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1.
Front Immunol ; 11: 2008, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013857

RESUMO

Coronavirus disease (COVID-19), caused by the virus SARS-CoV-2, is already responsible for more than 4.3 million confirmed cases and 295,000 deaths worldwide as of May 15, 2020. Ongoing efforts to control the pandemic include the development of peptide-based vaccines and diagnostic tests. In these approaches, HLA allelic diversity plays a crucial role. Despite its importance, current knowledge of HLA allele frequencies in South America is very limited. In this study, we have performed a literature review of datasets reporting HLA frequencies of South American populations, available in scientific literature and/or in the Allele Frequency Net Database. This allowed us to enrich the current scenario with more than 12.8 million data points. As a result, we are presenting updated HLA allelic frequencies based on country, including 91 alleles that were previously thought to have frequencies either under 5% or of an unknown value. Using alleles with an updated frequency of at least ≥5% in any South American country, we predicted epitopes in SARS-CoV-2 proteins using NetMHCpan (I and II) and MHC flurry. Then, the best predicted epitopes (class-I and -II) were selected based on their binding to South American alleles (Coverage Score). Class II predicted epitopes were also filtered based on their three-dimensional exposure. We obtained 14 class-I and four class-II candidate epitopes with experimental evidence (reported in the Immune Epitope Database and Analysis Resource), having good coverage scores for South America. Additionally, we are presenting 13 HLA-I and 30 HLA-II novel candidate epitopes without experimental evidence, including 16 class-II candidates in highly exposed conserved areas of the NTD and RBD regions of the Spike protein. These novel candidates have even better coverage scores for South America than those with experimental evidence. Finally, we show that recent similar studies presenting candidate epitopes also predicted some of our candidates but discarded them in the selection process, resulting in candidates with suboptimal coverage for South America. In conclusion, the candidate epitopes presented provide valuable information for the development of epitope-based strategies against SARS-CoV-2, such as peptide vaccines and diagnostic tests. Additionally, the updated HLA allelic frequencies provide a better representation of South America and may impact different immunogenetic studies.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/imunologia , Epitopos de Linfócito T/imunologia , Frequência do Gene , Antígenos HLA/genética , Pneumonia Viral/epidemiologia , Pneumonia Viral/imunologia , Proteínas do Envelope Viral/imunologia , Alelos , Sequência de Aminoácidos , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Variação Genética , Humanos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , América do Sul/epidemiologia , Vacinas de Subunidades/imunologia , Vacinas Virais/imunologia
2.
Medicine (Baltimore) ; 99(40): e22614, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019481

RESUMO

BACKGROUND: The relationship between MTHFR (5, 10-methylene tetrahydrofolate reductase) gene polymorphisms and Systemic Lupus Erythematosus (SLE) has been wildly studied, but the results are still conflicting. Therefore, the purpose of this meta and pooled analysis was to identify the role of the MTHFR SNP (single nucleotide polymorphism, rs1801133) in SLE in a large sample of subjects and to assess the risk of SLE. METHODS: Data were collected from EMBASE, PubMed and China National Knowledge Infrastructure from inception to August, 2019. Summary odds ratio (OR) with 95% confidence interval (CI) was applied to assess the association. Subgroup and sensitivity analysis were performed to assess the potential sources of heterogeneity of the pooled estimation. RESULTS: We identified seven eligible studies involving 882 cases and 991 controls. MTHFR rs1801133 T carrier was significantly associated with increased risk of SLE when comparing to C allele [ORs were 1.766 (1.014-3.075) for T carrier vs CC, P = .04]. Furthermore, the results of the subgroup analysis by genotyping methods suggested that T allele significantly contributed to the risk of SLE for both by polymerase chain reaction-TaqMan (PCR-TaqMan) [10.111 (2.634-38.813) for TT vs CC, 3.467 (1.324-9.078) for CT vs CC and 3.744 (1.143-12.264) for TT vs C carrier]. Also the results of the subgroup analysis by ethnicity suggested that T allele significantly contributed to the risk of SLE for Asians [9.679 (4.444-21.082) for TT vs CC, 5.866 (3.021-11.389) for T carrier vs CC and 8.052 (3.861-16.795) for TT vs C carrier]. CONCLUSION: This cumulative meta-analysis showed that the MTHFR SNP (rs1801133) contributed to susceptibility of SLE. However, more multicentre well-designed case-control studies and larger sample sizes are exceedingly required to validate our findings in the future.


Assuntos
Lúpus Eritematoso Sistêmico/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Portador Sadio , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Lúpus Eritematoso Sistêmico/etnologia , Masculino , Medição de Risco , Sensibilidade e Especificidade
3.
Wiad Lek ; 73(8): 1637-1640, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33055325

RESUMO

OBJECTIVE: The aim: To examine the association between polymorphisms of the IL-6 gene promoter and HF in patients with CAD and obesity. PATIENTS AND METHODS: Material and methods: 222 patients with coronary artery disease and obesity were identified. Comparison group consisted of 115 patients with coronary artery disease with normal body weight. The groups were comparable in age and sex. The exclusion group consisted of patients with severe concomitant diseases of the respiratory and digestive organs, kidneys and people with cancer. One single nucleotide polymorphisms in the interleukin-6 promoter region was analyzed. Odds ratio (OR) and 95 % confident interval (95 % CI) were calculated. RESULTS: Results: The combined course of coronary artery disease and obesity was characterized by the detection of allele C in 62 patients (27.93 %), allele G - in 160 patients (72.07 %), and genotypes CC, CG and GG - at 24 (10.81 %), 67 (30.18 %) and 131 (59.01 %) patients respectively. The results showed that the -174G allele and GG genotype in patients with coronary artery disease and obesity were associated with heart failure (OR = 2.55, 95% CI = [1.72-3.79], χ2 = 22.8; p<0.05) and (OR = 11.95, 95% CI = [3.41-41.91], χ2 = 22.5; p<0.05), whereas allele C-174 was associated with a decrease in the risk of heart failure (OR = 0.39, 95% CI = [0.26-0.58 ], χ2 = 22.75, p<0.05). CONCLUSION: Conclusions: The obtained results testify that the -174G>C polymorphism in the interleukin-6 gene is significantly associated with increased risk of heart failure in patients with coronary artery disease and obesity.


Assuntos
Doença da Artéria Coronariana , Insuficiência Cardíaca , Alelos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/genética , Insuficiência Cardíaca/genética , Humanos , Interleucina-6/genética , Obesidade/complicações , Obesidade/genética
4.
Yi Chuan ; 42(9): 889-897, 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32952123

RESUMO

Osteoporosis is a typical polygenic disease, and its heritability is as high as 85%. The incidence of osteoporosis has jumped to the fifth among the common diseases. Although a large number of osteoporosis-susceptible SNPs have been identified, most of them are in the non-coding regions of the genome and the functional mechanisms are unknown. The purpose of this study was to explore the function of non-coding osteoporosis-susceptible SNP rs4325274 and dissect the molecular regulatory mechanisms through integrating bioinformatics analysis and functional experiments. Firstly, we found the SNP rs4325274 resided in a putative enhancer element through functional annotation. eQTL and Hi-C analysis found that the SOX6 gene might be a potential distal target of rs4325274. We conducted the motif prediction using multiple databases and verified the result using ChIP-seq data from GEO database. The result showed that the transcription factor HNF1A could preferentially bind to SNP rs4325274-G allele. We further demonstrated that SNP rs4325274 acted as an enhancer regulating SOX6 gene expression by using dual-luciferase reporter assays. Knockdown of HNF1A decreased the SOX6 gene expression. Taken together, our results uncovered a new mechanism of a non-coding functional SNP rs4325274 as a distal enhancer to modulate SOX6 expression, which provides new insights into deciphering molecular regulatory mechanisms underlying non-coding susceptibility SNPs on complex diseases.


Assuntos
Osteoporose , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição SOXD/genética , Alelos , Predisposição Genética para Doença , Humanos , Osteoporose/genética , Locos de Características Quantitativas
6.
Nat Commun ; 11(1): 4593, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929070

RESUMO

Gene-targeted animal models that are generated by injecting Cas9 and sgRNAs into zygotes are often accompanied by undesired double-strand break (DSB)-induced byproducts and random biallelic targeting due to uncontrollable Cas9 targeting activity. Here, we establish a parental allele-specific gene-targeting (Past-CRISPR) method, based on the detailed observation that pronuclear transfer-mediated cytoplasmic dilution can effectively terminate Cas9 activity. We apply this method in embryos to efficiently target the given parental alleles of a gene of interest and observed little genomic mosaicism because of the spatiotemporal control of Cas9 activity. This method allows us to rapidly explore the function of individual parent-of-origin effects and to construct animal models with a single genomic change. More importantly, Past-CRISPR could also be used for therapeutic applications or disease model construction.


Assuntos
Alelos , Sistemas CRISPR-Cas/genética , Núcleo Celular/genética , Edição de Genes , Terapia de Substituição Mitocondrial , Animais , Sequência de Bases , Modelos Animais de Doenças , Nanismo/genética , Perda do Embrião/genética , Feminino , Marcação de Genes , Genes Dominantes , Impressão Genômica , Heterozigoto , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Reprodutibilidade dos Testes , Fatores de Tempo
7.
Nat Commun ; 11(1): 4703, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943643

RESUMO

Deep learning models have shown great promise in predicting regulatory effects from DNA sequence, but their informativeness for human complex diseases is not fully understood. Here, we evaluate genome-wide SNP annotations from two previous deep learning models, DeepSEA and Basenji, by applying stratified LD score regression to 41 diseases and traits (average N = 320K), conditioning on a broad set of coding, conserved and regulatory annotations. We aggregated annotations across all (respectively blood or brain) tissues/cell-types in meta-analyses across all (respectively 11 blood or 8 brain) traits. The annotations were highly enriched for disease heritability, but produced only limited conditionally significant results: non-tissue-specific and brain-specific Basenji-H3K4me3 for all traits and brain traits respectively. We conclude that deep learning models have yet to achieve their full potential to provide considerable unique information for complex disease, and that their conditional informativeness for disease cannot be inferred from their accuracy in predicting regulatory annotations.


Assuntos
Aprendizado Profundo , Doença/genética , Anotação de Sequência Molecular , Alelos , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla , Histonas/genética , Humanos , Desequilíbrio de Ligação , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único
8.
Medicine (Baltimore) ; 99(35): e21704, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871888

RESUMO

To explore the relationship between C3435T polymorphism of multi-drug resistance gene (MDR1) gene and susceptibility, clinicopathological characteristics, curative effect and hematological toxicity of diffuse large B-cell lymphoma (DLBCL) in XinJiang.The peripheral venous blood samples of 54 patients with DLBCL and 60 healthy controls were collected. The alleles and genotypes of MDR1 gene C3435T were detected by DNA direct extraction with PCR technique, and the frequency of C3435T allele and genotypes were detected by the chi-square test. The relationship between the allele and genotype distribution of C3435T locus and the susceptibility, clinicopathological characteristics, curative effect and hematological toxicity of DLBCL were analyzed.1 the frequency of CT heterozygote and CC homozygote mutation was significantly higher in the case group (46.3% in CT genotype and 42.6% in CC genotype) compared to the control group (P < 0.05). The frequency of CC genotype mutation in the case group was 42.6%, which was significantly higher than that in the control group (P < 0.05, OR 3.209, 95% CI: 1.288-7.997). 2 the genotypes of C3435T locus of MDR1 gene were distributed in age, sex, nationality, pathological characteristics, clinical-stage, IPI index, B symptoms, infection with EB virus, clinicopathological characteristics and clinical efficacy of hepatitis B in patients with DLBCL. There was no significant difference in myelosuppression (P > 0.05).The homozygous mutation genotype of CC is the risk genotype of DLBCL. The alleles and genotypes are not associated with the clinicopathological characteristics, efficacy and myelosuppression toxicity of DLBCL.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , China , Feminino , Heterozigoto , Homozigoto , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
9.
Medicine (Baltimore) ; 99(39): e22319, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991440

RESUMO

OBJECTIVE: Postpartum depression (PPD) is an episode of major depressive disorder that affecting women of childbearing age. 5-HTTLPR is 1 of the most extensively investigated polymorphisms in PPD. However, the previous results were inconsistent and inclusive. Hence, we performed a meta-analysis to precisely evaluate the association between 5-HTTLPR polymorphism and PPD susceptibility. METHODS: The studies were retrieved through databases including PubMed, web of science, EMASE, and CNKI. The odd ratios (ORs) and 95% confidence interval (CIs) were applied for evaluating the genetic association between 5-HTTLPR (L/S) polymorphism and PPD risk. RESULTS: Six studies with 519 cases and 737 controls were enrolled in the present study. The frequencies of allelic (OR = 0.72, 95%CI = 0.60-0.85, P = .0001) and dominant (OR = 0.57, 95%CI = 0.44-0.73, P = .004) models of 5-HTTLPR polymorphism significantly decreased in patients with PPD than those in the healthy controls. Subgroup analysis based on ethnicity revealed that the allelic (OR = 0.71, 95%CI = 0.60-0.85, P = .0001) and dominant (OR = 0.51, 95%CI = 0.32-0.79, P = .003) models of 5-HTTLPR polymorphism were significantly associated with PPD risk in Asian population (P > .05). No evidence was observed between the recessive model of 5-HTTLPR polymorphism and PPD risk (P > .05). CONCLUSIONS: The allelic and dominant models of 5-HTTLPR polymorphism might be protective factors for PPD. To confirm these results, larger number of association studies or multicenter case-control studies are necessary in the future.


Assuntos
Depressão Pós-Parto/genética , Transtorno Depressivo Maior/psicologia , Polimorfismo de Nucleotídeo Único/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Depressão Pós-Parto/epidemiologia , Feminino , Predisposição Genética para Doença/epidemiologia , Humanos , Incidência , Gravidez
10.
Anticancer Res ; 40(10): 5503-5508, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988873

RESUMO

BACKGROUND/AIM: Accumulating evidence shows that caspase-8 (Cas-8) rs3834129 genotypes determine susceptibility to various cancers, but their association with nasopharyngeal carcinoma (NPC) has not been examined. We aimed at investigating the association of Cas-8 rs3834129 with NPC risk. MATERIALS AND METHODS: Cas-8 rs3834129 genotypes and their associations with NPC risk were investigated among 176 NPC patients and 352 non-cancer subjects by the PCR-RFLP method. Additionally, the interaction of Cas-8 rs3834129 genotypes with smoking was examined. RESULTS: The II, ID and DD frequencies were 56.8, 36.9 and 6.3% among NPC patients and 54.8, 38.1 and 7.1% among control subjects (ptrend=0.8830). Allelic frequency distribution analysis also indicated that the D allele is not a risk factor for NPC (p=0.6183). There was no interaction between Cas-8 rs3834129 and smoking and NPC risk (p=0.8305). CONCLUSION: Cas-8 rs3834129 genotypes play a minor role in the risk for NPC.


Assuntos
Caspase 8/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Carcinoma Nasofaríngeo/genética , Alelos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/epidemiologia , Carcinoma Nasofaríngeo/patologia , Polimorfismo de Fragmento de Restrição/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Fatores de Risco , Fumar , Taiwan
11.
Anticancer Res ; 40(10): 5751-5756, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988902

RESUMO

BACKGROUND/AIM: A single study has shown positive association and genotype-phenotype correlation between metalloproteinase-9 (MMP-9) promoter genotypes and adult acute lymphocytic leukemia (ALL). However, there is no report about childhood ALL. Thus, this study aimed at examining the role of MMP-9 rs3918242 genotypes in childhood ALL risk. PATIENTS AND METHODS: A total of 266 childhood ALL cases and 266 healthy controls in Taiwan were examined for their MMP-9 rs3918242 genotypes via polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The MMP-9 rs3918242 CT or TT genotype carriers only had a slightly increased risk compared with CC carriers (p=0.6386 and 0.6005, respectively). The allelic frequency analysis also supported the idea that the variant T allele at MMP-9 rs3918242 is not differentially distributed between the case and control groups (p=0.4834). CONCLUSION: MMP-9 rs3918242 genotypes may indirectly influence the risk of childhood ALL. Further validations in other populations and analysis of the detail mechanisms are needed.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Metaloproteinase 9 da Matriz/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adulto , Alelos , Criança , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Regiões Promotoras Genéticas/genética
12.
PLoS One ; 15(8): e0237808, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32866209

RESUMO

In this study, we performed an analysis of the impact of performance enhancing polymorphisms (PEPs) on gymnastic aptitude while considering epistatic effects. Seven PEPs (rs1815739, rs8192678, rs4253778, rs6265, rs5443, rs1076560, rs362584) were considered in a case (gymnasts)-control (sedentary individuals) setting. The study sample comprised of two athletes' sets: 27 elite (aged 24.8 ± 2.1 years) and 46 sub-elite (aged 19.7 ± 2.4 years) sportsmen as well as a control group of 245 sedentary individuals (aged 22.5 ± 2.1 years). The DNA was derived from saliva and PEP alleles were determined by PCR, RT-PCR. Following Multifactor Dimensionality Reduction, logistic regression models were built. The synergistic effect for rs1815739 x rs362584 reached 5.43%. The rs1815739 x rs362584 epistatic regression model exhibited a good fit to the data (Chi-squared = 33.758, p ≈ 0) achieving a significant improvement in sportsmen identification over naïve guessing. The area under the receiver operating characteristic curve was 0.715 (Z-score = 38.917, p ≈ 0). In contrast, the additive ACTN3 -SNAP-25 logistic regression model has been verified as non-significant. We demonstrate that a gene involved in the differentiation of muscle architecture-ACTN3 and a gene, which plays an important role in the nervous system-SNAP-25 interact. From the perspective originally established by the Berlin Academy of Science in 1751, the matter of communication between the brain and muscles via nerves adopts molecular manifestations. Further in-vitro investigations are required to explain the molecular details of the rs1815739 -rs362584 interaction.


Assuntos
Actinina/genética , Aptidão , Epistasia Genética , Ginástica/fisiologia , Proteína 25 Associada a Sinaptossoma/genética , Adulto , Alelos , Área Sob a Curva , Bases de Dados Genéticas , Entropia , Feminino , Marcadores Genéticos , Humanos , Modelos Logísticos , Masculino , Modelos Genéticos , Redução Dimensional com Múltiplos Fatores , Polimorfismo de Nucleotídeo Único/genética , Adulto Jovem
13.
Medicine (Baltimore) ; 99(35): e21488, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871870

RESUMO

BACKGROUND: Celiac disease is an autoimmune enteropathy characterized by an aberrant immune response to ingested gluten in genetically predisposed individuals. Studies have pointed to a rising prevalence of celiac disease in recent decades. Changes in diet and use of medication that may impact the gut microbiome have been suggested as potential contributors. Exposure to protein pump inhibitors (PPIs) was recently found to be associated with an increased risk for subsequent diagnosis of celiac disease. We aimed to investigate potential mechanisms for this link by examining the relationship between PPI use and gluten-related immune responses in the context of changes in gut microbiome. METHODS: We performed a post hoc analysis of blood and fecal samples from a recent randomized trial in order to assess the potential association between PPI use and development of celiac disease serology in conjunction with alterations in gastrointestinal microbial composition. The study included 12 healthy participants who were administered a PPI (Omeprazole; 40 mg twice daily) for 4 or 8 weeks. RESULTS: The analysis did not reveal an overall significant change in levels of serologic markers of celiac disease for the study cohort in response to PPI treatment. However, one individual developed a marked increase in the celiac disease-specific autoantibody response to transglutaminase 2 in conjunction with enhanced immune reactivity to gluten during the trial. Genotyping revealed positivity for the celiac disease-associated HLA-DQ2 and -DQ8 alleles. Furthermore, the observed elevation in antibody responses was closely associated with a sharp increase in fecal abundance of bacteria of the order Actinomycetales. CONCLUSIONS: The results of this exploratory analysis support further investigation of molecular mechanisms involved in the contribution of PPIs to celiac disease risk through the potential enhancement of gluten immunopathology and changes in gut microbial population.


Assuntos
Doença Celíaca/sangue , Doença Celíaca/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Omeprazol/efeitos adversos , Inibidores da Bomba de Prótons/efeitos adversos , Actinomycetales/crescimento & desenvolvimento , Adulto , Alelos , Doença Celíaca/epidemiologia , Doença Celíaca/metabolismo , Fezes/microbiologia , Feminino , Proteínas de Ligação ao GTP/sangue , Proteínas de Ligação ao GTP/efeitos dos fármacos , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/microbiologia , Genótipo , Glutens/efeitos adversos , Glutens/imunologia , Antígenos HLA-DQ/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Omeprazol/administração & dosagem , Omeprazol/uso terapêutico , Prevalência , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/uso terapêutico , Transglutaminases/sangue , Transglutaminases/efeitos dos fármacos
14.
Medicine (Baltimore) ; 99(35): e21558, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871871

RESUMO

BACKGROUND: As indicated by numerous studies, there exists a relationship between the polymorphism of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to diabetic nephropathy (DN) in various populations; nonetheless, the findings remain inconsistent. Therefore, we carried out a meta-analysis to determine the relationship between the MTHFR gene polymorphism and DN susceptibility. MATERIALS AND METHOD: Related studies were identified from PubMed, Cochrane Library, EMBASE, and the China National Knowledge Infrastructure database (time period: from building the library to October 2019). The strength of the association was examined using odds ratios (ORs) with 95% confidence intervals (95% CIs). RESULTS: The findings illustrated that the C677T gene polymorphism was significantly associated with an enhanced susceptibility to DN compared to that with diabetes mellitus in allelic (OR = 1.64, 95% CI = 1.34-2.00, P < .001), dominant (OR = 1.85, 95% CI = 1.40-2.46, P < .001), codominant (heterozygote: OR = 1.67, 95% CI = 1.27-2.21, P < .001; homozygote: OR = 2.55, 95% CI = 1.82-3.57, P < .001), and recessive (OR = 1.89, 95% CI = 1.50-2.38, P < .001) models of the overall population. Moreover, as compared with the healthy controls, a significantly augmented susceptibility to DN was found in all 5 genetic comparison models (allelic: OR = 2.06, 95% CI = 1.58-2.67, P < .001; dominant: OR = 2.52, 95% CI = 1.73-3.69, P < .001; codominant: OR = 3.78, 95% CI = 2.50-5.70, P < .001; recessive: OR = 2.41, 95% CI = 1.96-2.97, P < .001). Furthermore, stratifying data by ethnicity revealed substantially augmented vulnerability to DN in not only Caucasian but also Asian populations. CONCLUSION: The present study suggests that the C677T polymorphism was associated with an augmented susceptibility to DN.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/epidemiologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/epidemiologia , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Humanos , Fatores de Risco
15.
Nat Commun ; 11(1): 4505, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908148

RESUMO

Evidence for transgenerational inheritance of epigenetic information in vertebrates is scarce. Aberrant patterns of DNA methylation in gametes may set the stage for transmission into future generations. Here, we describe a viable hypomorphic allele of dnmt1 in zebrafish that causes widespread demethylation of CpG dinucleotides in sperm and somatic tissues. We find that homozygous mutants are essentially normal, with the exception of drastically impaired lymphopoiesis, affecting both larval and adult phases of T cell development. The phenotype of impaired larval (but not adult) T cell development is transmitted to subsequent generations by genotypically wildtype fish. We further find that about 200 differentially methylated regions in sperm DNA of transmitting and non-transmitting males, including hypermethylated sites associated with runx3 and rptor genes, whose reduced activities are associated with impaired larval T cell development. Our results indicate a particular sensitivity of larval T cell development to transgenerationally inherited epimutations.


Assuntos
Diferenciação Celular/genética , Genes Recessivos , Larva/crescimento & desenvolvimento , Linfopoese/genética , Linfócitos T/fisiologia , Alelos , Animais , Animais Geneticamente Modificados , Subunidade alfa 3 de Fator de Ligação ao Core/genética , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Metilação de DNA , Epigênese Genética , Feminino , Genética , Larva/citologia , Masculino , Mutação , Proteína Regulatória Associada a mTOR/genética , Espermatozoides/metabolismo , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
16.
Nat Commun ; 11(1): 4572, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917907

RESUMO

Undomesticated wild species, crop wild relatives, and landraces represent sources of variation for wheat improvement to address challenges from climate change and the growing human population. Here, we study 56,342 domesticated hexaploid, 18,946 domesticated tetraploid and 3,903 crop wild relatives in a massive-scale genotyping and diversity analysis. Using DArTseqTM technology, we identify more than 300,000 high-quality SNPs and SilicoDArT markers and align them to three reference maps: the IWGSC RefSeq v1.0 genome assembly, the durum wheat genome assembly (cv. Svevo), and the DArT genetic map. On average, 72% of the markers are uniquely placed on these maps and 50% are linked to genes. The analysis reveals landraces with unexplored diversity and genetic footprints defined by regions under selection. This provides fertile ground to develop wheat varieties of the future by exploring specific gene or chromosome regions and identifying germplasm conserving allelic diversity missing in current breeding programs.


Assuntos
Variação Genética , Genoma de Planta , Triticum/genética , Alelos , Domesticação , Genótipo , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Alinhamento de Sequência , Tetraploidia
17.
Nat Commun ; 11(1): 4603, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929079

RESUMO

Amino acid propensities at a site change in the course of protein evolution. This may happen for two reasons. Changes may be triggered by substitutions at epistatically interacting sites elsewhere in the genome. Alternatively, they may arise due to environmental changes that are external to the genome. Here, we design a framework for distinguishing between these alternatives. Using analytical modelling and simulations, we show that they cause opposite dynamics of the fitness of the allele currently occupying the site: it tends to increase with the time since its origin due to epistasis ("entrenchment"), but to decrease due to random environmental fluctuations ("senescence"). By analysing the genomes of vertebrates and insects, we show that the amino acids originating at negatively selected sites experience strong entrenchment. By contrast, the amino acids originating at positively selected sites experience senescence. We propose that senescence of the current allele is a cause of adaptive evolution.


Assuntos
Aminoácidos/genética , Evolução Molecular , Alelos , Sequência de Aminoácidos , Animais , Simulação por Computador , Meio Ambiente , Genes Mitocondriais , Aptidão Genética , Heterogeneidade Genética , Insetos/genética , Seleção Genética , Vertebrados/genética
18.
Medicine (Baltimore) ; 99(36): e21946, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899028

RESUMO

Autism spectrum disorder (ASD) is a form of pervasive developmental disorder manifested by impairment in social interactions and repetitive behaviors. Although genetic contribution is strongly suspected in autism, the specific genetic factors remain unidentified. Hyperserotoninemia has been reported in some autistic patients, and several studies have demonstrated an association between 5-hydroxytryptamine-transporter-linked promoter region (5-HTTLPR) polymorphisms and rs25531 single nucleotide polymorphism in the serotonin transporter gene (solute carrier family 6 member 4; SLC6A4) and ASD, indicating a possible involvement of the serotonin system in the etiology of ASD.To explore this situation further, a case-control association study of 5-HTTLPR and rs25531 polymorphisms on Thai ASD patients was conducted. A total of 188 ASD cases fulfilling the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria (156 males and 32 females) and a total of 250 normal controls were recruited from the same ethnic backgrounds. 5-HTTLPR polymorphisms (Long, L; Short, S) and rs25531 (A/G) single nucleotide polymorphism were genotyped and compared between the patients and normal controls using chi-square statistics.The L/L genotype was more common in patients than in the controls (13.8% vs 5.2%, P = .006), and the LA haplotype was found in patients more than the controls (16.9% vs 12.2%, P = .048). When male patients were analyzed alone (156 individuals), the associations were also statistically significant with P = .017 for L/L genotype, and P = .019 for LA haplotype distribution.Our findings support previous reports suggesting an association between the 5-HTTLPR and rs25531 polymorphisms of SLC6A4 and patients with ASD.


Assuntos
Transtorno do Espectro Autista/genética , Predisposição Genética para Doença , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Alelos , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Tailândia
19.
Medicine (Baltimore) ; 99(30): e21331, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791730

RESUMO

The aim of this study was to elucidate the possible association between migration inhibitory factor (MIF)-173G/C gene polymorphisms and transcript and plasma levels of MIF in spinal tuberculosis (TB) patients. Clinical data were collected from 254 spinal TB patients and 262 healthy controls participating in the study. The genotype of the MIF-173G/C gene was amplified by polymerase chain reaction and genotyped by DNA sequencing technology. The level of mRNA expression was determined by real-time polymerase chain reaction and MIF plasma levels were measured by a solid-phase enzyme-linked immunosorbent assay. The frequency of the C allele and GC+CC genotype in MIF-173G/C was over-represented in spinal TB patients. The mean MIF mRNA level in spinal TB patients and patients with the GG and GC+CC genotype were significantly lower than controls; however, our study also indicated that the MIF concentration in spinal TB patients and patients with the GG and GC+CC genotypes were significantly higher than controls. Spinal TB patients with the GG genotype had higher MIF plasma levels than patients with the GC+CC genotype. The C-reactive protein level and erythrocyte sedimentation rate was correlated with the MIF plasma level. In summary, the association between the MIF-173G/C genetic polymorphism, reduced transcript and increased plasma levels of MIF in spinal TB patients, and MIF may play an important role in the occurrence, development, and damage of spinal TB in the northern Province population of China.


Assuntos
Fatores Inibidores da Migração de Macrófagos/sangue , Polimorfismo Genético/genética , RNA Mensageiro/genética , Tuberculose da Coluna Vertebral/genética , Adulto , Alelos , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , China/epidemiologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Análise de Sequência de DNA/métodos
20.
Genome Med ; 12(1): 70, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32791978

RESUMO

BACKGROUND: The ongoing COVID-19 pandemic has created an urgency to identify novel vaccine targets for protective immunity against SARS-CoV-2. Early reports identify protective roles for both humoral and cell-mediated immunity for SARS-CoV-2. METHODS: We leveraged our bioinformatics binding prediction tools for human leukocyte antigen (HLA)-I and HLA-II alleles that were developed using mass spectrometry-based profiling of individual HLA-I and HLA-II alleles to predict peptide binding to diverse allele sets. We applied these binding predictors to viral genomes from the Coronaviridae family and specifically focused on T cell epitopes from SARS-CoV-2 proteins. We assayed a subset of these epitopes in a T cell induction assay for their ability to elicit CD8+ T cell responses. RESULTS: We first validated HLA-I and HLA-II predictions on Coronaviridae family epitopes deposited in the Virus Pathogen Database and Analysis Resource (ViPR) database. We then utilized our HLA-I and HLA-II predictors to identify 11,897 HLA-I and 8046 HLA-II candidate peptides which were highly ranked for binding across 13 open reading frames (ORFs) of SARS-CoV-2. These peptides are predicted to provide over 99% allele coverage for the US, European, and Asian populations. From our SARS-CoV-2-predicted peptide-HLA-I allele pairs, 374 pairs identically matched what was previously reported in the ViPR database, originating from other coronaviruses with identical sequences. Of these pairs, 333 (89%) had a positive HLA binding assay result, reinforcing the validity of our predictions. We then demonstrated that a subset of these highly predicted epitopes were immunogenic based on their recognition by specific CD8+ T cells in healthy human donor peripheral blood mononuclear cells (PBMCs). Finally, we characterized the expression of SARS-CoV-2 proteins in virally infected cells to prioritize those which could be potential targets for T cell immunity. CONCLUSIONS: Using our bioinformatics platform, we identify multiple putative epitopes that are potential targets for CD4+ and CD8+ T cells, whose HLA binding properties cover nearly the entire population. We also confirm that our binding predictors can predict epitopes eliciting CD8+ T cell responses from multiple SARS-CoV-2 proteins. Protein expression and population HLA allele coverage, combined with the ability to identify T cell epitopes, should be considered in SARS-CoV-2 vaccine design strategies and immune monitoring.


Assuntos
Infecções por Coronavirus/imunologia , Epitopos/imunologia , Antígenos HLA/imunologia , Pneumonia Viral/imunologia , Linfócitos T/imunologia , Vacinas Virais/imunologia , Alelos , Afinidade de Anticorpos , Biologia Computacional , Infecções por Coronavirus/genética , Infecções por Coronavirus/prevenção & controle , Epitopos/química , Epitopos/genética , Genoma Viral , Antígenos HLA/química , Antígenos HLA/genética , Humanos , Imunogenicidade da Vacina , Espectrometria de Massas , Pandemias , Vacinas Virais/química , Vacinas Virais/genética
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