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1.
BMC Bioinformatics ; 22(1): 417, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34470617

RESUMO

BACKGROUND: Variation in mitochondrial DNA (mtDNA) identified by genotyping microarrays or by sequencing only the hypervariable regions of the genome may be insufficient to reliably assign mitochondrial genomes to phylogenetic lineages or haplogroups. This lack of resolution can limit functional and clinical interpretation of a substantial body of existing mtDNA data. To address this limitation, we developed and evaluated a large, curated reference alignment of complete mtDNA sequences as part of a pipeline for imputing missing mtDNA single nucleotide variants (mtSNVs). We call our reference alignment and pipeline MitoImpute. RESULTS: We aligned the sequences of 36,960 complete human mitochondrial genomes downloaded from GenBank, filtered and controlled for quality. These sequences were reformatted for use in imputation software, IMPUTE2. We assessed the imputation accuracy of MitoImpute by measuring haplogroup and genotype concordance in data from the 1000 Genomes Project and the Alzheimer's Disease Neuroimaging Initiative (ADNI). The mean improvement of haplogroup assignment in the 1000 Genomes samples was 42.7% (Matthew's correlation coefficient = 0.64). In the ADNI cohort, we imputed missing single nucleotide variants. CONCLUSION: These results show that our reference alignment and panel can be used to impute missing mtSNVs in existing data obtained from using microarrays, thereby broadening the scope of functional and clinical investigation of mtDNA. This improvement may be particularly useful in studies where participants have been recruited over time and mtDNA data obtained using different methods, enabling better integration of early data collected using less accurate methods with more recent sequence data.


Assuntos
DNA Mitocondrial , Polimorfismo de Nucleotídeo Único , DNA Mitocondrial/genética , Frequência do Gene , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Filogenia
2.
Saudi Med J ; 42(9): 969-974, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34470834

RESUMO

OBJECTIVES: To identify ribosome protein L5 gene variants and the risk of hepatic vein thrombosis in Saudi patients. METHODS: A case-control study was conducted during the period of May 2018 to September 2019. Sixty-five patient cases of hepatic vein thrombosis (HVT) were chosen, and 50 healthy individuals of the same ages and both gender were set as a control group. The genotype of the gene RPL5 was determined by PCR please provide abbreviation in full and capillary electrophoresis. Sanger sequencing for genetically screened variants was applied for the RPL5 gene. RESULTS: Alleles A at variant rs182018447 and T allele at variant rs559377519 were strongly corelated (p=0.009 and p=0.037, respectively) with the risk of HVT. The genotype frequencies of the RPL5 gene, the A/A genotypes at rs182018447 and T/T at rs559377519 were associated with HVT (p=0.000 and p=0.004; respectively) and an increase in risk for HVT among these patients. Please rephrase the highlighted text without using the word respectively. CONCLUSION: Our findings indicate that the 5 genetic novel variants examined in the RPL5 gene were associated with a risk of HVT in all our Saudi cases. Additionally, the A/A at rs182018447 and T/T at rs559377519 genotypes were substantially susceptible to HVT in all these patients.


Assuntos
Síndrome de Budd-Chiari , Proteínas Ribossômicas/genética , Alelos , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Arábia Saudita/epidemiologia
3.
BMC Res Notes ; 14(1): 346, 2021 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-34481515

RESUMO

OBJECTIVE: Studies on the genetic background of patients with multiple myeloma (MM) have been increasing; two important factors considered in such works are uncoupling protein-2 (UCP-2) and nuclear receptor subfamily 3 group C member 1 (NR3C1). We aim to reveal the association of MM with NR3C1 and UCP-2 gene polymorphisms. In this prospective study, 200 patients diagnosed between January 2009 and 2018 and 200 healthy individuals were included. For patients who had undergone autologous stem cell transplantation and control subjects, we statistically compared the CC, GC, and GG genotypes and the C and G alleles of the NR3C1 gene, as well as the AA, AG, and GG genotypes and the A and G alleles of the UCP-2 gene. RESULTS: While the AA genotype was significantly more common in the MM group (p = 0.001), the GG genotype was significantly more common in the control group (p = 0.016). Overall survival was found to be significantly shorter in patients with the UCP-2 GG genotype (p = 0.034). It was also found that having the GG genotype of the UCP-2 gene was a 2.48-fold risk factor for mortality. The fact that overall survival is significantly shorter in MM patients with the UCP-2 GG genotype and its definition as a risk factor for mortality have been put forward for the first time in the literature.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Receptores de Glucocorticoides , Proteína Desacopladora 2 , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Receptores de Glucocorticoides/genética , Transplante Autólogo , Resultado do Tratamento , Proteína Desacopladora 2/genética
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(9): 857-860, 2021 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-34487530

RESUMO

OBJECTIVE: To report on a patient with congenital muscular dystrophy (CMD) due to a missense variant of LMNA gene and explore its pathogenicity. METHODS: The 1-year-and-1-month-old boy has presented with motor development delay and elevation of muscle enzymes for more than half a year. Congenital myopathy was suspected. Following muscle biopsy, HE staining, immunostaining and electron microscopy were conducted to clarify the clinical diagnosis. Meanwhile, DNA was extracted from the child and his parents' peripheral venous blood samples. Trio-whole exome sequencing (trio-WES) was carried out to detect pathogenic variant in the child. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: Both light and electron microscopy showed a large area of necrotic muscle tissues with infiltration of inflammatory cells. Immunohistochemistry revealed a large amount of muscle cells to be diffusely positive for Dysferlin. The patient's motor delays, elevations of muscle enzymes and histopathological results suggested a clinical diagnosis of CMD. A de novo missense c.1072G>A (p.E358K) variant was detected in the LMNA gene by trio-WES. The variant was unreported previously (PS2) and was absent from major allele frequency databases (PM2). It was a loss of function variant and was considered as hotspot variant in the LMNA gene (PM1) as the amino acid (E), located in position 358, was highly conserved, and change of this amino acid was found to cause destruction of the filament domain (AA: 30-386), which may result in serious damage to the intermediate filament protein. Furthermore, c.1072G>A (p. E358K) in LMNA gene was also predicted to be pathogenic based on MutationTaster, PROVEAN and PolyPhen-2 (PP3) analysis. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the variant was classified to be likely pathogenic (PS2+PM1+PM2+PP3). CONCLUSION: The child's condition may be attributed to the de novo missense c.1072 G>A (p.E358K) variant of the LMNA gene. Above discovery has expanded the variant spectrum of the LMNA gene.


Assuntos
Lamina Tipo A , Distrofias Musculares , Frequência do Gene , Genômica , Humanos , Lactente , Lamina Tipo A/genética , Masculino , Distrofias Musculares/genética , Mutação , Sequenciamento Completo do Exoma
5.
J Pak Med Assoc ; 71(7): 1832-1837, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34410257

RESUMO

OBJECTIVE: To find the association of single nucleotide polymorphism of hypoxia-inducible factor-1 alpha, rs11549465 (1772 Cytosine > Thymine) with metabolic syndrome, and to compare the anthropometric and biochemical variables in different genotypes of hypoxia-inducible factor-1 alpha. METHODS: The cross-sectional comparative study was conducted at the University of Health Sciences, Lahore, Pakistan, from July 2016 to April 2019, and comprised patients of metabolic syndrome selected from the Sheikh Zayed Hospital, Lahore. Healthy controls were also enrolled. Fasting venous sample was taken for the determination of study parameters. The genetic variant of hypoxia-inducible factor-1 alpha was analysed by restriction fragment length polymorphism polymerase chain reaction. Data was analysed using SPSS 22. RESULTS: Out of 400 subjects, 200(50%) each were patients and controls. The frequency of CC genotype of hypoxia-inducible factor-1 alpha Cytosine > Thymine in patients was 166(83%) and in controls 147(73.5%); CT genotype was 34(17%) and 53(26.5%) respectively, while TT genotype was not observed. There was a significant association of the C allele and CC genotype (p=0.03) with the increased risk of metabolic syndrome (p=0.02). On comparison of study variables in the two genotypes, systolic blood pressure, anthropometric and lipid parameters were significantly higher in the wild CC genotype compared to CT in the control group (p<0.05), but there was no significant difference in the patients (p>0.05). CONCLUSIONS: Major allele C of hypoxia-inducible factor-1 alpha 1772 Cytosine > Thymine was found to be associated with increased risk of metabolic syndrome.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Síndrome Metabólica , Estudos de Casos e Controles , Estudos Transversais , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Hipóxia , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Polimorfismo de Nucleotídeo Único
6.
Fa Yi Xue Za Zhi ; 37(3): 372-377, 2021 Jun.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34379907

RESUMO

Abstract: Objective To derive the probability distribution formula of combined identity by state (CIBS) score among individuals with different relationships based on population data of autosomal multiallelic genetic markers. Methods The probabilities of different identity by state (IBS) scores occurring at a single locus between two individuals with different relationships were derived based on the principle of ITO method. Then the distribution probability formula of CIBS score between two individuals with different relationships when a certain number of genetic markers were used for relationship identification was derived based on the multinomial distribution theory. The formula was compared with the CIBS probability distribution formula based on binomial distribution theory. Results Between individuals with a certain relationship, labelled as RS, the probabilities of IBS=2, 1 and 0 occurring at a certain autosomal genetic marker x (that is, p2(RSx), p1(RSx) and p0(RSx)), can be calculated based on the allele frequency data of that genetic marker and the probability of two individuals with the corresponding RS relationship sharing 0, 1 or 2 identity by descent (IBD) alleles (that is, φ0, φ1 and φ2). For a genotyping system with multiple independent genetic markers, the distribution of CIBS score between pairs of individuals with relationships other than parent-child can be deducted using the averages of the 3 probabilities of all genetic markers (that is, p2(RS), p1(RS) and p0(RS)), based on multinomial distribution theory. Conclusion The calculation of CIBS score distribution formula can be extended to all kinships and has great application value in case interpretation and system effectiveness evaluation. In most situations, the results based on binomial distribution formula are similar to those based on the formula derived in this study, thus, there is little difference between the two methods in actual work.


Assuntos
Genótipo , Alelos , Frequência do Gene , Marcadores Genéticos , Humanos , Probabilidade
7.
Fa Yi Xue Za Zhi ; 37(3): 382-387, 2021 Jun.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34379909

RESUMO

Abstract: Objective To evaluate the discrimination efficiency of the SeqType® P52 Human Ancestry Identification SNP Detection Kit based on a high-throughput sequencing platform in five Chinese ethnic groups. Methods Using the SeqType® P52 Human Ancestry Identification SNP Detection Kit based on a high-throughput sequencing platform, a total of 350 samples from Han, Tibetan, Mongolian, Uygur, and Yi populations in China were detected and population cluster analysis was performed. Results The effective sequencing depth of a single site in a single sample was ≥720×, and the average report rate was 96%. The mean values of allele frequency differences between the Tibetan, Mongolian, Uygur, Yi and Han population were 0.20, 0.05, 0.24 and 0.11, respectively. Using Structure 2.3.4 software under K=5 mode, independent ancestral component in Han, Tibetan and Uygur could be detected, which was consistent with the result observed from the principal component analysis (PCA). For the Yi population, two thirds of them had relatively independent ancestral component close to the Tibetan population and one third were similar to the Uygur population. The Mongolian population had similar ancestral origin component with Han population. Conclusion The composite detection system with 52 screened ancestry-informative SNP sites has been established in this study, which can effectively analyze the composition and individual genetic components of populations from Han, Tibetan and Uygur. The ability to discriminate among Han, Mongolian and Yi needs to be further improved. The SeqType® P52 Human Ancestry Identification SNP Detection Kit can be used to infer the origin of an individual's ancestors in some forensic DNA cases.


Assuntos
DNA , Grupos Étnicos , Grupo com Ancestrais do Continente Asiático/genética , China , Grupos Étnicos/genética , Frequência do Gene , Genética Populacional , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Polimorfismo de Nucleotídeo Único
8.
In Vivo ; 35(5): 2535-2540, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34410940

RESUMO

AIM: There is very little literature reporting the association of matrix metalloproteinase-1 (MMP1) with personal susceptibility to bladder cancer. In the current study, we carried out the first examination of the contribution of MMP1 rs1799750 to bladder cancer risk in Taiwanese. MATERIALS AND METHODS: A total of 375 bladder cancer cases and 375 healthy controls were genotyped for MMP1 rs1799750 via polymerase chain reaction-restriction fragment length polymorphism methodology and this was evaluated for association with clinicopathological factors. RESULTS: The frequencies of MMP1 rs1799750 2G/2G, 1G/2G, and 1G/1G genotypes were 35.7%, 44.8% and 19.5% in the group with bladder cancer and 32.5%, 46.4%, and 21.1% in the healthy control group (p for trend=0.6362). The odds ratios (ORs) for bladder cancer risk after adjusting for age and gender for those carrying 1G/2G and 1G/1G genotypes at MMP1 rs1799750 were 0.88 (95% CI=0.62-1.24, p=0.4357) and 0.83 (95% CI=0.61-1.26, p=0.3990), respectively, compared with the wild-type 2G/2G genotype. In allelic frequency analysis, the adjusted OR for those carrying the 1G allele at MMP1 rs1799750 was 0.87 (95% CI=0.71-1.23, p=0.3479) compared to those people carrying a 2G allele. CONCLUSION: Our findings indicated that the genotypes at MMP1 rs1799750 appear to play little role in determining personal susceptibility to bladder cancer for Taiwanese.


Assuntos
Metaloproteinase 1 da Matriz , Neoplasias da Bexiga Urinária , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Metaloproteinase 1 da Matriz/genética , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Neoplasias da Bexiga Urinária/epidemiologia , Neoplasias da Bexiga Urinária/genética
9.
In Vivo ; 35(5): 2845-2853, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34410977

RESUMO

BACKGROUND: Multiple sclerosis (MS) is one of the most debilitating neurological diseases of young adults. The presence of a single nucleotide polymorphism in the promoter regions of the interleukin 27 gene (IL27 T4730C, rs181206) may alter the transcription and the production of cytokine levels, leading to MS. PATIENTS AND METHODS: We performed a case-control study including 82 individuals: 51 patients diagnosed with MS and 31 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism was used in order to determine the genotypes for the IL27 T4730С polymorphism and enzyme-linked immunosorbent assay to measure the serum IL27 level. RESULTS: Carriers of the T4730С polymorphism were found to have a 6-fold [95% confidence intervaI (CI)=1.83-19.63, p=0.002] increased risk for MS. Univariate logistic regression analysis showed an increased frequency of the TC4730 heterozygous genotype (39.2% vs. 9.7%) and also of the C4730 allele (27.45% vs. 8.06) in patients compared to controls, with a 6.02-fold increased risk (95% CI=1.61-22.46, p=0.006) and a 4.31-fold increased risk (95% CI=1.57-11.87, p=0.002) of developing MS. IL27 levels were significantly lower in patients compared to controls (12.35 versus 14.34 pg/ml, p=0.039), without significant differences between genotypes. Multivariate logistic analysis showed that IL27 T4730C polymorphism (odds ratio=6.272, 95% CI=1.84-21.40, p=0.003) and smoking (odds ratio=4.214, 95% CI=1.39-12.74, p=0.011) represented independent risk factors for MS. CONCLUSION: Our study provides a possible link between IL27 level and IL27 T4730C gene polymorphism and the risk for developing MS in a Romanian population.


Assuntos
Interleucina-27 , Esclerose Múltipla , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Interleucinas , Esclerose Múltipla/genética , Projetos Piloto , Polimorfismo de Nucleotídeo Único , Adulto Jovem
10.
HLA ; 98(4): 370-379, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34338446

RESUMO

The experience of individuals with Coronavirus Disease 2019 (COVID-19) ranges from asymptomatic to life threatening multi-organ dysfunction. Specific HLA alleles may affect the predisposition to severe COVID-19 because of their role in presenting viral peptides to launch the adaptive immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this population-based case-control study in the midwestern United States, we performed high-resolution HLA typing of 234 cases hospitalized for COVID-19 in the St. Louis metropolitan area and compared their HLA allele frequencies with those of 22,000 matched controls from the National Marrow Donor Program (NMDP). We identified two predisposing alleles, HLA-DRB1*08:02 in the Hispanic group (OR = 9.0, 95% confidence interval: 2.2-37.9; adjusted p = 0.03) and HLA-A*30:02 in younger African Americans with ages below the median (OR = 2.2, 1.4-3.6; adjusted p = 0.01), and several candidate alleles with potential associations with COVID-19 in African American, White, and Hispanic groups. We also detected risk-associated amino acid residues in the peptide binding grooves of some of these alleles, suggesting the presence of functional associations. These findings support the notion that specific HLA alleles may be protective or predisposing factors to COVID-19. Future consortium analysis of pooled cases and controls is warranted to validate and extend these findings, and correlation with viral peptide binding studies will provide additional evidence for the functional association between HLA alleles and COVID-19.


Assuntos
COVID-19 , Alelos , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Cadeias HLA-DRB1/genética , Humanos , Polimorfismo Genético , SARS-CoV-2
11.
Gene ; 802: 145867, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352299

RESUMO

Genome-wide association studies (GWAS) have identified DENND1A as a potential candidate gene linked to the fertility-related phenotypes in dairy cows. However, to date, no studies have examined the association of the DENND1A insertion/deletions (indels) to bovine fertility on a large scale. Herein, two indel sites, including P4-del-26-bp and P8-ins-15-bp were identified in 1064 Holstein cows. The values of the minor allelic frequency (MAF) ranged between 0.471 (deletion) and 0.230 (deletion), respectively, and combined four different haplotypes by analyzing the haplotype combination. It is noteworthy that P4-del-26-bp is associated with the ovarian width (P = 0.0004) and corpus luteum diameter (P = 0.004). Meanwhile, P8-ins-15-bp was found to have a significant association with the ovarian width (P = 0.020), ovarian weight (P = 0.004), the number of mature follicles (P = 0.020), and diameter of the mature follicles (P = 0.016). Furthermore, the combinatorial analysis showed that the two indel combined-genotypes were significantly related to several reproductive traits (ovarian width, ovarian weight, etc.). Collectively, our findings indicated that these two novel indels and their combinations are correlated with the reproductive traits, and hence, they can serve in the marker-assisted selection (MAS) in cattle breeding. Nevertheless, further functional experiments are needed for understanding the mechanisms of these indels in cattle reproduction in a better way.


Assuntos
Doenças dos Bovinos/genética , Mutação INDEL , Proteínas de Membrana Transportadoras/genética , Síndrome do Ovário Policístico/genética , Animais , Bovinos , Feminino , Fertilidade/genética , Frequência do Gene , Estudo de Associação Genômica Ampla/veterinária , Haplótipos , Reprodução/genética
12.
PLoS One ; 16(8): e0255608, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34352002

RESUMO

BACKGROUND: The diversity in the clinical course of COVID-19 has been related to differences in innate and adaptative immune response mechanisms. Natural killer (NK) lymphocytes are critical protagonists of human host defense against viral infections. It would seem that reduced circulating levels of these cells have an impact on COVID-19 progression and severity. Their activity is strongly regulated by killer-cell immuno-globulin-like receptors (KIRs) expressed on the NK cell surface. The present study's focus was to investigate the impact of KIRs and their HLA Class I ligands on SARS-CoV-2 infection. METHODS: KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 396 Sardinian patients with SARS-CoV-2 infection. Comparisons were made between 2 groups of patients divided according to disease severity: 240 patients were symptomatic or paucisymptomatic (Group A), 156 hospitalized patients had severe disease (Group S). The immunogenetic characteristics of patients were also compared to a population group of 400 individuals from the same geographical areas. RESULTS: Substantial differences were obtained for KIR genes, KIR haplotypes and KIR-HLA ligand combinations when comparing patients of Group S to those of Group A. Patients in Group S had a statistically significant higher frequency of the KIR A/A haplotype compared to patients in Group A [34.6% vs 23.8%, OR = 1.7 (95% CI 1.1-2.6); P = 0.02, Pc = 0.04]. Moreover, the KIR2DS2/HLA C1 combination was poorly represented in the group of patients with severe symptoms compared to those of the asymptomatic-paucisymptomatic group [33.3% vs 50.0%, OR = 0.5 (95% CI 0.3-0.8), P = 0.001, Pc = 0.002]. Multivariate analysis confirmed that, regardless of the sex and age of the patients, the latter genetic variable correlated with a less severe disease course [ORM = 0.4 (95% CI 0.3-0.7), PM = 0.0005, PMC = 0.005]. CONCLUSIONS: The KIR2DS2/HLA C1 functional unit resulted to have a strong protective effect against the adverse outcomes of COVID-19. Combined to other well known factors such as advanced age, male sex and concomitant autoimmune diseases, this marker could prove to be highly informative of the disease course and thus enable the timely intervention needed to reduce the mortality associated with the severe forms of SARS-CoV-2 infection. However, larger studies in other populations as well as experimental functional studies will be needed to confirm our findings and further pursue the effect of KIR receptors on NK cell immune-mediated response to SARS-Cov-2 infection.


Assuntos
COVID-19/imunologia , Células Matadoras Naturais/imunologia , Receptores KIR/imunologia , Adulto , Idoso , COVID-19/metabolismo , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Genes MHC Classe I/imunologia , Predisposição Genética para Doença , Antígenos HLA-C/genética , Haplótipos/genética , Humanos , Imunidade/imunologia , Imunogenética/métodos , Células Matadoras Naturais/metabolismo , Ligantes , Masculino , Pessoa de Meia-Idade , Receptores KIR/genética , Receptores KIR/metabolismo , SARS-CoV-2/patogenicidade , Índice de Gravidade de Doença
13.
PLoS One ; 16(8): e0244468, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34432798

RESUMO

The newly emerged and rapidly spreading SARS-CoV-2 causes coronavirus disease 2019 (COVID-19). To facilitate a deeper understanding of the viral biology we developed a capture sequencing methodology to generate SARS-CoV-2 genomic and transcriptome sequences from infected patients. We utilized an oligonucleotide probe-set representing the full-length genome to obtain both genomic and transcriptome (subgenomic open reading frames [ORFs]) sequences from 45 SARS-CoV-2 clinical samples with varying viral titers. For samples with higher viral loads (cycle threshold value under 33, based on the CDC qPCR assay) complete genomes were generated. Analysis of junction reads revealed regions of differential transcriptional activity among samples. Mixed allelic frequencies along the 20kb ORF1ab gene in one sample, suggested the presence of a defective viral RNA species subpopulation maintained in mixture with functional RNA in one sample. The associated workflow is straightforward, and hybridization-based capture offers an effective and scalable approach for sequencing SARS-CoV-2 from patient samples.


Assuntos
COVID-19/patologia , SARS-CoV-2/genética , Análise de Sequência de DNA/métodos , COVID-19/virologia , DNA Complementar/química , DNA Complementar/metabolismo , Frequência do Gene , Variação Genética , Genoma Viral , Humanos , Fases de Leitura Aberta/genética , RNA Viral/genética , RNA Viral/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , SARS-CoV-2/isolamento & purificação , Carga Viral
14.
Artigo em Inglês | MEDLINE | ID: mdl-34444495

RESUMO

Genetic polymorphisms involved in mercury toxicokinetics and toxicodynamics may be associated with severe mercury toxicity. This study aimed to investigate the impact of an ALAD polymorphism on chronic mercury exposure and the health situation of indigenous children from the Brazilian Amazon. One-hundred-and-three indigenous children (under 15 years old) were included and genotyped (rs1800435) using a TaqMan validated assay. The mean age was 6.6 ± 4.5 years old, 60% were female, 49% presented with anemia, and the mean hair mercury concentration was 7.0 ± 4.5 (1.4-23.9) µg/g, with 49% exceeding the reference limit (≥6.0 µg/g). Only two children were heterozygous ALAD, while the others were all wild type. Minor allele frequency (ALAD G) and heterozygous genotype (ALAD CG) were 1% and 2%, respectively. The two children (12 and 14 years old) with the ALAD polymorphism had mercury levels above the average as well as had neurological symptoms related to chronic mercury exposure, such as visual field alterations, memory deficit, distal neuropathy, and toe amyotrophy. Both children also reported frequent consumption of fish in the diet, at least three times a week. In conclusion, our data confirm that an ALAD polymorphism can contribute to mercury half-life time, harmful effects, and neuropsychological disorders in indigenous children with chronic mercury exposure to gold mining activity.


Assuntos
Mercúrio , Sintase do Porfobilinogênio , Animais , Criança , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Polimorfismo Genético , Sintase do Porfobilinogênio/genética
15.
Genes (Basel) ; 12(7)2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34356057

RESUMO

The virus responsible for the COVID-19 global health crisis, SARS-CoV-2, has been shown to utilize the ACE2 protein as an entry point to its target cells. The virus has been shown to rely on the actions of TMPRSS2 (a serine protease), as well as FURIN (a peptidase), for the critical priming of its spike protein. It has been postulated that variations in the sequence and expression of SARS-CoV-2's receptor (ACE2) and the two priming proteases (TMPRSS2 and FURIN) may be critical in contributing to SARS-CoV-2 infectivity. This study aims to examine the different expression levels of FURIN in various tissues and age ranges in light of ACE2 and TMPRSS2 expression levels using the LungMAP database. Furthermore, we retrieved expression quantitative trait loci (eQTLs) of the three genes and their annotation. We analyzed the frequency of the retrieved variants in data from various populations and compared it to the Egyptian population. We highlight FURIN's potential interplay with the immune response to SARS-CoV-2 and showcase a myriad of variants of the three genes that are differentially expressed across populations. Our findings provide insights into potential genetic factors that impact SARS-CoV-2 infectivity in different populations and shed light on the varying expression patterns of FURIN.


Assuntos
Alelos , Enzima de Conversão de Angiotensina 2 , COVID-19 , Bases de Dados de Ácidos Nucleicos , Furina , Regulação Enzimológica da Expressão Gênica , Frequência do Gene , Predisposição Genética para Doença , SARS-CoV-2/metabolismo , Serina Endopeptidases , Enzima de Conversão de Angiotensina 2/biossíntese , Enzima de Conversão de Angiotensina 2/genética , COVID-19/enzimologia , COVID-19/genética , Biologia Computacional , Feminino , Furina/biossíntese , Furina/genética , Humanos , Masculino , SARS-CoV-2/genética , Serina Endopeptidases/biossíntese , Serina Endopeptidases/genética
16.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(8): 719-722, 2021 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-34365609

RESUMO

OBJECTIVE: To analyze a pathogenic variant of MEFV gene in a family with autosomal dominant-familial Mediterranean fever (AD-FMF). METHODS: A 5-year-old boy presented with recurrent aseptic meningitis and his major symptoms included recurrent fever with headache and vomiting. His family members including his mother, sister and brother also had recurrent fever. A genetic disease was considered. DNAs were extracted from patient and all his family members' blood samples. Whole exome sequencing was performed to identify putative pathogenic variants that can explain this family's condition and Sanger sequencing was conducted. The impact of detected variants were predicted and validated by bioinformatics. RESULTS: A missense variant c.2229C>G (p.Phe743Leu) in MEFV gene was identified in the proband and his family members including his mother, sister and brother. This variant had not been reported in China previously, but the locus of it had already been reported in Arabic patient with AD-FMF (PS1). This variant was absent in major allele frequency databases (PM2) and had been predicted to be pathogenic based on Mutationtaster, PROVEAN and PolyPhen-2. In addition, the change of amino acid, locating in 743 locus of pyrin protein, encoding by MEFV gene, was found to cause SPRY_PRY_TRIM20 and SPRY_superfamily domain destroyed and finally influenced the fuction of pyrin protein. On the other hand, using UCSF chimera software, we find the variant c.2229C>G (p.Phe743Leu) can induce serious influence to the spatial structure of pyrin protein and loss of protein fuction (PP3). According to the ACMG variant classification guideline, the variant c.2229C>G (p.Phe743Leu) in MEFV gene was classified as likely pathogenic (PS1+PM2+PP3). CONCLUSION: The condition of this AD-FMF family may be attributed to the missense variant c.2229C>G (p.Phe743Leu) in MEFV gene. The recurrent aseptic meningitis was a very rare manifestation in AD-FMF patients and had not been reported in China previously. The clinical and genetic findings of the present study are helpful for the further understanding of AD-FMF.


Assuntos
Febre Familiar do Mediterrâneo , Pré-Escolar , Febre Familiar do Mediterrâneo/genética , Frequência do Gene , Testes Genéticos , Humanos , Masculino , Mutação , Pirina/genética , Sequenciamento Completo do Exoma
17.
Am J Hum Genet ; 108(8): 1401-1408, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216550

RESUMO

Precise interpretation of the effects of rare protein-truncating variants (PTVs) is important for accurate determination of variant impact. Current methods for assessing the ability of PTVs to induce nonsense-mediated decay (NMD) focus primarily on the position of the variant in the transcript. We used RNA sequencing of the Genotype Tissue Expression v.8 cohort to compute the efficiency of NMD using allelic imbalance for 2,320 rare (genome aggregation database minor allele frequency ≤ 1%) PTVs across 809 individuals in 49 tissues. We created an interpretable predictive model using penalized logistic regression in order to evaluate the comprehensive influence of variant annotation, tissue, and inter-individual variation on NMD. We found that variant position, allele frequency, the inclusion of ultra-rare and singleton variants, and conservation were predictive of allelic imbalance. Furthermore, we found that NMD effects were highly concordant across tissues and individuals. Due to this high consistency, we demonstrate in silico that utilizing peripheral tissues or cell lines provides accurate prediction of NMD for PTVs.


Assuntos
Códon sem Sentido/genética , Regulação da Expressão Gênica , Doenças Genéticas Inatas/patologia , Variação Genética , Mutação , Degradação do RNAm Mediada por Códon sem Sentido , RNA Mensageiro/genética , Frequência do Gene , Doenças Genéticas Inatas/genética , Humanos
18.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 38(7): 681-685, 2021 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-34247378

RESUMO

OBJECTIVE: To assess the association of polymorphisms of receptor of advanced glycation end products (RAGE) gene, monocyte to high-density lipoprotein cholesterol ratio (MHR) and variability of heart rate among patients with coronary heart disease (CHD). METHODS: 120 patients with CHD and 120 healthy individuals were respectively selected as the observation group and the control group. Allelic and genotypic differences of -429T>C, 1704G>T, 82G>S, MHR ratio and heart rate variability between the two groups and patients with different severity were analyzed. The correlation between their genotypes and MHR ratio and heart rate variability was analyzed. RESULTS: The 82G>S polymorphism of the RAGE gene and the allelic difference between the two groups and patients with different severity were statistically significant (P< 0.05). Compared with the control group and patients with mild to moderate phenotype, monocyte, total cholesterol, triglyceride, low density lipoprotein, MHR, low frequency in the observation group and patients with severe symptoms were significantly higher, while their high density lipoprotein, standard deviation of NN intervals (SDNN), standard deviation average of NN intervals (SDANN), root mean square successive differences, percentage of differences exceeding 50ms between adjacent normal number of intervals (PMN50), high frequency (HF) were significantly lower. The gene frequencies of G-Gly-T, T-Gly-T, G-Ser-T and G-Gly-C were correlated with SDNN, SDANN, rMSSD, PMN50, HF and MHR, but negatively correlated with low frequency. CONCLUSION: Polymorphisms of the RAGE gene in patients with coronary heart disease are associated with the MHR ratio and heart rate variability, which can be used as markers for the diagnosis and efficacy evaluation.


Assuntos
Doença das Coronárias , Produtos Finais de Glicação Avançada , Antígenos de Neoplasias , Doença das Coronárias/genética , Frequência do Gene , Frequência Cardíaca , Humanos , Proteínas Quinases Ativadas por Mitógeno , Polimorfismo Genético
19.
Nat Genet ; 53(8): 1260-1269, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34226706

RESUMO

Exome association studies to date have generally been underpowered to systematically evaluate the phenotypic impact of very rare coding variants. We leveraged extensive haplotype sharing between 49,960 exome-sequenced UK Biobank participants and the remainder of the cohort (total n ≈ 500,000) to impute exome-wide variants with accuracy R2 > 0.5 down to minor allele frequency (MAF) ~0.00005. Association and fine-mapping analyses of 54 quantitative traits identified 1,189 significant associations (P < 5 × 10-8) involving 675 distinct rare protein-altering variants (MAF < 0.01) that passed stringent filters for likely causality. Across all traits, 49% of associations (578/1,189) occurred in genes with two or more hits; follow-up analyses of these genes identified allelic series containing up to 45 distinct 'likely-causal' variants. Our results demonstrate the utility of within-cohort imputation in population-scale genome-wide association studies, provide a catalog of likely-causal, large-effect coding variant associations and foreshadow the insights that will be revealed as genetic biobank studies continue to grow.


Assuntos
Bancos de Espécimes Biológicos , Frequência do Gene , Proteínas/genética , Sequenciamento Completo do Exoma/estatística & dados numéricos , Pressão Sanguínea/genética , Mapeamento Cromossômico/métodos , Mapeamento Cromossômico/estatística & dados numéricos , Marcadores Genéticos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Desequilíbrio de Ligação , Proteínas de Membrana/genética , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único , Proteínas/metabolismo , Receptores do Fator Natriurético Atrial/genética , Reino Unido , Sequenciamento Completo do Exoma/métodos
20.
J Int Med Res ; 49(7): 3000605211019263, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34275374

RESUMO

OBJECTIVE: To investigate the relationship between angiotensin (AGT) rs2493132 gene polymorphism and the risk of developing non-alcoholic fatty liver disease (NAFLD) and coronary artery disease (CAD) in the Chinese Han population. METHODS: Polymerase chain reaction was performed to determine AGT genotypes. Anthropometric and clinical data were investigated and statistically analyzed in the clinical laboratory department of Qingdao Municipal Hospital. RESULTS: The AGT rs2493132 CT + TT genotype was an important risk factor for CAD in patients with NAFLD and NAFLD + CAD in healthy controls. The AGT rs2493132 T allele increased the risk of NAFLD + CAD in healthy controls. The AGT rs2493132 CT + TT genotype and T allele also significantly increased the risk of CAD in patients with NAFLD after adjustments for age, sex, and body mass index. In addition, AGT rs2493132 T allele carriers showed higher total cholesterol (TC) and low-density lipoprotein (LDL) levels compared with non-carriers. CONCLUSIONS: The AGT rs2493132 CT + TT genotype and T allele significantly increased the risk of developing CAD in patients with NAFLD in the Chinese Han population. The AGT rs2493132 T allele was associated with increased serum TC and LDL levels.


Assuntos
Doença da Artéria Coronariana , Hepatopatia Gordurosa não Alcoólica , Angiotensinogênio , Angiotensinas , Grupo com Ancestrais do Continente Asiático/genética , China , Doença da Artéria Coronariana/genética , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
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