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1.
BMC Genomics ; 22(1): 432, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34107879

RESUMO

BACKGROUND: Circulating white blood cell and platelet traits are clinically linked to various disease outcomes and differ across individuals and ancestry groups. Genetic factors play an important role in determining these traits and many loci have been identified. However, most of these findings were identified in populations of European ancestry (EA), with African Americans (AA), Hispanics/Latinos (HL), and other races/ethnicities being severely underrepresented. RESULTS: We performed ancestry-combined and ancestry-specific genome-wide association studies (GWAS) for white blood cell and platelet traits in the ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) Study, including 16,201 AA, 21,347 HL, and 27,236 EA participants. We identified six novel findings at suggestive significance (P < 5E-8), which need confirmation, and independent signals at six previously established regions at genome-wide significance (P < 2E-9). We confirmed multiple previously reported genome-wide significant variants in the single variant association analysis and multiple genes using PrediXcan. Evaluation of loci reported from a Euro-centric GWAS indicated attenuation of effect estimates in AA and HL compared to EA populations. CONCLUSIONS: Our results highlighted the potential to identify ancestry-specific and ancestry-agnostic variants in participants with diverse backgrounds and advocate for continued efforts in improving inclusion of racially/ethnically diverse populations in genetic association studies for complex traits.


Assuntos
Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , Genômica , Humanos , Leucócitos , Fenótipo
2.
BMC Plant Biol ; 21(1): 255, 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34082694

RESUMO

BACKGROUND: Rice (Oryza sativa) bacterial leaf blight (BLB), caused by the hemibiotrophic Xanthomonas oryzae pv. oryzae (Xoo), is one of the most devastating diseases affecting the production of rice worldwide. The development and use of resistant rice varieties or genes is currently the most effective strategy to control BLB. RESULTS: Here, we used 259 rice accessions, which are genotyped with 2 888 332 high-confidence single nucleotide polymorphisms (SNPs). Combining resistance variation data of 259 rice lines for two Xoo races observed in 2 years, we conducted a genome-wide association study (GWAS) to identify quantitative trait loci (QTL) conferring plant resistance against BLB. The expression levels of genes, which contains in GWAS results were also identified between the resistant and susceptible rice lines by transcriptome analysis at four time points after pathogen inoculation. From that 109 candidate resistance genes showing significant differential expression between resistant and susceptible rice lines were uncovered. Furthermore, the haplotype block structure analysis predicted 58 candidate genes for BLB resistance based on Chr. 7_707158 with a minimum P-value (-log 10 P = 9.72). Among them, two NLR protein-encoding genes, LOC_Os07g02560 and LOC_Os07g02570, exhibited significantly high expression in the resistant line, but had low expression in the susceptible line of rice. CONCLUSIONS: Together, our results reveal novel BLB resistance gene resources, and provide important genetic basis for BLB resistance breeding of rice crops.


Assuntos
Regulação da Expressão Gênica de Plantas , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Oryza/genética , Doenças das Plantas/microbiologia , Transcriptoma , Regulação da Expressão Gênica de Plantas/imunologia , Genótipo , Haplótipos , Doenças das Plantas/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
3.
Int J Mol Sci ; 22(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068765

RESUMO

Epigenetics refers to the DNA chemistry changes that result in the modification of gene transcription and translation independently of the underlying DNA coding sequence. Epigenetic modifications are reported to involve various molecular mechanisms, including classical epigenetic changes affecting DNA methylation and histone modifications and small RNA-mediated processes, particularly that of microRNAs. Epigenetic changes are reversible and are closely interconnected. They are recognised to play a critical role as mediators of gene regulation, and any alteration in these mechanisms has been identified to mediate various pathophysiological conditions. Moreover, genetic predisposition and environmental factors, including dietary alterations, lifestyle or metabolic status, are identified to interact with the human epigenome, highlighting the importance of epigenetic factors as underlying processes in the aetiology of various diseases such as MetS. This review will reflect on how both the classical and microRNA-regulated epigenetic changes are associated with the pathophysiology of metabolic syndrome. We will then focus on the various aspects of epigenetic-based strategies used to modify MetS outcomes, including epigenetic diet, epigenetic drugs, epigenome editing tools and miRNA-based therapies.


Assuntos
Epigênese Genética , Código das Histonas/genética , Síndrome Metabólica/genética , Metilação de DNA , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença , Histonas/genética , Humanos , Síndrome Metabólica/patologia , MicroRNAs/genética
4.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071723

RESUMO

Pathogenic copy number variations (CNVs) contribute to the etiology of neurodevelopmental/neuropsychiatric disorders (NDs). Increased CNV burden has been found to be critically involved in NDs compared with controls in clinical studies. The 1q21.1 CNVs, rare and large chromosomal microduplications and microdeletions, are detected in many patients with NDs. Phenotypes of duplication and deletion appear at the two ends of the spectrum. Microdeletions are predominant in individuals with schizophrenia (SCZ) and microcephaly, whereas microduplications are predominant in individuals with autism spectrum disorder (ASD) and macrocephaly. However, its complexity hinders the discovery of molecular pathways and phenotypic networks. In this review, we summarize the recent genome-wide association studies (GWASs) that have identified candidate genes positively correlated with 1q21.1 CNVs, which are likely to contribute to abnormal phenotypes in carriers. We discuss the clinical data implicated in the 1q21.1 genetic structure that is strongly associated with neurodevelopmental dysfunctions like cognitive impairment and reduced synaptic plasticity. We further present variations reported in the phenotypic severity, genomic penetrance and inheritance.


Assuntos
Anormalidades Múltiplas/genética , Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Megalencefalia/genética , Transtornos Mentais/genética , Transtorno do Espectro Autista/genética , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 1/genética , Estudo de Associação Genômica Ampla , Humanos , Microcefalia/genética , Doenças Neurodegenerativas/genética , Transtornos do Neurodesenvolvimento/genética , Esquizofrenia/genética
5.
Nat Commun ; 12(1): 3391, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099646

RESUMO

Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study's primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels (p = 0.0006, CI 95%: 4.12, 13.32) and particle number (p = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration (p = 0.024, CI 95%: 1.1, -26.5), cholesterol efflux capacity (p = 0.08, CI 95%: -0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele.


Assuntos
Aterosclerose/prevenção & controle , Inibidores de Janus Quinases/administração & dosagem , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Piperidinas/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Idoso , Animais , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/imunologia , HDL-Colesterol/sangue , Método Duplo-Cego , Feminino , Predisposição Genética para Doença , Fatores de Risco de Doenças Cardíacas , Humanos , Inibidores de Janus Quinases/efeitos adversos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Piperidinas/efeitos adversos , Pirimidinas/efeitos adversos , Fator de Transcrição STAT4/genética , Resultado do Tratamento , Rigidez Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Adulto Jovem
6.
Nat Commun ; 12(1): 3417, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099642

RESUMO

Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease.


Assuntos
Doença de Alzheimer/genética , Herança Multifatorial , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Apolipoproteínas E/genética , Estudos de Casos e Controles , Estudos de Coortes , Conjuntos de Dados como Assunto , Feminino , Seguimentos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco/métodos , Fatores de Risco
7.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 33(5): 630-632, 2021 May.
Artigo em Chinês | MEDLINE | ID: mdl-34112308

RESUMO

Sepsis is a clinical syndrome caused by the host reaction disorder induced by infection, which leads to serious organ function damage. Sepsis is a serious disease with high mortality, which is the main reason of death caused by infection. Single nucleotide polymorphisms (SNP) is one of the most common genetic variants in human, and is closely related to the genetic susceptibility, early diagnosis, disease development and prognosis of sepsis. This article makes a review on the relationship between CD14, Toll like receptor (TLR), tumor necrosis factor (TNF), interleukins (IL-1 and IL-6), plasminogen activator inhibitor 1 (PAI-1), angiotensin converting enzyme (ACE) and other gene polymorphisms and genetic susceptibility of sepsis, in order to affect in sepsis on the early prediction, diagnosis, and treatment.


Assuntos
Predisposição Genética para Doença , Sepse , Humanos , Polimorfismo de Nucleotídeo Único , Sepse/genética , Receptores Toll-Like , Fator de Necrose Tumoral alfa/genética
8.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065857

RESUMO

The mitochondria are essential for normal cell functioning. Changes in mitochondrial DNA (mtDNA) may affect the occurrence of some chronic diseases and cancer. This process is complex and not entirely understood. The assignment to a particular mitochondrial haplogroup may be a factor that either contributes to cancer development or reduces its likelihood. Mutations in mtDNA occurring via an increase in reactive oxygen species may favour the occurrence of further changes both in mitochondrial and nuclear DNA. Mitochondrial DNA mutations in postmitotic cells are not inherited, but may play a role both in initiation and progression of cancer. One of the first discovered polymorphisms associated with cancer was in the gene NADH-ubiquinone oxidoreductase chain 3 (mt-ND3) and it was typical of haplogroup N. In prostate cancer, these mutations and polymorphisms involve a gene encoding subunit I of respiratory complex IV cytochrome c oxidase subunit 1 gene (COI). At present, a growing number of studies also address the impact of mtDNA polymorphisms on prognosis in cancer patients. Some of the mitochondrial DNA polymorphisms occur in both chronic disease and cancer, for instance polymorphism G5913A characteristic of prostate cancer and hypertension.


Assuntos
DNA Mitocondrial/genética , Mitocôndrias/genética , Neoplasias/genética , Progressão da Doença , Complexo I de Transporte de Elétrons/genética , Complexo IV da Cadeia de Transporte de Elétrons/genética , Predisposição Genética para Doença , Humanos , Mutação , Neoplasias/metabolismo , Polimorfismo Genético , Espécies Reativas de Oxigênio/metabolismo
9.
BMC Med Inform Decis Mak ; 21(1): 180, 2021 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-34090422

RESUMO

BACKGROUND: Women with pathogenic BRCA1 and BRCA2 mutations possess a high risk of developing breast and ovarian cancer. They face difficult choices when considering preventive options. This study presents the development process of the first decision aids to support this complex decision-making process in the German healthcare system. METHODS: A six-step development process based on the International Patient Decision Aid Standards was used, including a systematic literature review of existing decision aids, a topical medical literature review, preparation of the decision aids, focus group discussions with women with BRCA1/2 mutations, internal and external reviews by clinical and self-help experts, and user tests. All reviews were followed by iterative revisions. RESULTS: No existing decision aids were transferable to the German setting. The medical research revealed a need to develop separate decision aids for women with BRCA1/2 mutations (A) without a history of cancer (previvors) and (B) with a history of unilateral breast cancer (survivors). The focus group discussions confirmed a high level of approval for the decision aids from both target groups. Additionally, previvors requested more information on risk-reducing breast surgery, risk-reducing removal of both ovaries and Fallopian tubes, and psychological aspects; survivors especially wanted more information on breast cancer on the affected side (e.g. biological parameters, treatment, and risk of recurrence). CONCLUSIONS: In a structured process, two target-group-specific DAs for previvors/survivors with BRCA1/2 mutations were developed to support decision-making on risk-adapted preventive options. These patient-oriented tools offer an important addition to existing specialist medical care in Germany.


Assuntos
Neoplasias da Mama , Neoplasias Ovarianas , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Técnicas de Apoio para a Decisão , Feminino , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Alemanha , Humanos , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle
10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(3): 690-695, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34105458

RESUMO

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


Assuntos
Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras , Alelos , Estudos de Casos e Controles , Criança , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Fator de Transcrição Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
11.
Int J Mol Sci ; 22(10)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065289

RESUMO

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


Assuntos
COVID-19/genética , COVID-19/metabolismo , Predisposição Genética para Doença , Receptores CCR5/genética , Receptores CCR5/metabolismo , Alelos , Brônquios/metabolismo , Brônquios/patologia , Brônquios/virologia , COVID-19/fisiopatologia , Cromossomos Humanos/genética , Estudos de Coortes , Biologia Computacional , Bases de Dados Genéticas , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Exoma
12.
Int J Mol Sci ; 22(9)2021 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-34066804

RESUMO

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


Assuntos
COVID-19/genética , Predisposição Genética para Doença , Peptidil Dipeptidase A/genética , Idoso , Alelos , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/metabolismo , COVID-19/fisiopatologia , COVID-19/virologia , Comorbidade , Antígenos HLA/genética , Antígenos HLA/metabolismo , Haplótipos , Humanos , Inflamação/genética , Inflamação/metabolismo , Homem de Neandertal/genética , Peptidil Dipeptidase A/metabolismo , Polimorfismo Genético , Fatores de Risco , Índice de Gravidade de Doença
13.
PLoS Med ; 18(6): e1003605, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34061844

RESUMO

BACKGROUND: Increased vitamin D levels, as reflected by 25-hydroxy vitamin D (25OHD) measurements, have been proposed to protect against COVID-19 based on in vitro, observational, and ecological studies. However, vitamin D levels are associated with many confounding variables, and thus associations described to date may not be causal. Vitamin D Mendelian randomization (MR) studies have provided results that are concordant with large-scale vitamin D randomized trials. Here, we used 2-sample MR to assess evidence supporting a causal effect of circulating 25OHD levels on COVID-19 susceptibility and severity. METHODS AND FINDINGS: Genetic variants strongly associated with 25OHD levels in a genome-wide association study (GWAS) of 443,734 participants of European ancestry (including 401,460 from the UK Biobank) were used as instrumental variables. GWASs of COVID-19 susceptibility, hospitalization, and severe disease from the COVID-19 Host Genetics Initiative were used as outcome GWASs. These included up to 14,134 individuals with COVID-19, and up to 1,284,876 without COVID-19, from up to 11 countries. SARS-CoV-2 positivity was determined by laboratory testing or medical chart review. Population controls without COVID-19 were also included in the control groups for all outcomes, including hospitalization and severe disease. Analyses were restricted to individuals of European descent when possible. Using inverse-weighted MR, genetically increased 25OHD levels by 1 standard deviation on the logarithmic scale had no significant association with COVID-19 susceptibility (odds ratio [OR] = 0.95; 95% CI 0.84, 1.08; p = 0.44), hospitalization (OR = 1.09; 95% CI: 0.89, 1.33; p = 0.41), and severe disease (OR = 0.97; 95% CI: 0.77, 1.22; p = 0.77). We used an additional 6 meta-analytic methods, as well as conducting sensitivity analyses after removal of variants at risk of horizontal pleiotropy, and obtained similar results. These results may be limited by weak instrument bias in some analyses. Further, our results do not apply to individuals with vitamin D deficiency. CONCLUSIONS: In this 2-sample MR study, we did not observe evidence to support an association between 25OHD levels and COVID-19 susceptibility, severity, or hospitalization. Hence, vitamin D supplementation as a means of protecting against worsened COVID-19 outcomes is not supported by genetic evidence. Other therapeutic or preventative avenues should be given higher priority for COVID-19 randomized controlled trials.


Assuntos
COVID-19/sangue , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença , Deficiência de Vitamina D/sangue , Vitamina D/análogos & derivados , Adulto , Idoso , COVID-19/etiologia , Estudos de Casos e Controles , Causalidade , Suplementos Nutricionais , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hospitalização , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , SARS-CoV-2 , Vitamina D/sangue , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/genética
15.
Rev Med Liege ; 76(5-6): 327-336, 2021 May.
Artigo em Francês | MEDLINE | ID: mdl-34080359

RESUMO

A personal or family history of cancer has now become the primary cause of genetic consultations. In recent years, various genes have been identified that are associated with a more or less marked genetic predisposition to the development of cancers. The syndrome associated with the hereditary risk of breast and ovarian cancer and the Lynch syndrome are the most frequent ones, but there are many other, much less common, situations associated with familial cancer risk. In most cases, there are clear recommendations regarding the indications for genetic testing and the follow-up of patients identified as having a predisposition to cancer. At the CHU of Liège, we currently perform more than 1.400 oncogenetic consultations per year and we maintain a positivity rate of genetic tests performed in this indication higher than 10%. In this way, we allow a multidisciplinary care of patients with a high oncological risk and participate in a prevention and surveillance activity. We also pay increasing attention to the hereditary risk associated with pediatric cancers and to patients with multiple cancers, especially when these develop at an early age. Finally, the oncogenetic consultation must consider the psychological, ethical and legal aspects of a diagnosis that involves the patient and his or her future, but also the whole family.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Hereditariedade , Neoplasias Ovarianas , Criança , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Feminino , Predisposição Genética para Doença , Testes Genéticos , Humanos
16.
Cells ; 10(6)2021 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-34070971

RESUMO

The recent SARS-CoV-2 pandemic has refocused attention to the betacoronaviruses, only eight years after the emergence of another zoonotic betacoronavirus, the Middle East respiratory syndrome coronavirus (MERS-CoV). While the wild source of SARS-CoV-2 may be disputed, for MERS-CoV, dromedaries are considered as source of zoonotic human infections. Testing 100 immune-response genes in 121 dromedaries from United Arab Emirates (UAE) for potential association with present MERS-CoV infection, we identified candidate genes with important functions in the adaptive, MHC-class I (HLA-A-24-like) and II (HLA-DPB1-like), and innate immune response (PTPN4, MAGOHB), and in cilia coating the respiratory tract (DNAH7). Some of these genes previously have been associated with viral replication in SARS-CoV-1/-2 in humans, others have an important role in the movement of bronchial cilia. These results suggest similar host genetic pathways associated with these betacoronaviruses, although further work is required to better understand the MERS-CoV disease dynamics in both dromedaries and humans.


Assuntos
Imunidade Adaptativa/genética , Camelus/virologia , Doenças Transmissíveis Emergentes/imunologia , Infecções por Coronavirus/imunologia , Imunidade Inata/genética , Zoonoses/imunologia , Animais , Anticorpos Antivirais , Brônquios/citologia , Brônquios/fisiologia , COVID-19/genética , COVID-19/imunologia , COVID-19/virologia , Camelus/genética , Camelus/imunologia , Cílios/fisiologia , Doenças Transmissíveis Emergentes/genética , Doenças Transmissíveis Emergentes/transmissão , Doenças Transmissíveis Emergentes/virologia , Infecções por Coronavirus/genética , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Reservatórios de Doenças/virologia , Feminino , Predisposição Genética para Doença , Interações entre Hospedeiro e Microrganismos/genética , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Masculino , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Coronavírus da Síndrome Respiratória do Oriente Médio/patogenicidade , Mucosa Respiratória/citologia , Mucosa Respiratória/fisiologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Emirados Árabes Unidos , Replicação Viral/genética , Replicação Viral/imunologia , Zoonoses/genética , Zoonoses/transmissão , Zoonoses/virologia
17.
Genes (Basel) ; 12(6)2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071309

RESUMO

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


Assuntos
COVID-19/genética , COVID-19/virologia , Receptor com Domínio Discoidina 1/genética , Predisposição Genética para Doença , Interferons/genética , Polimorfismo de Nucleotídeo Único , SARS-CoV-2/fisiologia , Metaloproteases Semelhantes a Toloide/genética , Alelos , Biomarcadores , COVID-19/diagnóstico , COVID-19/imunologia , Estudos de Casos e Controles , Comorbidade , Citocinas/metabolismo , Feminino , Genótipo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata , Masculino , Prognóstico , Índice de Gravidade de Doença , Carga Viral
18.
Genome Med ; 13(1): 83, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001247

RESUMO

BACKGROUND: While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challenge. Methods are needed to systematically bridge this crucial gap to facilitate experimental testing of hypotheses and translation to clinical utility. RESULTS: Here, we leveraged cross-phenotype associations to identify traits with shared genetic architecture, using linkage disequilibrium (LD) information to accurately capture shared SNPs by proxy, and calculate significance of enrichment. This shared genetic architecture was examined across differing biological scales through incorporating data from catalogs of clinical, cellular, and molecular GWAS. We have created an interactive web database (interactive Cross-Phenotype Analysis of GWAS database (iCPAGdb)) to facilitate exploration and allow rapid analysis of user-uploaded GWAS summary statistics. This database revealed well-known relationships among phenotypes, as well as the generation of novel hypotheses to explain the pathophysiology of common diseases. Application of iCPAGdb to a recent GWAS of severe COVID-19 demonstrated unexpected overlap of GWAS signals between COVID-19 and human diseases, including with idiopathic pulmonary fibrosis driven by the DPP9 locus. Transcriptomics from peripheral blood of COVID-19 patients demonstrated that DPP9 was induced in SARS-CoV-2 compared to healthy controls or those with bacterial infection. Further investigation of cross-phenotype SNPs associated with both severe COVID-19 and other human traits demonstrated colocalization of the GWAS signal at the ABO locus with plasma protein levels of a reported receptor of SARS-CoV-2, CD209 (DC-SIGN). This finding points to a possible mechanism whereby glycosylation of CD209 by ABO may regulate COVID-19 disease severity. CONCLUSIONS: Thus, connecting genetically related traits across phenotypic scales links human diseases to molecular and cellular measurements that can reveal mechanisms and lead to novel biomarkers and therapeutic approaches. The iCPAGdb web portal is accessible at http://cpag.oit.duke.edu and the software code at https://github.com/tbalmat/iCPAGdb .


Assuntos
/genética , Bases de Dados de Ácidos Nucleicos , Predisposição Genética para Doença , Desequilíbrio de Ligação , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , /genética , Estudo de Associação Genômica Ampla , Humanos
19.
Med Sci Monit ; 27: e929911, 2021 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-33935279

RESUMO

BACKGROUND We performed the present study to better elucidate the correlation of reduced folate carrier-1 (RFC1) A80G (rs1051266) polymorphism with the risk of congenital heart disease (CHD). MATERIAL AND METHODS According to the designed search strategy, a systematic literature search was performed through the PubMed, Cochrane Library, Web of Science, EMBASE, CNKI, VIP, and Wan Fang databases to collect published case-control studies on the correlation between RFC1 A80G polymorphism and CHD. All relevant studies up to October 1, 2019 were identified. The odds ratio (OR) and 95% confidence interval (CI) of the genotype distribution were used as the effect indicators. RESULTS A total of 6 eligible studies was finally included in our meta-analysis, including 724 children with CHD, 760 healthy children, 258 mothers of the children with CHD, and 334 mothers of healthy control children. The meta-analysis revealed that for fetal analysis, only in the heterozygous model (GA vs GG, OR=1.36, 95% CI [1.06, 1.75], P=0.02) was RFC1 A80G polymorphism associated with risk of CHD. In maternal analysis, 3 genetic models of RFC1 A80G polymorphism increased the risk of CHD: the allelic model (A vs G, OR=1.36, 95% CI [1.07, 1.71], P=0.01), the homozygote model (AA vs GG, OR=2.99, 95%CI [1.06, 8.41], P=0.04), and the dominance model (GA+AA vs GG, OR=1.53, 95%CI [1.08, 2.16], P=0.02). CONCLUSIONS The maternal RFC1 A80G polymorphism has a strong correlation with CHD. Compared with the G allele, the A allele increases the risk of CHD by 0.36-fold.


Assuntos
Predisposição Genética para Doença/genética , Cardiopatias Congênitas/genética , Polimorfismo de Nucleotídeo Único/genética , Proteína Carregadora de Folato Reduzido/genética , Alelos , Estudos de Casos e Controles , Genótipo , Humanos , Fatores de Risco
20.
Hum Genomics ; 15(1): 29, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001248

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a global health problem that causes millions of deaths worldwide. The clinical manifestation of COVID-19 widely varies from asymptomatic infection to severe pneumonia and systemic inflammatory disease. It is thought that host genetic variability may affect the host's response to the virus infection and thus cause severity of the disease. The SARS-CoV-2 virus requires interaction with its receptor complex in the host cells before infection. The transmembrane protease serine 2 (TMPRSS2) has been identified as one of the key molecules involved in SARS-CoV-2 virus receptor binding and cell invasion. Therefore, in this study, we investigated the correlation between a genetic variant within the human TMPRSS2 gene and COVID-19 severity and viral load. RESULTS: We genotyped 95 patients with COVID-19 hospitalised in Dr Soetomo General Hospital and Indrapura Field Hospital (Surabaya, Indonesia) for the TMPRSS2 p.Val160Met polymorphism. Polymorphism was detected using a TaqMan assay. We then analysed the association between the presence of the genetic variant and disease severity and viral load. We did not observe any correlation between the presence of TMPRSS2 genetic variant and the severity of the disease. However, we identified a significant association between the p.Val160Met polymorphism and the SARS-CoV-2 viral load, as estimated by the Ct value of the diagnostic nucleic acid amplification test. Furthermore, we observed a trend of association between the presence of the C allele and the mortality rate in patients with severe COVID-19. CONCLUSION: Our data indicate a possible association between TMPRSS2 p.Val160Met polymorphism and SARS-CoV-2 infectivity and the outcome of COVID-19.


Assuntos
/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Serina Endopeptidases/genética , Adulto , Alelos , /virologia , Estudos Transversais , Feminino , Frequência do Gene , Genótipo , Humanos , Indonésia , Masculino , Pessoa de Meia-Idade , Carga Viral/genética
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