients were performed. We used integrative bioinformatic approaches to annotate and prioritize the sepsis-associated single nucleotide polymorphisms (SNPs). An association of 139 SNPs with death based on a false discovery rate of 5% was detected. The most significant SNPs were within the CISH gene involved in cytokine regulation. Among the 139 SNPs associated with death and the 1311 SNPs in strong linkage disequilibrium with them, we investigated 1439 SNPs within non-coding regions to identify regulatory variants. The highest integrative weighted score (IW-score) was obtained for rs143356980, indicating that this SNP is a robust regulatory candidate. The rs143356980 region is located in a non-coding region close to the CISH gene. A CRISPR-Cas9-mediated deletion of this region and specific luciferase assays in K562 cells showed that rs143356980 modulates the enhancer activity in K562 cells. These analyses allowed us to identify several genes associated with death in patients with septic shock. They suggest that genetic variations in key genes, such as CISH, perturb relevant pathways, increasing the risk of death in sepsis patients.


Assuntos
Elementos Facilitadores Genéticos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Choque Séptico/etiologia , Choque Séptico/mortalidade , Proteínas Supressoras da Sinalização de Citocina/genética , Alelos , Biomarcadores , Biologia Computacional/métodos , Humanos , Interleucina-6/sangue , Anotação de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Prognóstico , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Curva ROC , Sequências Reguladoras de Ácido Nucleico , Reprodutibilidade dos Testes , Choque Séptico/metabolismo
3.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065289

RESUMO

Genome-wide association studies (GWAS) found locus 3p21.31 associated with severe COVID-19. CCR5 resides at the same locus and, given its known biological role in other infection diseases, we investigated if common noncoding and rare coding variants, affecting CCR5, can predispose to severe COVID-19. We combined single nucleotide polymorphisms (SNPs) that met the suggestive significance level (P ≤ 1 × 10-5) at the 3p21.31 locus in public GWAS datasets (6406 COVID-19 hospitalized patients and 902,088 controls) with gene expression data from 208 lung tissues, Hi-C, and Chip-seq data. Through whole exome sequencing (WES), we explored rare coding variants in 147 severe COVID-19 patients. We identified three SNPs (rs9845542, rs12639314, and rs35951367) associated with severe COVID-19 whose risk alleles correlated with low CCR5 expression in lung tissues. The rs35951367 resided in a CTFC binding site that interacts with CCR5 gene in lung tissues and was confirmed to be associated with severe COVID-19 in two independent datasets. We also identified a rare coding variant (rs34418657) associated with the risk of developing severe COVID-19. Our results suggest a biological role of CCR5 in the progression of COVID-19 as common and rare genetic variants can increase the risk of developing severe COVID-19 by affecting the functions of CCR5.


Assuntos
COVID-19/genética , COVID-19/metabolismo , Predisposição Genética para Doença , Receptores CCR5/genética , Receptores CCR5/metabolismo , Alelos , Brônquios/metabolismo , Brônquios/patologia , Brônquios/virologia , COVID-19/fisiopatologia , Cromossomos Humanos/genética , Estudos de Coortes , Biologia Computacional , Bases de Dados Genéticas , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Exoma
4.
Int J Mol Sci ; 22(9)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066804

RESUMO

The elderly and patients with several comorbidities experience more severe cases of coronavirus disease 2019 (COVID-19) than healthy patients without underlying medical conditions. However, it is unclear why these people are prone to developing alveolar pneumonia, rapid exacerbations, and death. Therefore, we hypothesized that people with comorbidities may have a genetic predisposition that makes them more vulnerable to various factors; for example, they are likely to become more severely ill when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To test this hypothesis, we searched the literature extensively. Polymorphisms of genes, such as those that encode angiotensin-converting enzyme 1 (ACE1), have been associated with numerous comorbidities, such as cardiovascular disease, hypertension, diabetes, chronic kidney disease, and obesity, and there are potential mechanisms to explain these associations (e.g., DD-type carriers have greater ACE1 activity, and patients with a genetic alpha-1 anti-trypsin (AAT) deficiency lack control over inflammatory mediators). Since comorbidities are associated with chronic inflammation and are closely related to the renin-angiotensin-aldosterone system (RAAS), these individuals may already have a mild ACE1/ACE2 imbalance before viral infection, which increases their risk for developing severe cases of COVID-19. However, there is still much debate about the association between ACE1 D/I polymorphism and comorbidities. The best explanation for this discrepancy could be that the D allele and DD subtypes are associated with comorbidities, but the DD genotype alone does not have an exceptionally large effect. This is also expected since the ACE1 D/I polymorphism is only an intron marker. We also discuss how polymorphisms of AAT and other genes are involved in comorbidities and the severity of SARS-CoV-2 infection. Presumably, a combination of multiple genes and non-genetic factors is involved in the establishment of comorbidities and aggravation of COVID-19.


Assuntos
COVID-19/genética , Predisposição Genética para Doença , Peptidil Dipeptidase A/genética , Idoso , Alelos , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/metabolismo , COVID-19/fisiopatologia , COVID-19/virologia , Comorbidade , Antígenos HLA/genética , Antígenos HLA/metabolismo , Haplótipos , Humanos , Inflamação/genética , Inflamação/metabolismo , Homem de Neandertal/genética , Peptidil Dipeptidase A/metabolismo , Polimorfismo Genético , Fatores de Risco , Índice de Gravidade de Doença
5.
Planta ; 253(6): 132, 2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34059984

RESUMO

MAIN CONCLUSION: The distribution of early flowering alleles of VRN-A3 was found to be biased to low latitudes, and these alleles may contribute to environmental adaptability to low latitudes in cultivated emmer wheat. In wheat (Triticum spp.), the flowering time is an important trait for successful seed production and yield by adapting to the regional environment. An early flowering allele of VRN-A3 with 7- and 25-bp insertions in the promoter region (Vrn-A3a-h1) has recently been reported from the analysis of an emmer wheat (Triticum turgidum L. ssp. dicoccum) accession, TN26. This early flowering allele of VRN-A3 might be associated with the regional adaptation of wheat. In this study, we elucidated its geographic distribution to assess the importance of the early flowering allele of VRN-A3 in worldwide wheat collection. From sequence analysis, we identified six VRN-A3 alleles with the 7- and 25-bp insertions, namely, Vrn-A3a-h2, Vrn-A3a-h3, Vrn-A3a-h4, Vrn-A3a-h5, Vrn-A3a-h6, and Vrn-A3c-h2 from wild emmer wheat, while we identified two VRN-A3 alleles with these insertions, Vrn-A3a-h2 and Vrn-A3c-h1 from cultivated tetraploid and hexaploid wheat species in addition to Vrn-A3a-h1. Among VRN-A3 alleles distributed in cultivated wheat, we found that Vrn-A3a-h2 promoted early heading, whereas Vrn-A3c-h1 did not affect heading time. Our analysis showed that the distribution of early flowering alleles of VRN-A3 dominated in cultivated emmer wheat in Ethiopia and India, which actually showed an early flowering phenotype. This implied that the early flowering alleles of VRN-A3 contribute to adaptability to a low-latitude environment in cultivated emmer wheat. We could not find durum (T. turgidum L. ssp. durum) and bread wheat (T. aestivum L. ssp. aestivum) accessions with these early flowering alleles. Our findings indicated that Vrn-A3a-h1 and Vrn-A3a-h2 were useful for breeding of early flowering cultivars in durum and bread wheat varieties.


Assuntos
Melhoramento Vegetal , Triticum , Alelos , Etiópia , Poliploidia , Triticum/genética
6.
Science ; 372(6546): 1085-1091, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-34083488

RESUMO

Whereas coding variants often have pleiotropic effects across multiple tissues, noncoding variants are thought to mediate their phenotypic effects by specific tissue and temporal regulation of gene expression. Here, we investigated the genetic and functional architecture of a genomic region within the FTO gene that is strongly associated with obesity risk. We show that multiple variants on a common haplotype modify the regulatory properties of several enhancers targeting IRX3 and IRX5 from megabase distances. We demonstrate that these enhancers affect gene expression in multiple tissues, including adipose and brain, and impart regulatory effects during a restricted temporal window. Our data indicate that the genetic architecture of disease-associated loci may involve extensive pleiotropy, allelic heterogeneity, shared allelic effects across tissues, and temporally restricted effects.


Assuntos
Tecido Adiposo/metabolismo , Encéfalo/metabolismo , Proteínas de Homeodomínio/genética , Obesidade/genética , Fatores de Transcrição/genética , Alelos , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Animais , Encéfalo/embriologia , Linhagem Celular , Cromatina/química , Cromatina/metabolismo , Desenvolvimento Embrionário , Elementos Facilitadores Genéticos , Comportamento Alimentar , Preferências Alimentares , Regulação da Expressão Gênica , Haplótipos , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Obesidade/fisiopatologia , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/metabolismo
7.
BMC Genomics ; 22(1): 410, 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34082698

RESUMO

BACKGROUND: There are two genetically distinct subspecies of cattle, Bos taurus taurus and Bos taurus indicus, which arose from independent domestication events. The two types of cattle show substantial phenotypic differences, some of which emerge during fetal development and are reflected in birth outcomes, including birth weight. We explored gene expression profiles in the placenta and four fetal tissues at mid-gestation from one taurine (Bos taurus taurus; Angus) and one indicine (Bos taurus indicus; Brahman) breed and their reciprocal crosses. RESULTS: In total 120 samples were analysed from a pure taurine breed, an indicine breed and their reciprocal cross fetuses, which identified 6456 differentially expressed genes (DEGs) between the two pure breeds in at least one fetal tissue of which 110 genes were differentially expressed in all five tissues examined. DEGs shared across tissues were enriched for pathways related to immune and stress response functions. Only the liver had a substantial number of DEGs when reciprocal crossed were compared among which 310 DEGs were found to be in common with DEGs identified between purebred livers; these DEGs were significantly enriched for metabolic process GO terms. Analysis of DEGs across purebred and crossbred tissues suggested an additive expression pattern for most genes, where both paternal and maternal alleles contributed to variation in gene expression levels. However, expression of 5% of DEGs in each tissue was consistent with parent of origin effects, with both paternal and maternal dominance effects identified. CONCLUSIONS: These data identify candidate genes potentially driving the tissue-specific differences between these taurine and indicine breeds and provide a biological insight into parental genome effects underlying phenotypic differences in bovine fetal development.


Assuntos
Bovinos/genética , Domesticação , Impressão Genômica , Alelos , Animais , Cruzamento , Cruzamentos Genéticos , Feminino , Expressão Gênica , Gravidez
8.
Sensors (Basel) ; 21(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068416

RESUMO

HLA-B*15:02 screening before administering carbamazepine is recommended to prevent life-threatening hypersensitivity. However, the unavailability of a point-of-care device impedes this screening process. Our research group previously developed a two-step HLA-B*15:02 detection technique utilizing loop-mediated isothermal amplification (LAMP) on the tube, which requires two-stage device development to translate into a portable platform. Here, we report a heater-integrated lab-on-a-chip device for the LAMP amplification, which can rapidly detect HLA-B alleles colorimetrically. A gold-patterned micro-sized heater was integrated into a 3D-printed chip, allowing microfluidic pumping, valving, and incubation. The performance of the chip was tested with color dye. Then LAMP assay was conducted with human genomic DNA samples of known HLA-B genotypes in the LAMP-chip parallel with the tube assay. The LAMP-on-chip results showed a complete match with the LAMP-on-tube assay, demonstrating the detection system's concurrence.


Assuntos
Hipersensibilidade a Drogas , Antígenos HLA-B , Dispositivos Lab-On-A-Chip , Alelos , Humanos , Técnicas de Diagnóstico Molecular , Técnicas de Amplificação de Ácido Nucleico
9.
Genes (Basel) ; 12(6)2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071309

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection provides a critical host-immunological challenge. AIM: We explore the effect of host-genetic variation in interferon-lambda-3 rs12979860, Tolloid Like-1 (TLL1) rs17047200 and Discoidin domain receptor 1(DDR1) rs4618569 on host response to respiratory viral infections and disease severity that may probe the mechanistic approach of allelic variation in virus-induced inflammatory responses. METHODS: 141 COVID-19 positive patients and 100 healthy controls were tested for interferon-lambda-3 rs12979860, TLL1 rs17047200 and DDR1 rs4618569 polymorphism by TaqMan probe-based genotyping. Different genotypes were assessed regarding the COVID-19 severity and prognosis. RESULTS: There were statistically significant differences between the studied cases and control group with regard to the presence of comorbidities, total leucocytic count, lymphocytic count, CRP, serum LDH, ferritin and D-dimer (p < 0.01). The CC genotype of rs12979860 cytokine, the AA genotype of TLL1 rs17047200 and the AA genotype of the rs4618569 variant of DDR1 showed a higher incidence of COVID-19 compared to the others. There were significant differences between the rs4618569 variant of DDR and the outcome of the disease, with the highest mortality in AG genotype 29 (60.4%) in comparison to 16 (33.3%) and 3 (6.2%) in the AA and GG genotypes, respectively (p = 0.007*), suggesting that the A allele is associated with a poor outcome in the disease. CONCLUSION: Among people who carry C and A alleles of SNPs IFN-λ rs12979860 and TLL1 rs17047200, respectively, the AG genotype of the DDR1 rs4618569 variant is correlated with a COVID-19 poor outcome. In those patients, the use of anti-IFN-λ 3, TLL1 and DDR1 therapy may be promising for personalized translational clinical practice.


Assuntos
COVID-19/genética , COVID-19/virologia , Receptor com Domínio Discoidina 1/genética , Predisposição Genética para Doença , Interferons/genética , Polimorfismo de Nucleotídeo Único , SARS-CoV-2/fisiologia , Metaloproteases Semelhantes a Toloide/genética , Alelos , Biomarcadores , COVID-19/diagnóstico , COVID-19/imunologia , Estudos de Casos e Controles , Comorbidade , Citocinas/metabolismo , Feminino , Genótipo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Masculino , Prognóstico , Índice de Gravidade de Doença , Carga Viral
10.
Genes (Basel) ; 12(6)2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072181

RESUMO

The genomic diversity of SARS-CoV-2 has been a focus during the ongoing COVID-19 pandemic. Here, we analyzed the distribution and character of emerging mutations in a data set comprising more than 95,000 virus genomes covering eight major SARS-CoV-2 lineages in the GISAID database, including genotypes arising during COVID-19 therapy. Globally, the C>U transitions and G>U transversions were the most represented mutations, accounting for the majority of single-nucleotide variations. Mutational spectra were not influenced by the time the virus had been circulating in its host or medical treatment. At the amino acid level, we observed about a 2-fold excess of substitutions in favor of hydrophobic amino acids over the reverse. However, most mutations constituting variants of interests of the S-protein (spike) lead to hydrophilic amino acids, counteracting the global trend. The C>U and G>U substitutions altered codons towards increased amino acid hydrophobicity values in more than 80% of cases. The bias is explained by the existing differences in the codon composition for amino acids bearing contrasting biochemical properties. Mutation asymmetries apparently influence the biochemical features of SARS CoV-2 proteins, which may impact protein-protein interactions, fusion of viral and cellular membranes, and virion assembly.


Assuntos
COVID-19/virologia , Genoma Viral , Interações Hidrofóbicas e Hidrofílicas , Mutação , SARS-CoV-2/genética , Proteínas Virais/química , Proteínas Virais/genética , Desaminases APOBEC , Alelos , Substituição de Aminoácidos , Aminoácidos/química , Aminoácidos/genética , Evolução Molecular , Variação Genética , Genótipo , Interações Hospedeiro-Patógeno , Humanos , Filogenia , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética
11.
Wiad Lek ; 74(5): 1200-1203, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34090290

RESUMO

OBJECTIVE: The aim: The objective of the study was to analyze the frequency of Arg16Gly polymorphism in the ß2 -adrenoceptor (ß2 -АR) gene in patients with bronchial asthma (BA) and to assess the association of the polymorphism with BA risk. PATIENTS AND METHODS: Materials and methods: We examined 553 BA patients and 95 apparently healthy individuals. Arg16Gly polymorphism in the ß2 -АR gene (rs1042713) was determined using polymerase chain reaction-restriction fragment length polymorphism analysis. Statistical analysis of obtained results was performed using SPSS-17 program. RESULTS: Results: It was established that distribution of Arg/Arg, Arg/Gly, and Gly/Gly genotypes for Arg16Gly polymorphism in the ß2 -АR gene was 44.2%, 40.0%, 15.8% in the control group vs. 31.3%; 45.7% and 23.0 among BA patients, respectively (χ2 = 6.59; р = 0.037). No significant difference was observed with regards to the distribution of genotypes for Arg16Gly polymorphism in the ß2 -АR gene in men and women controls (χ2 = 4.05; р = 0.13) and BA patients (χ2 = 4.34; р = 0.11). BA risk was 1.74 times higher in the minor allele carriers (Arg/Gly + Gly/Gly genotypes) for Arg16Gly polymorphism in the ß2 -АR gene. CONCLUSION: Conclusions: Analysis of Arg16Gly polymorphic variants in the ß2-AR gene showed a statistically significant difference in the distribution of Arg/Arg, Arg/Gly, and Gly/Gly genotypes in patients with BA and apparently healthy individuals due to the higher frequency of Arg/Arg genotype in controls and higher frequency of Gly/Gly genotype in patients with asthma. No difference with regard to gender was found in the distribution of genotypes.


Assuntos
Asma , Receptores Adrenérgicos beta 2 , Alelos , Asma/genética , Feminino , Genótipo , Humanos , Masculino , Polimorfismo Genético , Receptores Adrenérgicos beta 2/genética
12.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(6): 589-592, 2021 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-34096033

RESUMO

OBJECTIVE: To study the distribution of KIR3DL2 alleles among ethnic Han Chinese from Zhejiang. METHODS: Genomic DNA was extracted by using a magnetic bead method. The full sequence of the KIR3DL2 gene was amplified with four pairs by PCR primers. The coding regions of 208 unrelated ethnic Han Chinese blood donors were analyzed using a BigDye Terminator v3.1 Sequencing Kit. The genotypes were assigned based on the nucleotide polymorphism of the KIR3DL2 gene. RESULTS: Among the 208 samples, 133 were KIR3DL2 heterozygotes and 75 were homozygotes. Forty six KIR3DL2 genotypes were detected. Respectively, 70, 33 and 23 individuals were found to have a KIR3DL2*00201/KIR3DL2*00201, KIR3DL2*00201/KIR3DL2*00701, and KIR3DL2*00201/KIR3DL2*01001 genotype. Twenty-two KIR3DL2 alleles were discovered, and the frequencies of KIR3DL2*00201, KIR3DL2*00701 and KIR3DL2*01001 were 57.45%, 13.46% and 9.13%, respectively. CONCLUSION: The distribution of KIR3DL2 alleles among ethnic Han Chinese in Zhejiang has been determined and fits the criteria for genetic polymorphism.


Assuntos
Grupos Étnicos , Polimorfismo Genético , Alelos , China , Frequência do Gene , Humanos , Receptores KIR3DL2
13.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(3): 690-695, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34105458

RESUMO

OBJECTIVE: To investigate the relationship between single nucleotide polymorphisms (SNPs) of IKAROS family Zinc finger 3 (IKZF3) gene and the risk of acute lymphoblastic leukemia (ALL) in children. METHODS: The peripheral blood samples from 286 children with ALL and 382 healthy children were collected and divided into ALL group and control group, respectively. The genotypes of IKZF3 gene at rs62066988 C > T and rs12946510 C > T were detected by quantitative PCR with TaqMan detection system, and their correlation with ALL was analyzed. RESULTS: The distribution frequencies of CC, CT and TT genotypes at rs62066988 in ALL group were 58.39%, 37.06% and 4.55%, respectively, while those in control group were 69.19%, 27.68% and 3.13%, respectively. The distribution frequencies of CC, CT and TT genotypes at rs12946510 in ALL group were 58.16%, 34.75% and 7.09%, respectively, while those in control group were 55.76%, 37.43% and 6.81%, respectively. Compared with the control group, the distribution frequency of CT/TT genotype at rs62066988 was significantly increased in the ALL group (OR=1.59, 95%CI: 1.16-2.19, P=0.004). However, there was no significant difference in the distribution of rs12946510 C > T polymorphism between ALL group and control group. CONCLUSION: The CT/TT genotype of IKZF3 at the site of rs62066988 is associated with the increased risk of ALL in children.


Assuntos
Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras , Alelos , Estudos de Casos e Controles , Criança , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
14.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(3): 910-916, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34105493

RESUMO

OBJECTIVE: To investigate the indentification method of samples mistyped as O phenotype and to explore the precision transfusion strategy. METHODS: The blood samples from donors and patients admitted in our center from 2018 to 2019 was collected. The samples with O phenotype suspected subtypes were further determined by tube test, adsorption-elution test, etc. Molecular testing was used to sequence the related blood type genes of the subjects. RESULTS: Among 14 subjects misjudged as O, 11 different genotypes were identified, in which 3 blood donors were Ael02/O02, Bel03/O02, and one para-Bombay with B101/O02 (FUT1: h3h3; FUT2: Se357Se357); the genotypes of 11 patients were Ael02/O01, 2 cases with Ael02/O02, Ael08/O01, Aw37/O02, Aw43/O02, Bel03/O01, 3 cases with Bel03/O02, and one case was para-Bombay with A102/B101 (FUT1: h3h3; FUT2: Se357Se357). CONCLUSION: The phenotypes of Ael, Bel, Aw and para-Bombay subtypes are easily misjudged as type O. Molecular technology is helpful to identify the genotype of subtypes, and the corresponding transfusion strategies could be reasonably performed.


Assuntos
Sistema ABO de Grupos Sanguíneos , Transfusão de Sangue , Alelos , Fucosiltransferases/genética , Genótipo , Humanos , Fenótipo
15.
Int J Mol Sci ; 22(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068576

RESUMO

Apolipoprotein E (ApoE) is a protein that plays an important role in the transport of fatty acids and cholesterol and in cellular signaling. On the surface of the cells, ApoE lipoparticles bind to low density lipoprotein receptors (LDLR) that mediate the uptake of the lipids and downstream signaling events. There are three alleles of the human ApoE gene. Presence of ApoE4 allele is a major risk factor for developing Alzheimer's disease (AD) and other disorders late in life, but the mechanisms responsible for biological differences between different ApoE isoforms are not well understood. We here propose that the differences between ApoE isoforms can be explained by differences in the pH-dependence of the association between ApoE3 and ApoE4 isoforms and LDL-A repeats of LDLR. As a result, the following endocytosis ApoE3-associated LDLRs are recycled back to the plasma membrane but ApoE4-containing LDLR complexes are trapped in late endosomes and targeted for degradation. The proposed mechanism is predicted to lead to a reduction in steady-state surface levels of LDLRs and impaired cellular signaling in ApoE4-expressing cells. We hope that this proposal will stimulate experimental research in this direction that allows the testing of our hypothesis.


Assuntos
Apolipoproteína E3/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Receptores de LDL/genética , Alelos , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Endocitose/genética , Regulação da Expressão Gênica , Humanos , Isoformas de Proteínas/genética , Transdução de Sinais
18.
Nat Genet ; 53(5): 650-662, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33972799

RESUMO

In cancer cells, enhancer hijacking mediated by chromosomal alterations and/or increased deposition of acetylated histone H3 lysine 27 (H3K27ac) can support oncogene expression. However, how the chromatin conformation of enhancer-promoter interactions is affected by these events is unclear. In the present study, by comparing chromatin structure and H3K27ac levels in normal and lymphoma B cells, we show that enhancer-promoter-interacting regions assume different conformations according to the local abundance of H3K27ac. Genetic or pharmacological depletion of H3K27ac decreases the frequency and the spreading of these interactions, altering oncogene expression. Moreover, enhancer hijacking mediated by chromosomal translocations influences the epigenetic status of the regions flanking the breakpoint, prompting the formation of distinct intrachromosomal interactions in the two homologous chromosomes. These interactions are accompanied by allele-specific gene expression changes. Overall, our work indicates that H3K27ac dynamics modulates interaction frequency between regulatory regions and can lead to allele-specific chromatin configurations to sustain oncogene expression.


Assuntos
Alelos , Cromatina/química , Loci Gênicos , Histonas/metabolismo , Conformação de Ácido Nucleico , Oncogenes , Acetilação , Pareamento de Bases/genética , Linhagem Celular Tumoral , Elementos Facilitadores Genéticos , Epigênese Genética , Dosagem de Genes , Humanos , Lisina/metabolismo , Regiões Promotoras Genéticas
19.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(5): 496-498, 2021 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-33974265

RESUMO

OBJECTIVE: To delineate the serological and molecular profiles of a patient with A(w)37B subtype. METHODS: The ABO bloodtypes of the proband, his wife and daughter were determined with a standard serological method. Their ABO genotypes were determined by sequence-specific primer polymerase chain reaction (PCR-SSP). All exons of the ABO gene were directly sequenced. Exons 6 and 7 of the ABO gene were further analyzed by cloning and sequencing. RESULTS: The red blood cells of the proband showed a weak B phenotype. His serum sample contained weak reactive anti-A antibody, which was defined as A(w)B blood group based on the serological characteristics. The A and B alleles were detected by blood group genotyping. Gene cloning and sequencing have identified a characteristic c.940A>G variant (ABO*AW.37) in exon 7 of the ABO gene, which resulted in substitution of Lysine by Glutamate at position 314. The proband's daughter has inherited the ABO*AW.37 allele. CONCLUSION: The c.940A>G variant in exon 7 of the ABO gene probably underlay the decreased activity of GTA transferase and resulted in the Aw37 phenotype.


Assuntos
Sistema ABO de Grupos Sanguíneos , Sistema ABO de Grupos Sanguíneos/genética , Alelos , Genótipo , Humanos , Linhagem , Fenótipo
20.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(5): 499-502, 2021 May 10.
Artigo em Chinês | MEDLINE | ID: mdl-33974266

RESUMO

OBJECTIVE: To study the serological, molecular and genetic characteristics of an individual with para-Bombay blood group. METHODS: Serological method was used to detect the presence of A, B, H antigens in red blood cells and saliva, and Sanger sequencing was used to analyze the FUT1 gene of the proband and her family members. Genetic mechanism of the blood group was analyzed by pedigree analysis. RESULTS: Forward and reverse typing of the ABO blood group were inconsistent for the proband. A, B and H antigens were not found on erythrocytes, while B and H antigens were found in saliva, in addition with unexpected antibodies. The proband was found to have a genotype of ABO*B.01/ABO*O.01.04 caused by homozygous variant of c.948C>A (p.Tyr316Ter) of the FUT1 gene. CONCLUSION: A novel para-Bombay blood group was identified, which was due to the missense variant of c.948C>A in the coding region of the FUT1 gene, which has probably resulted in inability to synthesis active H antigen transferase.


Assuntos
Sistema ABO de Grupos Sanguíneos , Fucosiltransferases , Sistema ABO de Grupos Sanguíneos/genética , Alelos , Feminino , Fucosiltransferases/genética , Genótipo , Homozigoto , Humanos , Fenótipo
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