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1.
Int J Mol Sci ; 24(15)2023 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-37569459

RESUMO

Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to prioritize drugs targeting these routes, paving the road to clinical application. Here, we describe DAGGER (Drug Repositioning by Analysis of GWAS and Gene Expression in R), a straightforward pipeline to find currently approved drugs with repurposing potential. As a proof of concept, we analyzed a meta-GWAS of 1.6 × 107 single-nucleotide polymorphisms performed on Alzheimer's disease (AD). Our pipeline uses the Genotype-Tissue Expression (GTEx) and Drug Gene Interaction (DGI) databases for a rational prioritization of 22 druggable targets. Next, we performed a two-stage in vivo functional assay. We used a C. elegans humanized model over-expressing the Aß1-42 peptide. We assayed the five top-scoring candidate drugs, finding midostaurin, a multitarget protein kinase inhibitor, to be a protective drug. Next, 3xTg AD transgenic mice were used for a final evaluation of midostaurin's effect. Behavioral testing after three weeks of 20 mg/kg intraperitoneal treatment revealed a significant improvement in behavior, including locomotion, anxiety-like behavior, and new-place recognition. Altogether, we consider that our pipeline might be a useful tool for drug repurposing in complex diseases.


Assuntos
Doença de Alzheimer , Animais , Camundongos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Estudo de Associação Genômica Ampla , Caenorhabditis elegans/genética , Estaurosporina/uso terapêutico , Reposicionamento de Medicamentos
2.
Int J Mol Sci ; 24(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36674414

RESUMO

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer's disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10-20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Masculino , Feminino , Doença de Alzheimer/genética , Cromossomos Humanos Y/genética , Estudo de Associação Genômica Ampla , Mosaicismo , Fatores de Risco , Disfunção Cognitiva/genética , Proteínas tau/genética , Biomarcadores , Peptídeos beta-Amiloides/genética
3.
J Infect Dis ; 222(12): 2007-2011, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-32516401

RESUMO

Toll-like receptor 2 (TLR2) plays a key role in innate immune response recognizing molecular patterns expressed by pathogens. rs111200466 is a TLR2 promoter insertion/deletion polymorphism with contradictory data about its role in human immunodeficiency virus type 1 (HIV-1) infection. We analyzed rs111200466 in HIV-1 disease progression and showed a correlation with a faster progression to the CD4+ < 200 cells/µL outcome for deletion allele carriers (Cox regression analysis: hazard ratio, 2.4 [95% confidence interval, 1.4-4]; P = .001). When naive patients with CD4+ < 200 cells/µL started antiretroviral treatment, rs111200466-deletion carriers showed a trend toward a slower, recovery rate (time required to reach CD4+ > 350 cells/µL; Cox P = .36). Our data suggest rs111200466 as a prognosis factor for HIV-1 disease progression.


Assuntos
Contagem de Linfócito CD4 , Infecções por HIV/genética , Polimorfismo Genético , Receptor 2 Toll-Like/genética , Estudos de Coortes , Progressão da Doença , Feminino , HIV-1 , Humanos , Masculino , Prognóstico , Regiões Promotoras Genéticas , Análise de Sobrevida
4.
Int J Geriatr Psychiatry ; 35(11): 1292-1300, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32584440

RESUMO

OBJECTIVES: An increasing evidence suggests hypertension (HTN) could be linked to cognitive impairment and incident Alzheimer's disease (AD). The precise mechanisms linking HTN and AD are not well-known. The aim of this study was to assess the putative association between HTN and AD. METHODS: We assessed in patients with AD associations between HTN and demographic and clinical data, vascular risk factors, treatments, APOE genotypes, brain white matter hyperintensities (WMH), and medial temporal atrophy (MTA) in multivariate analysis of covariance. RESULTS: We studied 92 patients with AD (mean ± SD age: 72.12 ± 6.91; women: 66.30%). Patients with HTN had significantly worse cognitive and functional status and higher frequency and severity of neuropsychiatric symptoms (P = .010). Magnetic resonance imaging analyzes showed significant increases in WMH (P = .018) and in MTA (P = .012) in patients with AD with HTN compared with those without HTN. CONCLUSIONS: Neuroimaging burden (MTA and higher degree of severity of WMH) among patients with AD and HTN are associated with the impaired cognitive function and neuropsychiatric symptoms.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Hipertensão , Substância Branca , Idoso , Doença de Alzheimer/patologia , Atrofia/patologia , Cognição , Disfunção Cognitiva/patologia , Feminino , Humanos , Hipertensão/patologia , Imageamento por Ressonância Magnética , Lobo Temporal/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
5.
J Infect Dis ; 219(5): 772-776, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30289470

RESUMO

An interferon λ4 gene (IFNL4) knockout allele (rs368234815; TT) is associated with spontaneous and IFN-α-dependent cure of hepatitis C virus infection. The role of this polymorphism in the susceptibility to human immunodeficiency virus type 1 (HIV-1) infection is controversial. This study aimed to assess the association of this knockout IFNL4 variant and sexually transmitted HIV-1 infection. A total of 228 HIV-1-positive individuals and 136 HIV-exposed seronegative individuals were investigated for their association with IFNL4 rs368234815 genotypes. The IFNL4 ΔG functional allele is associated with increased susceptibility to HIV-1 infection through the sexual route (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.2-3.6; P = .004). A meta-analysis including a population of injection drug users suggests a codominant mode of inheritance of this risk factor (OR, 2.0; 95% CI, 1.3-3.2; P = .001).


Assuntos
Transmissão de Doença Infecciosa , Predisposição Genética para Doença , Infecções por HIV/genética , Infecções por HIV/transmissão , Interleucinas/genética , Deleção de Sequência , Feminino , Genótipo , Humanos , Masculino
6.
Alzheimers Dement ; 15(10): 1333-1347, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31473137

RESUMO

INTRODUCTION: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. METHODS: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. RESULTS: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. DISCUSSION: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series.


Assuntos
Doença de Alzheimer/genética , Endofenótipos , Loci Gênicos , Estudo de Associação Genômica Ampla , Idoso , Doença de Alzheimer/classificação , Demência/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Espanha
7.
Reprod Biomed Online ; 36(5): 560-567, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29602729

RESUMO

Spermatozoa and neurones share similar membrane characteristics and features. Associations of multiple polymorphisms traditionally related to neurotransmission were investigated. Infertile men were grouped into controls with normospermia (n = 182) and idiopathic infertile men with asthenozoospermia (n = 103), and analysed as a case-control study and as a quantitative association of each genotype. Ten neurotransmission-associated genetic variants were mapped by SNP analysis using quantitative polymerase chain reaction with TaqMan probes. Men with HTR2A rs6313 had a higher risk of asthenozoospermia (OR = 2.14; P = 0.04). MAOA rs3788862 G carriers displayed an increased risk of asthenozoospermia (OR = 2.29; P = 0.02). The SLC18A1 rs1390938 G allele was more frequent among such cases (0.75 versus 0.87; P < 0.01 and P < 0.01 for Armitage trend test); for SLC18A1 rs2270641 P = 0.02 (case-control frequency) and P = 0.01 (Armitage trend test). MAOA rs3788862 was correlated with sperm motility (Spearman ρ = 0.14; P = 0.02); SLC18A1 rs1390938 was correlated with sperm count and motility (Spearman ρ = 0.20; P < 0.01). Gene polymorphisms of HTR2A, MAOA and SLC18A1, related to neurotransmission, are individually associated with asthenozoospermia through variation in sperm count and motility, without detectable allelic or genotype interaction.


Assuntos
Astenozoospermia/genética , Monoaminoxidase/genética , Receptor 5-HT2A de Serotonina/genética , Contagem de Espermatozoides , Motilidade dos Espermatozoides/genética , Proteínas Vesiculares de Transporte de Monoamina/genética , Estudos de Casos e Controles , Genótipo , Humanos , Masculino , Monoaminoxidase/fisiologia , Polimorfismo Genético , Receptor 5-HT2A de Serotonina/fisiologia , Proteínas Vesiculares de Transporte de Monoamina/fisiologia
8.
Reprod Biomed Online ; 34(6): 653-658, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28410957

RESUMO

The present study was undertaken to determine the role of different polymorphisms affecting the testosterone/oestrogen pathway in miscarriage. Alpha 5-reductase (SRD5A2) rs523349 and rs9282858, cytochrome P450 aromatase (CYP19A1) rs4646, rs10046 and rs2236722 and oestrogen receptor (ESR1) rs9340799, rs2234693 and rs6932902 polymorphisms were selected. The case group consisted of 94 samples of formalin-fixed and paraffin-embedded fetal tissue from a miscarriage at ≤24 weeks. The control group comprised a population of 331 young healthy subjects. Only those single nucleotide polymorphisms (SNPs) fitting the Hardy-Weinberg equilibrium (n = 4) and euploid miscarriage samples (n = 67) were included for downstream analysis. Interestingly, SRD5A2 rs523349 (Val89Leu) was significantly associated with the risk of undergoing miscarriage after Bonferroni correction (odds ratio = 11.245, P < 2.2 × 10-9). Moreover, when Mantel-Cox regression analysis was performed, we observed that the effect was significantly constrained to the second trimester (P = 0.024, log rank). These results are compatible with an imbalance of testosterone/dihydrotestosterone, associated with a higher risk of miscarriage, especially in late pregnancy.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Aborto Espontâneo/genética , Aromatase/genética , Receptor alfa de Estrogênio/genética , Proteínas de Membrana/genética , Estudos de Casos e Controles , Feto/química , Humanos , Polimorfismo de Nucleotídeo Único
9.
Mol Cell Probes ; 29(6): 517-521, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26239731

RESUMO

Copy number variant (CNV) regions have been proven to have a significant impact on gene expression. Some of them have been also found to be associated to different human diseases. CNV genotyping is often prone to error and cross-validation with independent methods is frequently required. The platform of choice depends on whether it is a genome-wide discovery screening or a candidate CNV study, the cohort size and the number of CNVs included in the assay and, finally, the budget available. Here we illustrate a affordable approach to determine the CNV genotype using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) and based on the quantitative determination of single nucleotide duplicated mismatches (SNDM) mapping the CNV region and a paralogue genomic region that is used as a two-copy reference. We have genotyped nsv436327, a common CNV mapping SIRPB1 intron 1 that has been associated to human personality behavior. SIRP cluster region was subjected to several ancestral duplication events what makes SIRPB1 CNV genotyping technically challenging. We designed three sets of primer pairs that amplified paralogue regions inside and outside the CNV, containing three SNDMs. Post-PCR extension analyses of sequencing oligonucleotides mapping immediately upstream each SNDM allowed us to quantify using MALDI-MS the proportion of PCR products derived from the CNV region versus the external reference. In contrast to other approaches, setting up this genotyping method requires an affordable investment.


Assuntos
Variações do Número de Cópias de DNA , Receptores de Superfície Celular/genética , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Primers do DNA/genética , Evolução Molecular , Técnicas de Genotipagem , Humanos , Transtornos da Personalidade/genética , Polimorfismo de Nucleotídeo Único
10.
Methods ; 62(3): 241-5, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23619567

RESUMO

Zebrafish have been extensively used in biomedical research as a model to study vertebrate development but it is only recently that it has also been adopted into varied fields such as immunology and host-pathogen interactions. Zebrafish have a rapid life cycle, small size and the adults exhibit no territorial behavior in relatively dense cages. Under standard conditions each female lays an average of a hundred eggs per clutch, providing a large number of larvae per week. Their transparency during early life stages allows real time visualization of the different organs, which makes them especially suitable for the study of bacterial host-pathogen interactions. Traditionally, these studies have been technically challenging in higher organisms, given the loss of control over the bacteria once the pathogen infects its host. Here we describe an emerging approach to monitor Salmonella typhimurium infection progression using in vivo fluorescence upon parenteral infection. We have engineered Salmonella with the Cascade expression system; an efficient method to voluntarily activate bacterial heterologous gene expression at any point during infection once inside the Zebrafish macrophages, using a non-toxic inducer.


Assuntos
Embrião não Mamífero/imunologia , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Macrófagos/imunologia , Salmonella typhimurium/genética , Peixe-Zebra/imunologia , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Embrião não Mamífero/microbiologia , Engenharia Genética , Macrófagos/microbiologia , Macrófagos/ultraestrutura , Microinjeções , Microscopia de Fluorescência , Regiões Promotoras Genéticas/efeitos dos fármacos , Ácido Salicílico/farmacologia , Salmonella typhimurium/imunologia , Salmonella typhimurium/ultraestrutura , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Transcrição Gênica , Peixe-Zebra/microbiologia
11.
Proc Natl Acad Sci U S A ; 108(34): 14186-91, 2011 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-21844364

RESUMO

Specific regulatory states, i.e., sets of expressed transcription factors, define the gene expression capabilities of cells in animal development. Here we explore the functional significance of an unprecedented example of regulatory state conservation from the cnidarian Nematostella to Drosophila, sea urchin, fish, and mammals. Our probe is a deeply conserved cis-regulatory DNA module of the SRY-box B2 (soxB2), recognizable at the sequence level across many phyla. Transphyletic cis-regulatory DNA transfer experiments reveal that the plesiomorphic control function of this module may have been to respond to a regulatory state associated with neuronal differentiation. By introducing expression constructs driven by this module from any phyletic source into the genomes of diverse developing animals, we discover that the regulatory state to which it responds is used at different levels of the neurogenic developmental process, including patterning and development of the vertebrate forebrain and neurogenesis in the Drosophila optic lobe and brain. The regulatory state recognized by the conserved DNA sequence may have been redeployed to different levels of the developmental regulatory program during evolution of complex central nervous systems.


Assuntos
Evolução Biológica , Sequência Conservada/genética , Regulação da Expressão Gênica no Desenvolvimento , Filogenia , Animais , Animais Geneticamente Modificados , Sequência de Bases , Encéfalo/embriologia , Encéfalo/metabolismo , DNA Intergênico/genética , Drosophila/genética , Elementos Facilitadores Genéticos/genética , Larva/genética , Dados de Sequência Molecular , Fatores de Transcrição SOXB2/genética , Ouriços-do-Mar/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética
12.
Methods Mol Biol ; 2751: 19-30, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38265707

RESUMO

Studying host-pathogen interactions at a molecular level has always been technically challenging. Identifying the different biochemical and genetic pathways involved in the different stages of infection traditionally require complex molecular biology tools and often the use of costly animal models. In this chapter, we illustrate a complementary approach to address host-pathogen interactions, taking advantage of the natural interindividual genetic diversity. The application of genetic association studies allows us to identify alleles involved in infection progression or resistance. Thus, this strategy may be useful to unravel new molecular pathways underlying host-pathogen interactions. Here we present the general steps that might be followed to plan, execute, and analyze a population-based study in order to identify genetic variants affecting human exposition to pathogens.


Assuntos
Interações Hospedeiro-Patógeno , Biologia Molecular , Animais , Humanos , Alelos , Estudos de Associação Genética , Modelos Animais
13.
Antiviral Res ; 222: 105795, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38181855

RESUMO

BACKGROUND & AIMS: It has been reported that specific killer-cell immunoglobulin-like receptors (KIRs) and HLA genotype combinations, such as KIR2DS4/HLA-C1 with presence of KIRDL2 or KIRDL3, homozygous KIRDL3/HLA-C1 and KIR3DL1/≥2HLA-Bw4, are strongly associated with the lack of active infection and seroconversion after exposition to hepatitis C virus (HCV). OBJECTIVE: To determine whether these KIR-HLA combinations are relevant factors involved in that phenotype. PATIENTS AND METHODS: In this retrospective case-control study, genotype data from a genome-wide association study previously performed on low susceptibility to HCV-infection carried out on 27 high-risk HCV-seronegative (HRSN) individuals and 743 chronically infected (CI) subjects were used. HLA alleles were imputed using R package HIBAG v1.2223 and KIR genotypes were imputed using the online resource KIR*IMP v1.2.0. RESULTS: It was possible to successfully impute at least one KIR-HLA genotype combination previously associated with the lack of infection and seroconversion after exposition to HCV in a total of 23 (85.2%) HRSN individuals and in 650 (87.5%) CI subjects. No KIR-HLA genotype combination analyzed was related to the HRSN condition. CONCLUSIONS: Our results suggest that those KIR-HLA genotype combinations are not relevant factors involved in the lack of infection and seroconversion after exposition to HCV. More studies will be needed to completely understand this phenotype.


Assuntos
Hepacivirus , Hepatite C , Humanos , Hepacivirus/genética , Estudos de Casos e Controles , Estudos Retrospectivos , Estudo de Associação Genômica Ampla , Soroconversão , Genótipo , Receptores KIR/genética
14.
medRxiv ; 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39281766

RESUMO

Background: Alzheimer's disease (AD) has a high heritable component characteristic of complex diseases, yet many of the genetic risk factors remain unknown. We combined genome-wide association studies (GWAS) on amyloid endophenotypes measured in cerebrospinal fluid (CSF) and positron emission tomography (PET) as surrogates of amyloid pathology, which may be helpful to understand the underlying biology of the disease. Methods: We performed a meta-analysis of GWAS of CSF Aß42 and PET measures combining six independent cohorts (n=2,076). Due to the opposite effect direction of Aß phenotypes in CSF and PET measures, only genetic signals in the opposite direction were considered for analysis (n=376,599). Polygenic risk scores (PRS) were calculated and evaluated for AD status and amyloid endophenotypes. We then searched the CSF proteome signature of brain amyloidosis using SOMAscan proteomic data (Ace cohort, n=1,008) and connected it with GWAS results of loci modulating amyloidosis. Finally, we compared our results with a large meta-analysis using publicly available datasets in CSF (n=13,409) and PET (n=13,116). This combined approach enabled the identification of overlapping genes and proteins associated with amyloid burden and the assessment of their biological significance using enrichment analyses. Results: After filtering the meta-GWAS, we observed genome-wide significance in the rs429358-APOE locus and nine suggestive hits were annotated. We replicated the APOE loci using the large CSF-PET meta-GWAS and identified multiple AD-associated genes as well as the novel GADL1 locus. Additionally, we found a significant association between the AD PRS and amyloid levels, whereas no significant association was found between any Aß PRS with AD risk. CSF SOMAscan analysis identified 1,387 FDR-significant proteins associated with CSF Aß42 levels. The overlap among GWAS loci and proteins associated with amyloid burden was very poor (n=35). The enrichment analysis of overlapping hits strongly suggested several signalling pathways connecting amyloidosis with the anchored component of the plasma membrane, synapse physiology and mental disorders that were replicated in the large CSF-PET meta-analysis. Conclusions: The strategy of combining CSF and PET amyloid endophenotypes GWAS with CSF proteome analyses might be effective for identifying signals associated with the AD pathological process and elucidate causative molecular mechanisms behind the amyloid mobilization in AD.

16.
J Med Genet ; 49(7): 442-50, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22791839

RESUMO

BACKGROUND: SHOX, located in the pseudoautosomal region 1 (PAR1) of the sexual chromosomes, encodes a transcription factor implicated in human growth. Defects in SHOX or its enhancers have been observed in ∼60% of Leri-Weill dyschondrosteosis (LWD) patients, a skeletal dysplasia characterised by short stature and/or the characteristic Madelung deformity, and in 2-5% of idiopathic short stature (ISS). To identify the molecular defect in the remaining genetically undiagnosed LWD and ISS patients, this study screened previously unanalysed PAR1 regions in 124 LWD and 576 ISS probands. METHODS: PAR1 screening was undertaken by multiplex ligation dependent probe amplification (MLPA). Copy number alterations were subsequently confirmed and delimited by locus-specific custom-designed MLPA, array comparative genomic hybridisation (CGH) and breakpoint junction PCR/sequencing. RESULTS: A recurrent PAR1 deletion downstream of SHOX spanning 47543 bp with identical breakpoints was identified in 19 LWD (15.3%) and 11 ISS (1.9%) probands, from 30 unrelated families. Eight evolutionarily conserved regions (ECRs 1-8) identified within the deleted sequence were evaluated for SHOX regulatory activity by means of chromosome conformation capture (3C) in chicken embryo limbs and luciferase reporter assays in human U2OS osteosarcoma cells. The 3C assay indicated potential SHOX regulatory activity by ECR1, which was subsequently confirmed to act as a SHOX enhancer, operating in an orientation and position independent manner, in human U2OS cells. CONCLUSIONS: This study has identified the first recurrent PAR1 deletion in LWD and ISS, which results in the loss of a previously uncharacterised SHOX enhancer. The loss of this enhancer may decrease SHOX transcription, resulting in LWD or ISS due to SHOX haploinsufficiency.


Assuntos
Elementos Facilitadores Genéticos , Transtornos do Crescimento/genética , Proteínas de Homeodomínio/genética , Osteocondrodisplasias/genética , Deleção de Sequência/genética , Cromossomos Sexuais/genética , Animais , Embrião de Galinha , Criança , Estudos de Coortes , Extremidades/patologia , Feminino , Dosagem de Genes , Frequência do Gene , Haploinsuficiência , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Cromossomos Sexuais/metabolismo , Proteína de Homoeobox de Baixa Estatura , Fatores de Transcrição/genética
17.
Gene ; 850: 146958, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36220449

RESUMO

Genome variations contribute to the vast majority of interindividual differences and may decisively influence sports capability. This study was conceived as a means of finding out when exactly polymorphisms start being physically discriminative. The polymorphisms we studied were two of the best characterized ones: ACE I/D and ACTN3 R577X. These germline variants were determined in a cohort of 200 healthy volunteers from the university environment who underwent a series of physical evaluations that included a Cooper test, a 20-meter sprint test and a vertical jump test. Initially, no statistical association was found because the genetic effect was masked by those subjects with sedentary lifestyles. But when only physically active volunteers were considered, the ACE and ACTN3 genotypes were found to have an impact on heart rate after the Cooper test (p-value = 0.033 and 0.032 respectively) and ACTN3 was found to correlate with the total distance covered in the same test (p-value = 0.051). This can therefore be considered a paradigmatic example in which the environment might hide the genetic effect, with genotypic differences arising only upon training.


Assuntos
Actinina , Exercício Físico , Peptidil Dipeptidase A , Desempenho Físico Funcional , Humanos , Actinina/genética , Exercício Físico/genética , Exercício Físico/fisiologia , Genótipo , Peptidil Dipeptidase A/genética , Polimorfismo Genético
18.
iScience ; 26(7): 107214, 2023 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-37456859

RESUMO

Some HIV controllers experience immunologic progression with CD4+ T cell decline. We aimed to identify genetic factors associated with CD4+ T cell lost in HIV controllers. A total of 561 HIV controllers were included, 442 and 119 from the International HIV controllers Study Cohort and the Swiss HIV Cohort Study, respectively. No SNP or gene was associated with the long-term non-progressor HIV spontaneous control phenotype in the individual GWAS or in the meta-analysis. However, SNPs previously associated with natural HIV control linked to HLA-B (rs2395029 [p = 0.005; OR = 1.70], rs59440261 [p = 0.003; OR = 1.78]), MICA (rs112243036 [p = 0.011; OR = 1.45]), and PSORS1C1 loci (rs3815087 [p = 0.017; OR = 1.39]) showed nominal association with this phenotype. Genetic factors associated with the long-term HIV controllers without risk of immunologic progression are those previously related to the overall HIV controller phenotype.

19.
JAMA Netw Open ; 6(5): e2313734, 2023 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-37195665

RESUMO

Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, Setting, and Participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main Outcomes and Measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). Conclusions and Relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation.


Assuntos
Doença de Alzheimer , Humanos , Feminino , Idoso , Idoso de 80 Anos ou mais , Masculino , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , HDL-Colesterol , Fatores de Risco , Causalidade
20.
Cell J ; 22(4): 572-574, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32347052

RESUMO

Recently, it has been proposed the association of a common deletion affecting toll-like receptor 2 promoter (-196 to -177) to type 2 diabetes mellitus risk. However, genotyping results show a significant deviation from the Hardy- Weinberg Equilibrium (HWE). The law of Hardy-Weinberg shows that for an autosomal biallelic marker with allele frequencies fA=p and fa=q, the proportion of subjects with genotypes AA, Aa, and aa should follow the following: fAA=p2, fAa=2pq, and faa=q2. Departure from HWE or Hardy-Weinberg Disequilibrium (HWD) in a human control population can be caused by natural factors such as selective pressure against a certain genotype. However their prevalence is scarce and magnitude of effect over the HWE are small. Other factors such as inbreeding caused by consanguinity, population stratification, or technical problems in genotyping are more usual. Nevertheless, if the control population follows a perfect HWE, the presence HWD among patients might be explained by the genetic association and evidencing a real link between the locus and the trait under study. However, HWD affecting both cases and controls, such as the one reported might be explained by one of the aforementioned issues.

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