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1.
Medicine (Baltimore) ; 100(29): e26614, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34398016

RESUMO

ABSTRACT: Cytochrome P450 enzymes play a central role in the phase I biotransformation process of a wide range of compounds, including xenobiotics, drugs, hormones and vitamins. It is noteworthy that these enzymes are highly polymorphic and, depending on the genetic makeup, an individual may have impaired enzymatic activity. Therefore, the identification of genetic variants in these genes could facilitate the implementation of pharmacogenetic studies and genetic predisposition to multifactorial diseases. We have established the frequencies of CYP2B6 (rs3745274; rs2279343) and CYP3A4 (rs2740574) alleles and genotypes in 209 healthy Malian subjects using TaqMan drug metabolism genotyping assays for allelic discrimination. Allele frequencies were 37% for CYP2B6 rs3745274; 38% for CYP2B6 rs2279343; and 75% for CYP3A4 rs2740574 respectively. Overall, the frequencies observed in Mali are statistically comparable to those reported across Africa except North Africa. The major haplotypes in CYP2B6 rs3745274 and CYP2B6 rs2279343 were represented by GA (60.24%) followed by TG (35.36%). We noted a strong linkage disequilibrium between CYP2B6 rs3745274 and CYP2B6 rs2279343 with D' = 0.91 and r2 = 0.9. The frequencies of the genotypic combinations were 43.5% (GT/AG), 37.3% (GG/AA) and 11.5% (TT/GG) in the combination of CYP2B6-rs3745274 and CYP2B6-rs2279343; 26.8% (GT/CC), 25.4%, (GT/CT), 17.2% and GG/CT in the combination CYP2B6-rs3745274-CYP3A4-rs2740574; 26.8% (AG/CC), 23.9% (AA/CC), 19.1% (AG/CT), and 11% (AA/CT) in the combination CYP2B6-rs2279343-CYP3A4-rs2740574, respectively. The most common triple genotype was GT/AG/CC with 24.9%, followed by GG/AA/CC with 23.9%, GT/AG/CT with 16.7%, and GG/AA/CT with 10%. Our results provide new insights into the distribution of these pharmacogenetically relevant genes in the Malian population. Moreover, these data will be useful for studies of individual genetic variability to drugs and genetic predisposition to diseases.


Assuntos
Alelos , Genótipo , Haplótipos/genética , Adolescente , Adulto , Idoso , Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP3A/genética , Feminino , Humanos , Malásia/etnologia , Masculino , Pessoa de Meia-Idade , Farmacogenética/métodos
2.
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
3.
Nat Commun ; 12(1): 4279, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257313

RESUMO

Divergent mitonuclear coadaptation could facilitate speciation. We investigate this possibility in two hybridizing species of warblers, Setophaga occidentalis and S. townsendi, in western North America. Inland S. townsendi harbor distinct mitochondrial DNA haplotypes from those of S. occidentalis. These populations also differ in several nuclear DNA regions. Coastal S. townsendi demonstrate mixed mitonuclear ancestry from S. occidentalis and inland S. townsendi. Of the few highly-differentiated chromosomal regions between inland S. townsendi and S. occidentalis, a 1.2 Mb gene block on chromosome 5 is also differentiated between coastal and inland S. townsendi. Genes in this block are associated with fatty acid oxidation and energy-related signaling transduction, thus linked to mitochondrial functions. Genetic variation within this candidate gene block covaries with mitochondrial DNA and shows signatures of divergent selection. Spatial variation in mitonuclear ancestries is correlated with climatic conditions. Together, these observations suggest divergent mitonuclear coadaptation underpins cryptic differentiation in this species complex.


Assuntos
Núcleo Celular/genética , DNA Mitocondrial/genética , Animais , Variação Genética/genética , Haplótipos/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Aves Canoras/genética
4.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201603

RESUMO

Melon (Cucumis melo L.) is an economically important horticultural crop with abundant morphological and genetic variability. Complex genetic variations exist even among melon varieties and remain unclear to date. Therefore, unraveling the genetic variability among the three different melon varieties, muskmelon (C. melo subsp. melo), makuwa (C. melo L. var. makuwa), and cantaloupes (C. melo subsp. melo var. cantalupensis), could provide a basis for evolutionary research. In this study, we attempted a systematic approach with genotyping-by-sequencing (GBS)-derived single nucleotide polymorphisms (SNPs) to reveal the genetic structure and diversity, haplotype differences, and marker-based varieties differentiation. A total of 6406 GBS-derived SNPs were selected for the diversity analysis, in which the muskmelon varieties showed higher heterozygote SNPs. Linkage disequilibrium (LD) decay varied significantly among the three melon varieties, in which more rapid LD decay was observed in muskmelon (r2 = 0.25) varieties. The Bayesian phylogenetic tree provided the intraspecific relationships among the three melon varieties that formed, as expected, individual clusters exhibiting the greatest genetic distance based on the posterior probability. The haplotype analysis also supported the phylogeny result by generating three major networks for 48 haplotypes. Further investigation for varieties discrimination allowed us to detect a total of 52 SNP markers that discriminated muskmelon from makuwa varieties, of which two SNPs were converted into cleaved amplified polymorphic sequence markers for practical use. In addition to these markers, the genome-wide association study identified two SNPs located in the genes on chromosome 6, which were significantly associated with the phenotypic traits of melon seed. This study demonstrated that a systematic approach using GBS-derived SNPs could serve to efficiently classify and manage the melon varieties in the genebank.


Assuntos
Cucumis melo/genética , Marcadores Genéticos , Polimorfismo de Nucleotídeo Único , Variação Genética , Genética Populacional , Genoma de Planta , Estudo de Associação Genômica Ampla , Haplótipos/genética , Desequilíbrio de Ligação , Fenótipo , Filogenia , Sementes/genética
5.
BMC Plant Biol ; 21(1): 325, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34229602

RESUMO

BACKGROUND: Plant phylogeographic studies of species in subtropical China have mainly focused on rare and endangered species, whereas few studies have been conducted on taxa with relatively wide distribution, especially polyploid species. We investigated the cytotype and haplotype distribution pattern of the Actinidia chinensis complex, a widespread geographically woody liana with variable ploidy in subtropical China comprising two varieties, with three chloroplast fragments DNA (ndhF-rpl132, rps16-trnQ and trnE-trnT). Macroevolutionary, microevolutionary and niche modeling tools were also combined to disentangle the origin and the demographic history of the species or cytotypes. RESULTS: The ploidy levels of 3338 individuals from 128 populations sampled throughout the species distribution range were estimated with flow cytometry. The widespread cytotypes were diploids followed by tetraploids and hexaploids, whereas triploids and octoploids occurred in a few populations. Thirty-one chloroplast haplotypes were detected. The genetic diversity and genetic structure were found to be high between varieties (or ploidy races) chinensis and deliciosa. Our results revealed that these two varieties inhabit significantly different climatic niche spaces. Ecological niche models (ENMs) indicate that all varieties' ranges contracted during the Last Inter Glacial (LIG), and expanded eastward or northward during the Last Glacial Maximum (LGM). CONCLUSIONS: Pliocene and Plio-Pleistocene climatic fluctuations and vicariance appear to have played key roles in shaping current population structure and historical demography in the A. chinensis complex. The polyploidization process also appears to have played an important role in the historical demography of the complex through improving their adaptability to environmental changes.


Assuntos
Actinidia/classificação , Actinidia/citologia , Cloroplastos/classificação , Filogeografia , Teorema de Bayes , China , DNA de Cloroplastos/genética , Ecossistema , Variação Genética , Genética Populacional , Haplótipos/genética , Método de Monte Carlo , Ploidias
6.
Cell Mol Life Sci ; 78(15): 5743-5754, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34196733

RESUMO

GWAS involves testing genetic variants across the genomes of many individuals of a population to identify genotype-phenotype association. It was initially developed and has proven highly successful in human disease genetics. In plants genome-wide association studies (GWAS) initially focused on single feature polymorphism and recombination and linkage disequilibrium but has now been embraced by a plethora of different disciplines with several thousand studies being published in model and crop species within the last decade or so. Here we will provide a comprehensive review of these studies providing cases studies on biotic resistance, abiotic tolerance, yield associated traits, and metabolic composition. We also detail current strategies of candidate gene validation as well as the functional study of haplotypes. Furthermore, we provide a critical evaluation of the GWAS strategy and its alternatives as well as future perspectives that are emerging with the emergence of pan-genomic datasets.


Assuntos
Produtos Agrícolas/genética , Genoma de Planta/genética , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla/métodos , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Polimorfismo de Nucleotídeo Único/genética
7.
Plant Sci ; 310: 110980, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34315596

RESUMO

Flowering is an important turning point from vegetative growth to reproductive growth, and vernalization is an essential condition for the flowering of annual winter plants. To investigate the genetic architecture of flowering time in rapeseed, we used the 60 K Brassica Infinium SNP array to perform a genome-wide analysis of haplotype blocks associated with flowering time in 203 Chinese semi-winter rapeseed inbred lines. Twenty-one haplotype regions carrying one or more candidate genes showed a significant association with flowering time. Interestingly, we detected a SNP (Bn-scaff_22728_1-p285715) located in exon 3 of the BnVIN3-C03 gene that showed a significant association with flowering time on chromosome C03. Based on the SNP alleles A and G, two groups of accessions with early and late flowering time phenotypes were selected, respectively, and PCR amplification and gene expression analysis were combined to reveal the structural variation of the BnVIN3-C03 gene that affected flowering time. Moreover, we found that BnVIN3-C03 inhibited the expression of BnFLC-A02, BnFLC-A03.1, BnFLC-A10 and BnFLC-C03.1, thus modulating the flowering time of Brassica napus. This result provides insight into the genetic improvement of flowering time in B. napus.


Assuntos
Brassica napus/genética , Estudo de Associação Genômica Ampla/métodos , Transcriptoma/genética , Alelos , Mapeamento Cromossômico , Flores/genética , Haplótipos/genética , Proteínas de Plantas/genética , Locos de Características Quantitativas/genética
8.
Clin Pharmacol Ther ; 110(3): 662-676, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34109627

RESUMO

The Pharmacogene Variation Consortium (PharmVar) catalogues star (*) allele nomenclature for the polymorphic human CYP2C9 gene. Genetic variation within the CYP2C9 gene locus impacts the metabolism or bioactivation of many clinically important drugs, including nonsteroidal anti-inflammatory drugs, phenytoin, antidiabetic agents, and angiotensin receptor blockers. Variable CYP2C9 activity is of particular importance regarding efficacy and safety of warfarin and siponimod as indicated in their package inserts. This GeneFocus provides a comprehensive overview and summary of CYP2C9 and describes how haplotype information catalogued by PharmVar is utilized by the Pharmacogenomics Knowledgebase and the Clinical Pharmacogenetics Implementation Consortium.


Assuntos
Citocromo P-450 CYP2C9/genética , Polimorfismo Genético/genética , Alelos , Haplótipos/genética , Humanos , Bases de Conhecimento , Preparações Farmacêuticas/administração & dosagem , Farmacogenética/métodos
9.
Viruses ; 13(5)2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064904

RESUMO

The emergence of SARS-CoV-2 variants, as observed with the D614G spike protein mutant and, more recently, with B.1.1.7 (501Y.V1), B.1.351 (501Y.V2) and B.1.1.28.1 (P.1) lineages, represent a continuous threat and might lead to strains of higher infectivity and/or virulence. We report on the occurrence of a SARS-CoV-2 haplotype with nine mutations including D614G/T307I double-mutation of the spike. This variant expanded and completely replaced previous lineages within a short period in the subantarctic Magallanes Region, southern Chile. The rapid lineage shift was accompanied by a significant increase of cases, resulting in one of the highest incidence rates worldwide. Comparative coarse-grained molecular dynamic simulations indicated that T307I and D614G belong to a previously unrecognized dynamic domain, interfering with the mobility of the receptor binding domain of the spike. The T307I mutation showed a synergistic effect with the D614G. Continuous surveillance of new mutations and molecular analyses of such variations are important tools to understand the molecular mechanisms defining infectivity and virulence of current and future SARS-CoV-2 strains.


Assuntos
SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética , Regiões Antárticas , Anticorpos Neutralizantes/metabolismo , Anticorpos Antivirais/genética , COVID-19/epidemiologia , COVID-19/genética , COVID-19/metabolismo , Chile , Haplótipos/genética , Humanos , Proteínas Mutantes/genética , Mutação , Ligação Proteica , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus/ultraestrutura
10.
Genes (Basel) ; 12(5)2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-34069212

RESUMO

Clinical tests based on whole-genome sequencing are generally focused on a single task approach, testing one or several parameters, although whole-genome sequencing (WGS) provides us with large data sets that can be used for many supportive analyses. In spite of low genome coverage, data of WGS-based non-invasive prenatal testing (NIPT) contain fully sequenced mitochondrial DNA (mtDNA). This mtDNA can be used for variant calling, ancestry analysis, population studies and other approaches that extend NIPT functionality. In this study, we analyse mtDNA pool from 645 cell-free DNA (cfDNA) samples of pregnant women from different regions of Russia, explore the effects of transportation and storing conditions on mtDNA content, analyse effects, frequency and location of mitochondrial variants called from samples and perform haplogroup analysis, revealing the most common mitochondrial superclades. We have shown that, despite the relatively low sequencing depth of unamplified mtDNA from cfDNA samples, the mtDNA analysis in these samples is still an informative instrument suitable for research and screening purposes.


Assuntos
Ácidos Nucleicos Livres/genética , DNA Mitocondrial/genética , Haplótipos/genética , Mitocôndrias/genética , Polimorfismo de Nucleotídeo Único/genética , Feminino , Humanos , Teste Pré-Natal não Invasivo/métodos , Projetos Piloto , Gravidez , Controle de Qualidade , Federação Russa , Sequenciamento Completo do Genoma/métodos
11.
Clin Pharmacol Ther ; 110(3): 768-776, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34043814

RESUMO

This study aimed to analyze associations between genetic variants and the occurrence of clinical outcomes in dabigatran, apixaban, and rivaroxaban users. This was a retrospective real-world study linking genotype data of three Finnish biobanks with national register data on drug dispensations and healthcare encounters. We investigated several single-nucleotide variants (SNVs) in the ABCG2, ABCB1, CES1, and CYP3A5 genes potentially associated with bleeding or thromboembolic events in direct oral anticoagulant (DOAC) users based on earlier research. We used Cox regression models to compare the incidence of clinical outcomes between carriers and noncarriers of the SNVs or haplotypes. In total, 1,806 patients on apixaban, dabigatran, or rivaroxaban were studied. The ABCB1 c.3435C>T (p.Ile1145=, rs1045642) SNV (hazard ratio (HR) 0.42, 95% confidence interval (CI), 0.18-0.98, P = 0.044) and 1236T-2677T-3435T (rs1128503-rs2032582-rs1045642) haplotype (HR 0.44, 95% CI, 0.20-0.95, P = 0.036) were associated with a reduced risk for thromboembolic outcomes, and the 1236C-2677G-3435C (HR 2.55, 95% CI, 1.03-6.36, P = 0.044) and 1236T-2677G-3435C (HR 5.88, 95% CI, 2.35-14.72, P < 0.001) haplotypes with an increased risk for thromboembolic outcomes in rivaroxaban users. The ABCB1 c.2482-2236G>A (rs4148738) SNV associated with a lower risk for bleeding events (HR 0.37, 95% CI, 0.16-0.89, P = 0.025) in apixaban users. ABCB1 variants are potential factors affecting thromboembolic events in rivaroxaban users and bleeding events in apixaban users. Studies with larger numbers of patients are warranted for comprehensive assessment of the pharmacogenetic associations of DOACs and their relevance for clinical practice.


Assuntos
Anticoagulantes/efeitos adversos , Hemorragia/induzido quimicamente , Hemorragia/genética , Tromboembolia/induzido quimicamente , Tromboembolia/genética , Idoso , Feminino , Genótipo , Haplótipos/genética , Humanos , Masculino , Farmacogenética/métodos , Polimorfismo de Nucleotídeo Único/genética , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Estudos Retrospectivos , Risco , Rivaroxabana/efeitos adversos
12.
Front Immunol ; 12: 658570, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33968060

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19) was announced as an outbreak by the World Health Organization (WHO) in January 2020 and as a pandemic in March 2020. The majority of infected individuals have experienced no or only mild symptoms, ranging from fully asymptomatic cases to mild pneumonic disease. However, a minority of infected individuals develop severe respiratory symptoms. The objective of this study was to identify susceptible HLA alleles and clinical markers that can be used in risk prediction model for the early identification of severe COVID-19 among hospitalized COVID-19 patients. A total of 137 patients with mild COVID-19 (mCOVID-19) and 53 patients with severe COVID-19 (sCOVID-19) were recruited from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan for the period of February-August 2020. High-resolution sequencing-based typing for eight HLA genes was performed using next-generation sequencing. In the HLA association studies, HLA-A*11:01:01:01 [Pc = 0.013, OR = 2.26 (1.27-3.91)] and HLA-C*12:02:02:01-HLA-B*52:01:01:02 [Pc = 0.020, OR = 2.25 (1.24-3.92)] were found to be significantly associated with the severity of COVID-19. After multivariate analysis controlling for other confounding factors and comorbidities, HLA-A*11:01:01:01 [P = 3.34E-03, OR = 3.41 (1.50-7.73)], age at diagnosis [P = 1.29E-02, OR = 1.04 (1.01-1.07)] and sex at birth [P = 8.88E-03, OR = 2.92 (1.31-6.54)] remained significant. The area under the curve of the risk prediction model utilizing HLA-A*11:01:01:01, age at diagnosis, and sex at birth was 0.772, with sensitivity of 0.715 and specificity of 0.717. To the best of our knowledge, this is the first article that describes associations of HLA alleles with COVID-19 at the 4-field (highest) resolution level. Early identification of potential sCOVID-19 could help clinicians prioritize medical utility and significantly decrease mortality from COVID-19.


Assuntos
COVID-19/patologia , Frequência do Gene/genética , Antígeno HLA-A11/genética , Antígeno HLA-B52/genética , Antígenos HLA-C/genética , Fatores Etários , COVID-19/imunologia , Estudos de Casos e Controles , Comorbidade , Feminino , Estudos de Associação Genética , Haplótipos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Insuficiência Respiratória/genética , Insuficiência Respiratória/virologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Fatores Sexuais
13.
Biomed Res Int ; 2021: 6634253, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33937403

RESUMO

Emerging evidence suggests that the long noncoding RNA (lncRNA) growth arrest special 5 (GAS5) plays crucial roles in the pathogenesis of ischemic stroke (IS). The current research is aimed at assessing the correlation between two functional GAS5 variants (rs145204276 and rs55829688) and susceptibility to IS in a Han Chinese population. This study genotyped the two GAS5 variants in 1086 IS patients as well as 1045 age-matched healthy controls by using an improved multitemperature ligase detection reaction (iMLDR-TM) genotyping technology. We observed a considerable change in the frequencies of the rs145204276 allele and genotype among the IS patients and healthy control group. The del-T haplotype was substantially more prevalent in the IS cases compared to the control individuals. When study participants were stratified according to environmental factors, we found that the rs145204276 del allele was correlated with a higher risk of IS in male, smokers, hypertensive, and those ≥65 years old. Additional stratification conforming to IS subtypes exhibited that individuals carrying the rs145204276 del allele conferred a higher risk of expanding a larger artery atherosclerosis stroke subset. Moreover, there was a significant association between the rs145204276 del allele and elevated expression of GAS5 in IS patients. In contrast, the frequency of the allele related to rs55829688 was not statistically correlated with IS in all analysis. Our study supports a model wherein the rs145204276 variant in the GAS5 lncRNA is associated with IS risk, thus representing a potentially viable biomarker for IS prevention and treatment.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Predisposição Genética para Doença , Variação Genética , AVC Isquêmico/genética , RNA Longo não Codificante/genética , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , RNA Longo não Codificante/metabolismo , Fatores de Risco
14.
Gene ; 791: 145708, 2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-33984441

RESUMO

The true mahseer (Tor spp.) is one of the highest valued fish in the world due to its high nutritional value and great unique taste. Nevertheless, its morphological characterization and single mitochondrial gene phylogeny in the past had yet to resolve the ambiguity in its taxonomical classification. In this study, we sequenced and assembled 11 complete mahseer mitogenomes collected from Java of Indonesia, Pahang and Terengganu of Peninsular Malaysia as well as Sarawak of East Malaysia. The mitogenome evolutionary relationships among closely related Tor spp. samples were investigated based on maximum likelihood phylogenetic tree construction. Compared to the commonly used COX1 gene fragment, the complete COX1, Cytb, ND2, ND4 and ND5 genes appear to be better phylogenetic markers for genetic differentiation at the population level. In addition, a total of six population-specific mitolineage haplotypes were identified among the mahseer samples analyzed, which this offers hints towards its taxonomical landscape.


Assuntos
Cyprinidae/classificação , Cyprinidae/genética , Genoma Mitocondrial/genética , Animais , Sequência de Bases/genética , Biomarcadores , DNA Mitocondrial/genética , Genes Mitocondriais/genética , Haplótipos/genética , Indonésia , Malásia , Mitocôndrias/genética , Filogenia , Análise de Sequência de DNA/métodos
15.
Aging (Albany NY) ; 13(10): 13954-13967, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33982673

RESUMO

To examine the role of S100B in genetic susceptibility to Alzheimer's disease (AD), we conducted a case-control study to analyze four polymorphism loci (rs2839364, rs1051169, rs2300403, and rs9722) of the S100B gene and AD risk. We found an independent increased risk of AD in ApoE ε4(-) subjects carrying the rs9722 AA-genotype (OR = 2.622, 95% CI = 1.399-4.915, P = 0.003). Further investigation revealed the serum S100B levels to be lower in rs9722 GG carriers than in rs9722 AA carriers (P = 0.003). We identified three miRNAs (miR-340-3p, miR-593-3p, miR-6827-3p) in which the seed match region covered locus rs9722. Luciferase assays indicated that the rs9722 G allele has a higher binding affinity to miR-6827-3p than the rs9722 A allele, leading to a significantly decreased fluorescence intensity. Subsequent western blot analysis showed that the S100B protein level of SH-SY5Y cells, which carry the rs9722 G allele, decreased significantly following miR-6827-3p stimulation (P = 0.009). The present study suggests that the rs9722 polymorphism may upregulate the expression of S100B by altering the miRNA binding capacity and may thus increase the AD risk. This finding would be of great help for the early diagnosis of AD.


Assuntos
Doença de Alzheimer/sangue , Doença de Alzheimer/genética , Predisposição Genética para Doença , MicroRNAs/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Subunidade beta da Proteína Ligante de Cálcio S100/sangue , Subunidade beta da Proteína Ligante de Cálcio S100/genética , Idoso , Sequência de Bases , Estudos de Casos e Controles , Linhagem Celular Tumoral , Ensaios Enzimáticos , Feminino , Frequência do Gene/genética , Haplótipos/genética , Humanos , Luciferases/metabolismo , Masculino , MicroRNAs/genética , Ligação Proteica/genética
16.
Nature ; 594(7862): 227-233, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33910227

RESUMO

The accurate and complete assembly of both haplotype sequences of a diploid organism is essential to understanding the role of variation in genome functions, phenotypes and diseases1. Here, using a trio-binning approach, we present a high-quality, diploid reference genome, with both haplotypes assembled independently at the chromosome level, for the common marmoset (Callithrix jacchus), an primate model system that is widely used in biomedical research2,3. The full spectrum of heterozygosity between the two haplotypes involves 1.36% of the genome-much higher than the 0.13% indicated by the standard estimation based on single-nucleotide heterozygosity alone. The de novo mutation rate is 0.43 × 10-8 per site per generation, and the paternal inherited genome acquired twice as many mutations as the maternal. Our diploid assembly enabled us to discover a recent expansion of the sex-differentiation region and unique evolutionary changes in the marmoset Y chromosome. In addition, we identified many genes with signatures of positive selection that might have contributed to the evolution of Callithrix biological features. Brain-related genes were highly conserved between marmosets and humans, although several genes experienced lineage-specific copy number variations or diversifying selection, with implications for the use of marmosets as a model system.


Assuntos
Callithrix/genética , Diploide , Evolução Molecular , Genoma/genética , Genômica/normas , Animais , Pesquisa Biomédica , Variações do Número de Cópias de DNA , Feminino , Mutação em Linhagem Germinativa/genética , Haplótipos/genética , Heterozigoto , Humanos , Mutação INDEL/genética , Masculino , Padrões de Referência , Seleção Genética , Diferenciação Sexual/genética , Cromossomo Y/genética
17.
Viruses ; 13(3)2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33802100

RESUMO

Novirhabdoviruses cause large epizootics and economic losses of farmed trout. In this study, we surveyed Viral hemorrhagic septicemia virus and Infectious hematopoietic and necrosis virus (VHSV and IHNV) through both monitoring and investigation of clinical outbreaks reported by farmers in the regions with major rainbow trout production in Iran from 2015 to 2019. RT-PCR assays of the kidney samples and cell culture (EPC/FHM cells) samples confirmed the presence of the viruses, with 9 VHSV and 4 IHNV isolates, in both endemic and new areas of Iran. Sequence analysis of the G gene revealed that VHSV isolates belonged to genogroup Ia, and IHNV isolates were clustered into genogroup E, both typical for isolates from European countries. A haplotype analysis based on non-homologous amino acids of the G gene supports the emergence of two lineages of IHNV from clade 1 (E-1), as well as VHSV clade 2 (Ia-2) of the European genogroups, confirming that VHSV and IHNV isolates in Iran, have originated from Europe possibly via imported eggs.


Assuntos
Doenças dos Peixes/epidemiologia , Vírus da Necrose Hematopoética Infecciosa/isolamento & purificação , Oncorhynchus mykiss/virologia , Infecções por Rhabdoviridae/epidemiologia , Infecções por Rhabdoviridae/veterinária , Animais , Sequência de Bases , Surtos de Doenças , Europa (Continente)/epidemiologia , Doenças dos Peixes/virologia , Pesqueiros , Genótipo , Haplótipos/genética , Vírus da Necrose Hematopoética Infecciosa/genética , Irã (Geográfico)/epidemiologia , Epidemiologia Molecular , Novirhabdovirus/genética , Novirhabdovirus/isolamento & purificação , Filogenia , Análise de Sequência de DNA
18.
Clin Pharmacol Ther ; 110(3): 750-758, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33792048

RESUMO

The metabolic activity of the polymorphic CYP2D6 enzyme is dependent on the CYP2D6 genotype; however, the guidelines for translating the genotype into phenotype, which are of relevance for adequate drug dose personalization, are ambiguous. In the present study, retrospective therapeutic drug monitoring data from 4,700 CYP2D6 genotyped patients treated with risperidone, venlafaxine, and/or aripiprazole were analyzed to quantify the effect of CYP2D6 genotype on the CYP2D6 metabolic activities, as measured by metabolic ratios of these substrates. The patients were categorized into diplotypes based on the presence of normal function (CYP2D6Norm), nonfunctional (CYP2D6Nonf), and decreased function (CYP2D6Decr; i.e., CYP2D6*9, CYP2D6*10, and CYP2D6*41) CYP2D6 haplotypes. Significant correlations between the metabolic ratios were observed in patients (n = 77-103) cotreated with risperidone and venlafaxine, risperidone and aripiprazole, or venlafaxine and aripiprazole (ρ = 0.874, 0.785, and 0.644, respectively; P < 0.001 for all). Relative metabolic CYP2D6 diplotype activity was calculated based on that the metabolic ratios, where median values for CYP2D6Nonf/Nonf and CYP2D6Norm/Norm subgroups were set to 0% and 100%, respectively. The relative CYP2D6 activities were: 7.0% for CYP2D6Nonf/*41, 16.7% for CYP2D6Nonf/*9-10, 13.2% for CYP2D6*41/*41, 24.9% for CYP2D6*41/*9-10, 33.1% for CYP2D6*9-10/*9-10, 41.3% for CYP2D6Nonf/Norm, 55.0% for CYP2D6*41/Norm, 58.9% for CYP2D6*9-10/Norm, and 149.2% for CYP2D6Norm/Normx2. Compared with the CYP2D6Norm alleles, the activity scores of CYP2D6*41 and CYP2D6*9-10 alleles were estimated to be one sixth and one third, respectively. The results of this highly powered study provide a solid basis for the translation of the CYP2D6 genotype into a drug metabolic phenotype.


Assuntos
Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Citocromo P-450 CYP2D6/genética , Haplótipos/genética , Risperidona/uso terapêutico , Cloridrato de Venlafaxina/uso terapêutico , Adulto , Alelos , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos
19.
Clin Pharmacol Ther ; 110(3): 777-785, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33837531

RESUMO

Studying drug-metabolizing enzymes, encoded by pharmacogenes, may inform biological mechanisms underlying the diseases for which a medication is prescribed. Until recently, pharmacogenes could not be studied at biobank scale. In 7,649 unrelated African-ancestry (AFR) and 326,214 unrelated European-ancestry (EUR) participants from the UK Biobank, we associated pharmacogene haplotypes from 50 genes with 265 (EUR) and 17 (AFR) medication use phenotypes using generalized linear models. In EUR, N-acetyltransferase 2 (NAT2) metabolizer phenotype and activity score were associated with simvastatin use. The dose of NAT2*1 was associated with simvastatin use when compared with NAT2*5 (the most common haplotype). This association was robust to effects of low-density lipoprotein cholesterol (LDL-C) concentration (NAT2*1 odds ratio (OR) = 1.07, 95% CI: 1.05-1.09, P = 1.14 × 10-8 ) and polygenic risk for LDL-C concentration (NAT2*1 OR = 1.09, 95% CI: 1.04-1.14, P = 2.26 × 10-4 ). Interactive effects between NAT2*1 and simvastatin use on LDL-C concentration (OR = 0.957, 95% CI: 0.916-0.998, P = 0.045) were replicated in the electronic Medical Records and Genomics Pharmacogenetic Sequencing Pilot (eMERGE-PGx) cohort (OR = 0.987, 95% CI: 0.976-0.998, P = 0.029). We used biobank-scale data to uncover and replicate an association between NAT2 locus variation and better response to statin therapy. Testing NAT2 alleles may be useful for making clinical decisions regarding the potential benefit (e.g., absolute risk reduction) in LDL-C concentration prior to statin treatment.


Assuntos
Inativação Metabólica/genética , Sinvastatina/uso terapêutico , Adulto , Idoso , Arilamina N-Acetiltransferase/genética , Bancos de Espécimes Biológicos , LDL-Colesterol/genética , Estudos de Coortes , Feminino , Genótipo , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Farmacogenética/métodos , Fenótipo , Projetos Piloto
20.
Genes (Basel) ; 12(3)2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804213

RESUMO

Genetic variations at the Apolipoprotein E (ApoE) and microtubule-associated protein tau (MAPT) loci have been implicated in multiple neurogenerative diseases, but their exact molecular mechanisms are unclear. In this study, we performed transcript level linear modelling using the blood whole transcriptome data and genotypes of the 570 subjects in the Parkinson's Progression Markers Initiative (PPMI) cohort. ApoE, MAPT haplotypes and two SNPs at the SNCA locus (rs356181, rs3910105) were used to detect expression quantitative trait loci eQTLs associated with the transcriptome and differential usage of transcript isoforms. As a result, we identified 151 genes associated with the genotypic variations, 29 cis and 122 trans eQTL positions. Profound effect with genome-wide significance of ApoE e4 haplotype on the expression of TOMM40 transcripts was identified. This finding potentially explains in part the frequently established genetic association with the APOE e4 haplotypes in neurodegenerative diseases. Moreover, MAPT haplotypes had significant differential impact on 23 transcripts from the 17q21.31 and 17q24.1 loci. MAPT haplotypes had also the largest up-regulating (256) and the largest down-regulating (-178) effect sizes measured as ß values on two different transcripts from the same gene (LRRC37A2). Intronic SNP in the SNCA gene, rs3910105, differentially induced expression of three SNCA isoforms. In conclusion, this study established clear association between well-known haplotypic variance and transcript specific regulation in the blood. APOE e4 and MAPT H1/H2 haplotypic variants are associated with the expression of several genes related to the neurodegeneration.


Assuntos
Apolipoproteínas E/genética , Haplótipos/genética , Doenças Neurodegenerativas/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas tau/genética , Expressão Gênica/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Transcriptoma/genética
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