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1.
Cells ; 10(6)2021 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204705

RESUMO

Coronavirus disease 2019 (COVID-19), a global pandemic, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV-2 and transmembrane serine protease 2 (TMPRSS2) facilitates ACE2-mediated virus entry. Moreover, the expression of ACE2 in the testes of infertile men is higher than normal, which indicates that infertile men may be susceptible to be infected and SARS-CoV-2 may cause reproductive disorder through the pathway induced by ACE2 and TMPRSS2. Little is known about the pathway regulation of ACE2 and TMPRSS2 expression in male reproductive disorder. Since the regulation of gene expression is mediated by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) at the post-transcriptional level, the aim of this study was to analyze the dysregulated miRNA-lncRNA interactions of ACE2 and TMPRSS2 in male reproductive disorder. Using bioinformatics analysis, we speculate that the predicted miRNAs including miR-125a-5p, miR-125b-5p, miR-574-5p, and miR-936 as regulators of ACE2 and miR-204-5p as a modulator of TMPRSS2 are associated with male infertility. The lncRNAs with a tissue-specific expression for testis including GRM7-AS3, ARHGAP26-AS1, BSN-AS1, KRBOX1-AS1, CACNA1C-IT3, AC012361.1, FGF14-IT1, AC012494.1, and GS1-24F4.2 were predicted. The identified miRNAs and lncRNAs are proposed as potential biomarkers to study the possible association between COVID-19 and male infertility. This study encourages further studies of miRNA-lncRNA interactions to explain the molecular mechanisms of male infertility in COVID-19 patients.


Assuntos
COVID-19/complicações , Redes Reguladoras de Genes , Infertilidade Masculina/virologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Adulto , Enzima de Conversão de Angiotensina 2/fisiologia , COVID-19/genética , Biologia Computacional/métodos , Simulação por Computador , Interação Gene-Ambiente , Humanos , Infertilidade Masculina/genética , Masculino , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , SARS-CoV-2/fisiologia , Serina Endopeptidases/fisiologia , Testículo/metabolismo , Testículo/patologia , Testículo/virologia , Internalização do Vírus
2.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204586

RESUMO

Thyroid hormones are necessary for the normal functioning of physiological systems. Therefore, knowledge of any factor (whether genetic, environmental or intrinsic) that alters the levels of thyroid-stimulating hormone (TSH) and thyroid hormones is crucial. Genetic factors contribute up to 65% of interindividual variations in TSH and thyroid hormone levels, but many environmental factors can also affect thyroid function. This review discusses studies that have analyzed the impact of environmental factors on TSH and thyroid hormone levels in healthy adults. We included lifestyle factors (smoking, alcohol consumption, diet and exercise) and pollutants (chemicals and heavy metals). Many inconsistencies in the results have been observed between studies, making it difficult to draw a general conclusion about how a particular environmental factor influences TSH and thyroid hormone levels. However, lifestyle factors that showed the clearest association with TSH and thyroid hormones were smoking, body mass index (BMI) and iodine (micronutrient taken from the diet). Smoking mainly led to a decrease in TSH levels and an increase in triiodothyronine (T3) and thyroxine (T4) levels, while BMI levels were positively correlated with TSH and free T3 levels. Excess iodine led to an increase in TSH levels and a decrease in thyroid hormone levels. Among the pollutants analyzed, most studies observed a decrease in thyroid hormone levels after exposure to perchlorate. Future studies should continue to analyze the impact of environmental factors on thyroid function as they could contribute to understanding the complex background of gene-environment interactions underlying the pathology of thyroid diseases.


Assuntos
Meio Ambiente , Regulação da Expressão Gênica , Interação Gene-Ambiente , Hormônios Tireóideos/genética , Tireotropina/genética , Animais , Biomarcadores , Dieta , Poluentes Ambientais , Patrimônio Genético , Humanos , Estilo de Vida , Hormônios Tireóideos/metabolismo , Tireotropina/metabolismo
3.
Atherosclerosis ; 328: 33-37, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34082327

RESUMO

BACKGROUND AND AIMS: The APOE ε4 genotype has a higher risk for developing coronary artery disease (CAD), but there is preliminary evidence that antioxidative lifestyle factors interact with APOE genotype on CAD risk. Here, we assessed the effect modification of physical activity, oily fish and polyunsaturated fatty acid (PUFA) intake with APOE genotype on risk of incident CAD. METHODS: The present study comprised 345,659 white European participants from UK Biobank (mean age: 56.5 years, 45.7% men) without a history of CAD. Information regarding physical activity, oily fish intake and PUFA intake was collected through questionnaires, and information on incident CAD through linkage with hospital admission records. Analyses were performed using Cox proportional hazard models adjusted for age and sex. RESULTS: Higher physical activity level and oily fish intake were both associated with a lower incidence of CAD. However, these associations were similar across the different APOE genotypes (p-values for interaction > 0.05). Most notable, higher PUFA intake was associated with a lower CAD risk in APOE ε4 genotype carriers (hazard ratio: 0.76, 95% confidence interval: 0.63-0.92), and not in APOE ε3/ε3 genotype carriers (0.90; 0.79, 1.02), but without statistical evidence for effect modification (p-valueinteraction = 0.137). CONCLUSIONS: While higher physical activity and high fish and PUFA intake were associated with a lower risk of incident CAD, no evidence for interaction of these lifestyle factors with APOE genotype was observed in UK Biobank participants. Interventions intended to reduce cardiovascular risk might therefore be similarly effective across the APOE genotype carriers.


Assuntos
Doença da Artéria Coronariana , Animais , Apolipoproteínas E/genética , Bancos de Espécimes Biológicos , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Feminino , Interação Gene-Ambiente , Genótipo , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Reino Unido/epidemiologia
4.
Nat Commun ; 12(1): 3447, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103494

RESUMO

Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene-environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women.


Assuntos
Sistema Cardiovascular/embriologia , Embrião de Mamíferos/patologia , Ferro/deficiência , Animais , Aorta Torácica/anormalidades , Biomarcadores/metabolismo , Diferenciação Celular , Vasos Coronários/embriologia , Vasos Coronários/patologia , Suplementos Nutricionais , Edema/patologia , Embrião de Mamíferos/anormalidades , Desenvolvimento Embrionário , Feminino , Perfilação da Expressão Gênica , Interação Gene-Ambiente , Proteínas de Fluorescência Verde/metabolismo , Ferro/metabolismo , Vasos Linfáticos/embriologia , Vasos Linfáticos/patologia , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Penetrância , Fenótipo , Gravidez , Transdução de Sinais , Células-Tronco/patologia , Transgenes , Tretinoína/metabolismo
5.
Nat Commun ; 12(1): 3357, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099680

RESUMO

Social group structure is highly variable and can be important for nearly every aspect of behavior and its fitness consequences. Group structure can be modeled using social network analysis, but we know little about the evolutionary factors shaping and maintaining variation in how individuals are embedded within their networks (i.e., network position). While network position is a pervasive target of selection, it remains unclear whether network position is heritable and can respond to selection. Furthermore, it is unclear how environmental factors interact with genotypic effects on network positions, or how environmental factors shape selection on heritable network structure. Here we show multiple measures of social network position are heritable, using replicate genotypes and replicate social groups of Drosophila melanogaster flies. Our results indicate genotypic differences in network position are largely robust to changes in the environment flies experience, though some measures of network position do vary across environments. We also show selection on multiple network position metrics depends on the environmental context they are expressed in, laying the groundwork for better understanding how spatio-temporal variation in selection contributes to the evolution of variable social group structure.


Assuntos
Drosophila melanogaster/genética , Variação Genética , Padrões de Herança/genética , Seleção Genética , Comportamento Social , Animais , Meio Ambiente , Interação Gene-Ambiente , Aptidão Genética/genética , Genótipo
6.
Lancet Oncol ; 22(7): 1014-1022, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34111421

RESUMO

BACKGROUND: Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. METHODS: In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. FINDINGS: 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p<0·0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A>T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. INTERPRETATION: Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. FUNDING: National Health and Medical Research Council, Australia.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Interação Gene-Ambiente , Características de Residência , Adulto , Fatores Etários , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores Sexuais
7.
Nat Commun ; 12(1): 3867, 2021 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-34162839

RESUMO

Enzymes can evolve new catalytic activity when environmental changes present them with novel substrates. Despite this seemingly straightforward relationship, factors other than the direct catalytic target can also impact adaptation. Here, we characterize the catalytic activity of a recently evolved bacterial methyl-parathion hydrolase for all possible combinations of the five functionally relevant mutations under eight different laboratory conditions (in which an alternative divalent metal is supplemented). The resultant adaptive landscapes across this historical evolutionary transition vary in terms of both the number of "fitness peaks" as well as the genotype(s) at which they are found as a result of genotype-by-environment interactions and environment-dependent epistasis. This suggests that adaptive landscapes may be fluid and molecular adaptation is highly contingent not only on obvious factors (such as catalytic targets), but also on less obvious secondary environmental factors that can direct it towards distinct outcomes.


Assuntos
Adaptação Fisiológica/genética , Bactérias/genética , Proteínas de Bactérias/genética , Epistasia Genética , Hidrolases/genética , Sequência de Aminoácidos , Bactérias/enzimologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Biocatálise , Evolução Molecular , Interação Gene-Ambiente , Genótipo , Hidrolases/química , Hidrolases/metabolismo , Cinética , Metais/química , Metais/metabolismo , Metil Paration/química , Metil Paration/metabolismo , Mutação , Domínios Proteicos , Homologia de Sequência de Aminoácidos
8.
N Engl J Med ; 385(1): 78-86, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34192436

RESUMO

Companies have recently begun to sell a new service to patients considering in vitro fertilization: embryo selection based on polygenic scores (ESPS). These scores represent individualized predictions of health and other outcomes derived from genomewide association studies in adults to partially predict these outcomes. This article includes a discussion of many factors that lower the predictive power of polygenic scores in the context of embryo selection and quantifies these effects for a variety of clinical and nonclinical traits. Also discussed are potential unintended consequences of ESPS (including selecting for adverse traits, altering population demographics, exacerbating inequalities in society, and devaluing certain traits). Recommendations for the responsible communication about ESPS by practitioners are provided, and a call for a society-wide conversation about this technology is made. (Funded by the National Institute on Aging and others.).


Assuntos
Embrião de Mamíferos , Fertilização In Vitro , Testes Genéticos , Variação Genética , Herança Multifatorial/genética , Fenótipo , Diagnóstico Pré-Implantação , Escolaridade , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Humanos , Valor Preditivo dos Testes
9.
Science ; 372(6542)2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33958448

RESUMO

Phenotypes associated with genetic variants can be altered by interactions with other genetic variants (GxG), with the environment (GxE), or both (GxGxE). Yeast genetic interactions have been mapped on a global scale, but the environmental influence on the plasticity of genetic networks has not been examined systematically. To assess environmental rewiring of genetic networks, we examined 14 diverse conditions and scored 30,000 functionally representative yeast gene pairs for dynamic, differential interactions. Different conditions revealed novel differential interactions, which often uncovered functional connections between distantly related gene pairs. However, the majority of observed genetic interactions remained unchanged in different conditions, suggesting that the global yeast genetic interaction network is robust to environmental perturbation and captures the fundamental functional architecture of a eukaryotic cell.


Assuntos
Redes Reguladoras de Genes , Interação Gene-Ambiente , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Alelos , Aptidão Genética , Mutação
10.
BMC Bioinformatics ; 22(1): 230, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33947323

RESUMO

BACKGROUND: The identification of gene-gene and gene-environment interactions in genome-wide association studies is challenging due to the unknown nature of the interactions and the overwhelmingly large number of possible combinations. Parametric regression models are suitable to look for prespecified interactions. Nonparametric models such as tree ensemble models, with the ability to detect any unspecified interaction, have previously been difficult to interpret. However, with the development of methods for model explainability, it is now possible to interpret tree ensemble models efficiently and with a strong theoretical basis. RESULTS: We propose a tree ensemble- and SHAP-based method for identifying as well as interpreting potential gene-gene and gene-environment interactions on large-scale biobank data. A set of independent cross-validation runs are used to implicitly investigate the whole genome. We apply and evaluate the method using data from the UK Biobank with obesity as the phenotype. The results are in line with previous research on obesity as we identify top SNPs previously associated with obesity. We further demonstrate how to interpret and visualize interaction candidates. CONCLUSIONS: The new method identifies interaction candidates otherwise not detected with parametric regression models. However, further research is needed to evaluate the uncertainties of these candidates. The method can be applied to large-scale biobanks with high-dimensional data.


Assuntos
Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Algoritmos , Polimorfismo de Nucleotídeo Único , Árvores
11.
Hum Genet ; 140(8): 1217-1228, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34041609

RESUMO

Case-only (CO) studies are a powerful means to uncover gene-environment (G × E) interactions for complex human diseases. Moreover, such studies may in principle also draw upon genotype imputation to increase statistical power even further. However, genotype imputation usually employs healthy controls such as the Haplotype Reference Consortium (HRC) data as an imputation base, which may systematically perturb CO studies in genomic regions with main effects upon disease risk. Using genotype data from 719 German Crohn Disease (CD) patients, we investigated the level of imputation accuracy achievable for single nucleotide polymorphisms (SNPs) with or without a genetic main effect, and with varying minor allele frequency (MAF). Genotypes were imputed from neighbouring SNPs at different levels of linkage disequilibrium (LD) to the target SNP using the HRC data as an imputation base. Comparison of the true and imputed genotypes revealed lower imputation accuracy for SNPs with strong main effects. We also simulated different levels of G × E interaction to evaluate the potential loss of statistical validity and power incurred by the use of imputed genotypes. Simulations under the null hypothesis revealed that genotype imputation does not inflate the type I error rate of CO studies of G × E. However, the statistical power was found to be reduced by imputation, particularly for SNPs with low MAF, and a gradual loss of statistical power resulted when the level of LD to the SNPs driving the imputation decreased. Our study thus highlights that genotype imputation should be employed with great care in CO studies of G × E interaction.


Assuntos
Doença de Crohn/genética , Interação Gene-Ambiente , Genótipo , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Algoritmos , Alelos , Simulação por Computador , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Frequência do Gene , Genoma Humano , Alemanha , Humanos , Desequilíbrio de Ligação
12.
Mol Genet Genomics ; 296(4): 919-938, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33966103

RESUMO

The studies investigating gene-gene and gene-environment (or gene-behavior) interactions provide valuable insight into the pathomechanisms underlying obese phenotypes. The Pakistani population due to its unique characteristics offers numerous advantages for conducting such studies. In this view, the current study was undertaken to examine the effects of gene-gene and gene-environment/behavior interactions on the risk of obesity in a sample of Pakistani population. A total of 578 adult participants including 290 overweight/obese cases and 288 normal-weight controls were involved. The five key obesity-associated genetic variants namely MC4R rs17782313, BDNF rs6265, FTO rs1421085, TMEM18 rs7561317, and NEGR1 rs2815752 were genotyped using the TaqMan allelic discrimination assays. The data related to behavioral factors, such as eating pattern, diet consciousness, the tendency toward fat-dense food (TFDF), sleep duration, sleep-wake cycle (SWC), shift work (SW), and physical activity levels were collected via a questionnaire. Gene-gene and gene-behavior interactions were analyzed by multifactor dimensionality reduction and linear regression, respectively. In our study, only TMEM18 rs7561317 was found to be significantly associated with anthropometric traits with no significant effect of gene-gene interactions were observed on obesity-related phenotypes. However, the genetic variants were found to interact with the behavioral factors to significantly influence various obesity-related anthropometric traits including BMI, waist circumference, hip circumference, waist-to-hip ratio, waist-to-height ratio, and percentage of body fat. In conclusion, the interaction between genetic architecture and behavior/environment determines the outcome of obesity-related anthropometric phenotypes. Thus, gene-environment/behavior interaction studies should be promoted to explore the risk of complex and multifactorial disorders, such as obesity.


Assuntos
Interação Gene-Ambiente , Comportamentos Relacionados com a Saúde/fisiologia , Obesidade/etiologia , Adulto , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Índice de Massa Corporal , Peso Corporal/genética , Estudos de Casos e Controles , Epistasia Genética/fisiologia , Comportamento Alimentar/fisiologia , Feminino , Preferências Alimentares/fisiologia , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/genética , Sobrepeso/epidemiologia , Sobrepeso/etiologia , Sobrepeso/genética , Paquistão/epidemiologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Adulto Jovem
13.
J Dairy Sci ; 104(7): 8122-8134, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33934864

RESUMO

National and international across-population selection is often recommended and fairly common in the current breeding practice of dairy cattle, with the primary aims to increase genetic gain and genetic variability. The aim of this study was to test the hypothesis that the strategy of truncation selection of sires across populations [i.e., competitive gene flow strategy (CGF)] may not necessarily maximize genetic gain in the long term in the presence of genotype-by-environment interaction (G×E). Two alternative strategies used to be compared with CGF were forced gene flow (FGF) strategies, with 10 or 50% of domestic dams forced to be mated with foreign sires (FGF10%, FGF50%). Two equal-size populations (Ndams = 1,000) that were selected for the same breeding goal trait (h2 = 0.3) under G×E correlation (rg) of either 0.9 or 0.8 were simulated to test these 3 different strategies. Each population first experienced either 5 or 20 differentiation generations (Gd), then 15 migration generations. Discrete generations were simulated for simplicity. Each population performed a within-population conventional breeding program during differentiation generations and the 3 across-population sire selection strategies based on joint genomic prediction during migration generations. The 4 Gd_rg combinations defined 4 different levels of differentiation degree between the 2 populations at the start of migration. The true rate of inbreeding over the last 10 migration generations in each scenario was constrained at 0.01 to provide a fair basis for comparison of genetic gain across scenarios. Results showed that CGF maximized the genetic gain after 15 migration generations in 5_0.9 combination only, the case of the lowest differentiation degree, with a superiority of 0.4% (0.04 genetic SD units) over the suboptimal strategy. While in 5_0.8, 20_0.9, and 20_0.8 combinations, 2 FGF strategies had a superiority in genetic gain of 2.3 to 12.5% (0.21-1.07 genetic SD units) over CGF after 15 migration generations, especially FGF50%. The superiority of FGF strategies over CGF was that they alleviated inbreeding, introduced new genetic variance in the early migration period, and improved accuracy in the entire migration period. Therefore, we concluded that CGF does not necessarily maximize the genetic gain of across-population genomic breeding programs given moderate G×E. The across-population selection strategy remains to be optimized to maximize genetic gain.


Assuntos
Fluxo Gênico , Interação Gene-Ambiente , Animais , Bovinos/genética , Genômica , Genótipo , Modelos Genéticos , Seleção Genética
14.
Curr Protoc ; 1(5): e136, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34043288

RESUMO

The use of genome editing tools is expanding our understanding of various human diseases by providing insight into gene-disease interactions. Despite the recognized role of toxicants in the development of human health issues and conditions, there is currently limited characterization of their mechanisms of action, and the application of CRISPR-based genome editing to the study of toxicants could help in the identification of novel gene-environment interactions. CRISPR-based functional screens enable identification of cellular mechanisms fundamental for response and susceptibility to a given toxicant. The aim of this review is to inform future directions in the application of CRISPR technologies in toxicological studies. We review and compare different types of CRISPR-based methods including pooled, anchored, combinatorial, and perturb-sequencing screens in vitro, in addition to pooled screenings in model organisms. © 2021 Wiley Periodicals LLC.


Assuntos
Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Sistemas CRISPR-Cas/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Edição de Genes , Interação Gene-Ambiente , Humanos , Análise de Sequência
16.
Sci Rep ; 11(1): 7647, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33828129

RESUMO

Unemployment shocks from the COVID-19 pandemic have reignited concerns over the long-term effects of job loss on population health. Past research has highlighted the corrosive effects of unemployment on health and health behaviors. This study examines whether the effects of job loss on changes in body mass index (BMI) are moderated by genetic predisposition using data from the U.S. Health and Retirement Study (HRS). To improve detection of gene-by-environment (G × E) interplay, we interacted layoffs from business closures-a plausibly exogenous environmental exposure-with whole-genome polygenic scores (PGSs) that capture genetic contributions to both the population mean (mPGS) and variance (vPGS) of BMI. Results show evidence of genetic moderation using a vPGS (as opposed to an mPGS) and indicate genome-wide summary measures of phenotypic plasticity may further our understanding of how environmental stimuli modify the distribution of complex traits in a population.


Assuntos
Índice de Massa Corporal , Interação Gene-Ambiente , Desemprego , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Ocupações , Aposentadoria
17.
Int J Mol Sci ; 22(9)2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33925009

RESUMO

Asthma exacerbations are associated with significant childhood morbidity and mortality. Recurrent asthma attacks contribute to progressive loss of lung function and can sometimes be fatal or near-fatal, even in mild asthma. Exacerbation prevention becomes a primary target in the management of all asthmatic patients. Our work reviews current advances on exacerbation predictive factors, focusing on the role of non-invasive biomarkers and genetics in order to identify subjects at higher risk of asthma attacks. Easy-to-perform tests are necessary in children; therefore, interest has increased on samples like exhaled breath condensate, urine and saliva. The variability of biomarker levels suggests the use of seriate measurements and composite markers. Genetic predisposition to childhood asthma onset has been largely investigated. Recent studies highlighted the influence of single nucleotide polymorphisms even on exacerbation susceptibility, through involvement of both intrinsic mechanisms and gene-environment interaction. The role of molecular and genetic aspects in exacerbation prediction supports an individual-shaped approach, in which follow-up planning and therapy optimization take into account not only the severity degree, but also the risk of recurrent exacerbations. Further efforts should be made to improve and validate the application of biomarkers and genomics in clinical settings.


Assuntos
Asma/etiologia , Asma/genética , Asma/metabolismo , Biomarcadores/metabolismo , Criança , Progressão da Doença , Eosinofilia/imunologia , Eosinofilia/patologia , Expiração , Interação Gene-Ambiente , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Interleucina-6/sangue , Óxido Nítrico/metabolismo , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Índice de Gravidade de Doença , Transcriptoma , Compostos Orgânicos Voláteis/metabolismo
18.
J Environ Sci Health B ; 56(5): 477-482, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33872129

RESUMO

The aim of this study was to explore the association between metabolizing enzyme gene polymorphisms and the decrease in cholinesterase activity induced by omethoate exposure. A total of 180 workers exposed to omethoate over an extended period were recruited along with 115 healthy controls. Cholinesterase activity in whole blood, erythrocyte, and plasma was detected using acetylthiocholine and the dithio-bis-(nitrobenzoic acid) method. Six polymorphic loci of GSTT1(+/-), GSTM1(+/-), GSTP1 rs1695, CYP2E1 rs6413432, CYP2E1 rs3813867, and PON2 rs12026 were detected by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The gene-environment interactions were analyzed using the generalized linear model method. The cholinesterase activity of erythrocyte and plasma in the exposure group was significantly lower than that in the control group (P < 0.001) in general. The plasma cholinesterase activity in the TT + AT genotype in CYP2E1 rs6413432 was lower than that in the AA genotype in the exposure group (P = 0.016). Interaction between the AA genotype in CYP2E1 rs6413432 and omethoate exposure had a significant effect on plasma cholinesterase activity (P = 0.079). The decrease in plasma cholinesterase activity was associated with interaction between the AA genotypes in rs6413432 and omethoate exposure.


Assuntos
Colinesterases/sangue , Citocromo P-450 CYP2E1/genética , Dimetoato/análogos & derivados , Exposição Ocupacional/efeitos adversos , Adulto , Dimetoato/efeitos adversos , Eritrócitos/enzimologia , Feminino , Interação Gene-Ambiente , Genótipo , Humanos , Masculino , Polimorfismo Genético
19.
Mol Genet Genomics ; 296(4): 837-844, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33880640

RESUMO

Evidence shows that mutations in vitamin D receptor (VDR) have been linked with an increased risk of type 2 diabetes (T2D). However, the interaction effect between VDR variants and environmental factors on the T2D susceptibility remained unclear. Therefore, the current study was conducted to explore the joint effect of VDR polymorphisms and serum triglyceride level on T2D. A total of 2017 participants were included in the cross-sectional study. Taqman probe assays were applied to rs3847987 and rs739837 genotyping. Multiple logistic regression and general linear model were used to examine the effect of interaction between VDR variants and TG on T2D susceptibility and fasting serum glucose, respectively. The results showed that rs739837 polymorphism was significantly associated with an increased risk of T2D under the dominant model (OR = 1.30, 95% CI 1.02-1.66), after adjusting for potential risk factors. Meanwhile, there was a significant additive interaction between rs3847987 and hypertriglyceridemia (synergy index [SI]: 2.98, 95% CI: 1.23-7.23) and between rs739837 and hypertriglyceridemia (SI: 2.36, 95% CI: 1.05-5.31) on T2D susceptibility. Additionally, a significant linear association between fasting glucose and rs3847987 had been found at high triglyceride level (> 1.90 mmol/L) with an inversely concentration-dependent manner. The study provided further evidence that rs739837 and high level of triglyceride were both associated with higher T2D susceptibility in Chinese population. Additionally, the detrimental effect of VDR variants on T2D could be modified by hypertriglyceridemia status.


Assuntos
Diabetes Mellitus Tipo 2/genética , Hipertrigliceridemia/genética , Receptores de Calcitriol/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , China/epidemiologia , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Interação Gene-Ambiente , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/complicações , Hipertrigliceridemia/epidemiologia , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue
20.
G3 (Bethesda) ; 11(4)2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33835165

RESUMO

Envirotyping is an essential technique used to unfold the nongenetic drivers associated with the phenotypic adaptation of living organisms. Here, we introduce the EnvRtype R package, a novel toolkit developed to interplay large-scale envirotyping data (enviromics) into quantitative genomics. To start a user-friendly envirotyping pipeline, this package offers: (1) remote sensing tools for collecting (get_weather and extract_GIS functions) and processing ecophysiological variables (processWTH function) from raw environmental data at single locations or worldwide; (2) environmental characterization by typing environments and profiling descriptors of environmental quality (env_typing function), in addition to gathering environmental covariables as quantitative descriptors for predictive purposes (W_matrix function); and (3) identification of environmental similarity that can be used as an enviromic-based kernel (env_typing function) in whole-genome prediction (GP), aimed at increasing ecophysiological knowledge in genomic best-unbiased predictions (GBLUP) and emulating reaction norm effects (get_kernel and kernel_model functions). We highlight literature mining concepts in fine-tuning envirotyping parameters for each plant species and target growing environments. We show that envirotyping for predictive breeding collects raw data and processes it in an eco-physiologically smart way. Examples of its use for creating global-scale envirotyping networks and integrating reaction-norm modeling in GP are also outlined. We conclude that EnvRtype provides a cost-effective envirotyping pipeline capable of providing high quality enviromic data for a diverse set of genomic-based studies, especially for increasing accuracy in GP across untested growing environments.


Assuntos
Interação Gene-Ambiente , Modelos Genéticos , Agricultura , Genômica , Genótipo , Fenótipo , Software
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