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1.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204499

RESUMO

BACKGROUND: Brugada syndrome (BrS) is an autosomal dominantly inherited cardiac disease characterized by "coved type" ST-segment elevation in the right precordial leads, high susceptibility to ventricular arrhythmia and a family history of sudden cardiac death. The SCN5A gene, encoding for the cardiac voltage-gated sodium channel Nav1.5, accounts for ~20-30% of BrS cases and is considered clinically relevant. METHODS: Here, we describe the clinical findings of two Italian families affected by BrS and provide the functional characterization of two novel SCN5A mutations, the missense variant Pro1310Leu and the in-frame insertion Gly1687_Ile1688insGlyArg. RESULTS: Despite being clinically different, both patients have a family history of sudden cardiac death and had history of arrhythmic events. The Pro1310Leu mutation significantly reduced peak sodium current density without affecting channel membrane localization. Changes in the gating properties of expressed Pro1310Leu channel likely account for the loss-of-function phenotype. On the other hand, Gly1687_Ile1688insGlyArg channel, identified in a female patient, yielded a nearly undetectable sodium current. Following mexiletine incubation, the Gly1687_Ile1688insGlyArg channel showed detectable, albeit very small, currents and biophysical properties similar to those of the Nav1.5 wild-type channel. CONCLUSIONS: Overall, our results suggest that the degree of loss-of-function shown by the two Nav1.5 mutant channels correlates with the aggressive clinical phenotype of the two probands. This genotype-phenotype correlation is fundamental to set out appropriate therapeutical intervention.


Assuntos
Síndrome de Brugada/diagnóstico , Síndrome de Brugada/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Potenciais de Ação , Idoso , Idoso de 80 Anos ou mais , Alelos , Substituição de Aminoácidos , Eletrocardiografia , Feminino , Estudos de Associação Genética/métodos , Genótipo , Humanos , Itália , Masculino , Modelos Biológicos , Modelos Moleculares , Canal de Sódio Disparado por Voltagem NAV1.5/química , Canal de Sódio Disparado por Voltagem NAV1.5/metabolismo , Linhagem , Fenótipo , Conformação Proteica , Transporte Proteico
2.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204582

RESUMO

Autosomal recessive polycystic kidney disease (ARPKD) is a rare disorder and one of the most severe forms of polycystic kidney disease, leading to end-stage renal disease (ESRD) in childhood. PKHD1 is the gene that is responsible for the vast majority of ARPKD. However, some cases have been related to a new gene that was recently identified (DZIP1L gene), as well as several ciliary genes that can mimic a ARPKD-like phenotypic spectrum. In addition, a number of molecular pathways involved in the ARPKD pathogenesis and progression were elucidated using cellular and animal models. However, the function of the ARPKD proteins and the molecular mechanism of the disease currently remain incompletely understood. Here, we review the clinics, treatment, genetics, and molecular basis of ARPKD, highlighting the most recent findings in the field.


Assuntos
Suscetibilidade a Doenças , Rim Policístico Autossômico Recessivo/etiologia , Rim Policístico Autossômico Recessivo/metabolismo , Animais , Biomarcadores , Ensaios Clínicos como Assunto , Terapia Combinada , Diagnóstico Diferencial , Gerenciamento Clínico , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Humanos , Mutação , Fenótipo , Rim Policístico Autossômico Recessivo/patologia , Locos de Características Quantitativas , Receptores de Superfície Celular/química , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade , Resultado do Tratamento
3.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202524

RESUMO

Left ventricular non-compaction cardiomyopathy (LVNC) is a rare heart disease, with or without left ventricular dysfunction, which is characterized by a two-layer structure of the myocardium and an increased number of trabeculae. The study of familial forms of LVNC is helpful for risk prediction and genetic counseling of relatives. Here, we present a family consisting of three members with LVNC. Using a next-generation sequencing approach a combination of two (likely) pathogenic nonsense mutations DSG2-p.S363X and TBX20-p.D278X was identified in all three patients. TBX20 encodes the cardiac T-box transcription factor 20. DSG2 encodes desmoglein-2, which is part of the cardiac desmosomes and belongs to the cadherin family. Since the identified nonsense variant (DSG2-p.S363X) is localized in the extracellular domain of DSG2, we performed in vitro cell transfection experiments. These experiments revealed the absence of truncated DSG2 at the plasma membrane, supporting the pathogenic relevance of DSG2-p.S363X. In conclusion, we suggest that in the future, these findings might be helpful for genetic screening and counseling of patients with LVNC.


Assuntos
Cardiomiopatias/diagnóstico , Cardiomiopatias/etiologia , Desmogleína 2/genética , Mutação , Proteínas com Domínio T/genética , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/etiologia , Adulto , Células Cultivadas , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Testes de Função Cardíaca , Humanos , Imageamento por Ressonância Magnética/métodos , Linhagem , Avaliação de Sintomas
4.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072296

RESUMO

Diacylglycerol kinases are intracellular enzymes that control the balance between the secondary messengers diacylglycerol and phosphatidic acid. DGKα and DGKζ are the prominent isoforms that restrain the intensity of T cell receptor signalling by metabolizing PLCγ generated diacylglycerol. Thus, their activity must be tightly controlled to grant cellular homeostasis and refine immune responses. DGKα is specifically inhibited by strong T cell activating signals to allow for full diacylglycerol signalling which mediates T cell response. In X-linked lymphoproliferative disease 1, deficiency of the adaptor protein SAP results in altered T cell receptor signalling, due in part to persistent DGKα activity. This activity constrains diacylglycerol levels, attenuating downstream pathways such as PKCθ and Ras/MAPK and decreasing T cell restimulation induced cell death. This is a form of apoptosis triggered by prolonged T cell activation that is indeed defective in CD8+ cells of X-linked lymphoproliferative disease type 1 patients. Accordingly, inhibition or downregulation of DGKα activity restores in vitro a correct diacylglycerol dependent signal transduction, cytokines production and restimulation induced apoptosis. In animal disease models, DGKα inhibitors limit CD8+ expansion and immune-mediated tissue damage, suggesting the possibility of using inhibitors of diacylglycerol kinase as a new therapeutic approach.


Assuntos
Diacilglicerol Quinase/genética , Diacilglicerol Quinase/metabolismo , Suscetibilidade a Doenças , Genes Ligados ao Cromossomo X , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/metabolismo , Animais , Biomarcadores , Diacilglicerol Quinase/química , Ativação Enzimática , Estudos de Associação Genética/métodos , Loci Gênicos , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Transtornos Linfoproliferativos/diagnóstico , Ligação Proteica , Transdução de Sinais , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/metabolismo , Relação Estrutura-Atividade , Linfócitos T/imunologia , Linfócitos T/metabolismo
5.
Int J Mol Sci ; 22(11)2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-34072463

RESUMO

The NBN gene has been included in breast cancer (BC) multigene panels based on early studies suggesting an increased BC risk for carriers, though not confirmed by recent research. To evaluate the impact of NBN analysis, we assessed the results of NBN sequencing in 116 BRCA-negative BC patients and reviewed the literature. Three patients (2.6%) carried potentially relevant variants: two, apparently unrelated, carried the frameshift variant c.156_157delTT and another one the c.628G>T variant. The latter was subsequently found in 4/1390 (0.3%) BC cases and 8/1580 (0.5%) controls in an independent sample, which, together with in silico predictions, provided evidence against its pathogenicity. Conversely, the rare c.156_157delTT variant was absent in the case-control set; moreover, a 50% reduction of NBN expression was demonstrated in one carrier. However, in one family it failed to co-segregate with BC, while the other carrier was found to harbor also a probably pathogenic TP53 variant that may explain her phenotype. Therefore, the c.156_157delTT, although functionally deleterious, was not supported as a cancer-predisposing defect. Pathogenic/likely pathogenic NBN variants were detected by multigene panels in 31/12314 (0.25%) patients included in 15 studies. The risk of misinterpretation of such findings is substantial and supports the exclusion of NBN from multigene panels.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Proteínas de Ciclo Celular/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Proteínas Nucleares/genética , Adulto , Alelos , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética/métodos , Testes Genéticos , Genótipo , Haplótipos , Humanos , Linhagem
6.
Neurology ; 96(18): e2251-e2260, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-34038384

RESUMO

OBJECTIVE: To identify the causative gene in a large unsolved family with genetic epilepsy with febrile seizures plus (GEFS+), we sequenced the genomes of family members, and then determined the contribution of the identified gene to the pathogenicity of epilepsies by examining sequencing data from 2,772 additional patients. METHODS: We performed whole genome sequencing of 3 members of a GEFS+ family. Subsequently, whole exome sequencing data from 1,165 patients with epilepsy from the Epi4K dataset and 1,329 Australian patients with epilepsy from the Epi25 dataset were interrogated. Targeted resequencing was performed on 278 patients with febrile seizures or GEFS+ phenotypes. Variants were validated and familial segregation examined by Sanger sequencing. RESULTS: Eight previously unreported missense variants were identified in SLC32A1, coding for the vesicular inhibitory amino acid cotransporter VGAT. Two variants cosegregated with the phenotype in 2 large GEFS+ families containing 8 and 10 affected individuals, respectively. Six further variants were identified in smaller families with GEFS+ or idiopathic generalized epilepsy (IGE). CONCLUSION: Missense variants in SLC32A1 cause GEFS+ and IGE. These variants are predicted to alter γ-aminobutyric acid (GABA) transport into synaptic vesicles, leading to altered neuronal inhibition. Examination of further epilepsy cohorts will determine the full genotype-phenotype spectrum associated with SLC32A1 variants.


Assuntos
Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/genética , Variação Genética/genética , Mutação de Sentido Incorreto/genética , Convulsões Febris/diagnóstico , Convulsões Febris/genética , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/genética , Feminino , Estudos de Associação Genética/métodos , Humanos , Masculino , Linhagem
7.
Nat Commun ; 12(1): 2878, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001886

RESUMO

Structural variations of the human brain are heritable and highly polygenic traits, with hundreds of associated genes identified in recent genome-wide association studies (GWAS). Transcriptome-wide association studies (TWAS) can both prioritize these GWAS findings and also identify additional gene-trait associations. Here we perform cross-tissue TWAS analysis of 211 structural neuroimaging and discover 278 associated genes exceeding Bonferroni significance threshold of 1.04 × 10-8. The TWAS-significant genes for brain structures have been linked to a wide range of complex traits in different domains. Through TWAS gene-based polygenic risk scores (PRS) prediction, we find that TWAS PRS gains substantial power in association analysis compared to conventional variant-based GWAS PRS, and up to 6.97% of phenotypic variance (p-value = 7.56 × 10-31) can be explained in independent testing data sets. In conclusion, our study illustrates that TWAS can be a powerful supplement to traditional GWAS in imaging genetics studies for gene discovery-validation, genetic co-architecture analysis, and polygenic risk prediction.


Assuntos
Encéfalo/metabolismo , Perfilação da Expressão Gênica/métodos , Pleiotropia Genética/genética , Estudo de Associação Genômica Ampla/métodos , Herança Multifatorial/genética , Encéfalo/diagnóstico por imagem , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Humanos , Neuroimagem/métodos , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética
8.
Int J Mol Sci ; 22(7)2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33807176

RESUMO

Uterine fibroid tissues are often compared to their matched myometrium in an effort to understand their pathophysiology, but it is not clear whether the myometria of uterine fibroid patients represent truly non-disease control tissues. We analyzed the transcriptomes of myometrial samples from non-fibroid patients (M) and compared them with fibroid (F) and matched myometrial (MF) samples to determine whether there is a phenotypic difference between fibroid and non-fibroid myometria. Multidimensional scaling plots revealed that M samples clustered separately from both MF and F samples. A total of 1169 differentially expressed genes (DEGs) (false discovery rate < 0.05) were observed in the MF comparison with M. Overrepresented Gene Ontology terms showed a high concordance of upregulated gene sets in MF compared to M, particularly extracellular matrix and structure organization. Gene set enrichment analyses showed that the leading-edge genes from the TGFß signaling and inflammatory response gene sets were significantly enriched in MF. Overall comparison of the three tissues by three-dimensional principal component analyses showed that M, MF, and F samples clustered separately from each other and that a total of 732 DEGs from F vs. M were not found in the F vs. MF, which are likely understudied in the pathogenesis of uterine fibroids and could be key genes for future investigation. These results suggest that the transcriptome of fibroid-associated myometrium is different from that of non-diseased myometrium and that fibroid studies should consider using both matched myometrium and non-diseased myometrium as controls.


Assuntos
Leiomioma/genética , Miométrio/patologia , Útero/patologia , Adulto , Feminino , Perfilação da Expressão Gênica/métodos , Estudos de Associação Genética/métodos , Genótipo , Humanos , Leiomioma/patologia , Pessoa de Meia-Idade , Miométrio/metabolismo , Fenótipo , Análise de Componente Principal/métodos , Transcriptoma/genética , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Útero/metabolismo
9.
Mol Genet Genomics ; 296(4): 905-918, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33914130

RESUMO

Phenotype is one of the most significant concepts in genetics, which is used to describe all the characteristics of a research object that can be observed. Considering that phenotype reflects the integrated features of genotype and environment factors, it is hard to define phenotype characteristics, even difficult to predict unknown phenotypes. Restricted by current biological techniques, it is still quite expensive and time-consuming to obtain sufficient structural information of large-scale phenotype-associated genes/proteins. Various bioinformatics methods have been presented to solve such problem, and researchers have confirmed the efficacy and prediction accuracy of functional network-based prediction. But general functional descriptions have highly complicated inner structures for phenotype prediction. To further address this issue and improve the efficacy of phenotype prediction on more than ten kinds of phenotypes, we first extract functional enrichment features from GO and KEGG, and then use node2vec to learn functional embedding features of genes from a gene-gene network. All these features are analyzed by some feature selection methods (Boruta, minimum redundancy maximum relevance) to generate a feature list. Such list is fed into the incremental feature selection, incorporating some multi-label classifiers built by RAkEL and some classic base classifiers, to build an optimum multi-label multi-class classification model for phenotype prediction. According to recent researches, our method has indeed identified many literature-supported genes/proteins and their associated phenotypes, and even some candidate genes with re-assigned new phenotypes, which provide a new computational tool for the accurate and effective phenotypic prediction.


Assuntos
Algoritmos , Biologia Computacional/métodos , Estudos de Associação Genética/métodos , Conjuntos de Dados como Assunto , Redes Reguladoras de Genes/fisiologia , Redes e Vias Metabólicas/genética , Fenótipo , Proteínas/química , Proteínas/genética , Proteínas/fisiologia , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/fisiologia , Relação Estrutura-Atividade
10.
Front Immunol ; 12: 589639, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33859633

RESUMO

Interleukin (IL)33, a member of the IL1 superfamily, functions as a nuclear factor and mediates biological effects by interacting with the ST2 receptor. Recent studies have described IL33 as an emerging pro-inflammatory cytokine in the immune system, and IL33/ST2 gene polymorphisms have been implicated in the pathogenesis of various immune diseases. However, the underlying mechanisms of IL33/ST2 in Behcet's disease (BD) remain to be defined. Here, we investigated the association between IL33/ST2 gene polymorphisms and BD in 585 BD uveitis (BDU) patients and 834 healthy controls using Agena MassARRAY iPLEX platform. We found that rs3821204 was associated with the development of BDU. Moreover, the frequency of rs2210463 G allele was lower in patients with genital involvement. Association analysis revealed a much greater genetic difference between complete-type and incomplete-type BD groups, including three SNPs (rs7044343, rs1048274, and rs2210463). Our findings suggest that IL33/ST2 gene polymorphisms are involved in the pathogenesis of BDU. Different genetic backgrounds may exist in complete-type and incomplete-type BD patients.


Assuntos
Síndrome de Behçet/diagnóstico , Síndrome de Behçet/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Interleucina-33/genética , Polimorfismo de Nucleotídeo Único , Alelos , Feminino , Estudos de Associação Genética/métodos , Genótipo , Humanos , Masculino , Fenótipo
11.
Int J Mol Sci ; 22(7)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808237

RESUMO

Global wheat (Triticum aestivum L.) production is constrained by different biotic and abiotic stresses, which are increasing with climate change. An improved root system is essential for adaptability and sustainable wheat production. In this study, 10 pairs of near-isogenic lines (NILs)-targeting four genomic regions (GRs) on chromosome arms 4BS, 4BL, 4AS, and 7AL of hexaploid wheat-were used to phenotype root traits in a semi-hydroponic system. Seven of the 10 NIL pairs significantly differed between their isolines for 11 root traits. The NIL pairs targeting qDSI.4B.1 GR varied the most, followed by the NIL pair targeting qDT.4A.1 and QHtscc.ksu-7A GRs. For pairs 5-7 targeting qDT.4A.1 GR, pair 6 significantly differed in the most root traits. Of the 4 NIL pairs targeting qDSI.4B.1 GR, pairs 2 and 4 significantly differed in 3 and 4 root traits, respectively. Pairs 9 and 10 targeting QHtscc.ksu-7A GR significantly differed in 1 and 4 root traits, respectively. Using the wheat 90K Illumina iSelect array, we identified 15 putative candidate genes associated with different root traits in the contrasting isolines, in which two UDP-glycosyltransferase (UGT)-encoding genes, TraesCS4A02G185300 and TraesCS4A02G442700, and a leucine-rich repeat receptor-like protein kinase (LRR-RLK)-encoding gene, TraesCS4A02G330900, also showed important functions for root trait control in other crops. This study characterized, for the first time, that these GRs control root traits in wheat, and identified candidate genes, although the candidate genes will need further confirmation and validation for marker-assisted wheat breeding.


Assuntos
Melhoramento Vegetal/métodos , Raízes de Plantas/genética , Triticum/genética , Mapeamento Cromossômico/métodos , Cromossomos de Plantas/genética , Estudos de Associação Genética/métodos , Genótipo , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Triticum/crescimento & desenvolvimento
12.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33801843

RESUMO

Recessive variants of the SLC26A4 gene are globally a common cause of hearing impairment. In the past, cell lines and transgenic mice were widely used to investigate the pathogenicity associated with SLC26A4 variants. However, discrepancies in pathogenicity between humans and cell lines or transgenic mice were documented for some SLC26A4 variants. For instance, the p.C565Y variant, which was reported to be pathogenic in humans, did not exhibit functional pathogenic consequences in cell lines. To address the pathogenicity of p.C565Y, we used a genotype-based approach in which we generated knock-in mice that were heterozygous (Slc26a4+/C565Y), homozygous (Slc26a4C565Y/C565Y), and compound heterozygous (Slc26a4919-2A>G/C565Y) for this variant. Subsequent phenotypic characterization revealed that mice with these genotypes demonstrated normal auditory and vestibular functions, and normal inner-ear morphology and pendrin expression. These findings indicate that the p.C565Y variant is nonpathogenic for mice, and that a single p.C565Y allele is sufficient to maintain normal inner-ear physiology in mice. Our results highlight the differences in pathogenicity associated with certain SLC26A4 variants between transgenic mice and humans, which should be considered when interpreting the results of animal studies for SLC26A4-related deafness.


Assuntos
Modelos Animais de Doenças , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/genética , Perda Auditiva Neurossensorial/genética , Mutação , Transportadores de Sulfato/genética , Animais , Genótipo , Perda Auditiva Neurossensorial/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fenótipo , Transportadores de Sulfato/fisiologia , Aqueduto Vestibular/metabolismo , Aqueduto Vestibular/patologia
13.
Front Immunol ; 12: 607966, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717091

RESUMO

Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) are well-known key immune checkpoints that play a crucial dampening effect on regulating T-cell homeostasis and self-tolerance. In this study, we aimed to evaluate the association between immune checkpoints (CTLA-4 and PD-1) and Posner-Schlossman syndrome (PSS) in a southern Chinese population. A total of 137 patients with PSS and 139 healthy controls from a southern Chinese population were recruited. Five single nucleotide polymorphisms (SNPs) of CTLA-4 (rs733618, rs4553808, rs5742909, rs231775, and rs3087243) and five SNPs of PD-1 (rs10204525, rs2227981, rs2227982, rs41386349, and rs36084323) were genotyped by SNaPshot technique. Soluble CTLA-4 (sCTLA-4) and soluble PD-1 (sPD-1) were determined by ELISA and antibody array assay, respectively. The frequencies of T allele at rs733618 and A allele at rs231775 of CTLA-4 were significantly higher in PSS patients than in healthy controls (corrected p (Pc ) = 0.037; Pc = 0.044, respectively). The haplotype frequencies of CACGG haplotype (rs733618-rs4553808-rs5742909-rs231775-rs3087243) of CTLA-4 and TGAGC haplotype (rs10204525-rs2227981-rs2227982-rs41386349-rs36084323) of PD-1 in the PSS group was significantly lower than those in the control group (Pc = 0.015, p = 0.034, respectively). Circulating plasma levels of sCTLA-4 and sPD-1 in PSS patients were significantly higher than those in controls (all p < 0.001). The present study suggests that CTLA-4 and PD-1 genetic polymorphisms are associated with the susceptibility to PSS in a southern Chinese population. The upregulated circulating plasma protein levels of sCTLA-4 and sPD-1 might provide some hints regarding the dysfunction of immune checkpoints in PSS during the active status.


Assuntos
Antígeno CTLA-4/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas de Checkpoint Imunológico/sangue , Proteínas de Checkpoint Imunológico/genética , Polimorfismo de Nucleotídeo Único , Receptor de Morte Celular Programada 1/genética , Adulto , Alelos , Biomarcadores , Estudos de Casos e Controles , China , Feminino , Frequência do Gene , Estudos de Associação Genética/métodos , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade
14.
Front Immunol ; 12: 606620, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33746952

RESUMO

Polycystic ovary syndrome (PCOS) and Hashimoto's thyroiditis (HT) are endocrine disorders that commonly occur among young women. A higher prevalence of HT in women with PCOS, relative to healthy individuals, is observed consistently. Combined occurrence of both diseases is associated with a higher risk of severe metabolic and reproductive complications. Genetic factors strongly impact the pathogenesis of both PCOS and HT and several susceptibility loci associated with a higher risk of both disorders have been identified. Furthermore, some candidate gene polymorphisms are thought to be functionally relevant; however, few genetic variants are proposed to be causally associated with the incidence of both disorders together.


Assuntos
Predisposição Genética para Doença , Doença de Hashimoto/epidemiologia , Doença de Hashimoto/etiologia , Síndrome do Ovário Policístico/epidemiologia , Síndrome do Ovário Policístico/etiologia , Alelos , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/etiologia , Autoimunidade/genética , Feminino , Estudos de Associação Genética/métodos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Prevalência
15.
Acta Biochim Pol ; 68(1): 77-81, 2021 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-33676378

RESUMO

The global prevalence of type-two diabetes mellitus (T2DM) makes it a disease of public health concern. T2DM is strongly linked with insulin resistance caused by increased levels of visceral fat. Visceral fat secretes several adipocytokines that regulate body metabolism. Resistin is one of these adipocytokines which is encoded by the RETN gene. Herein, we tested the association of the RETN +299(G>A) and -420(C>G) single nucleotide polymorphisms (SNPs) with T2DM. T2DM patients (n=282) and healthy subjects (n=125) were included in the study. Subjects with metabolic syndromes other than diabetes were excluded. Genotyping of subjects was performed using PCR-RFLP. The +299(G>A) SNP was associated with T2DM (P=0.038). The AA genotype was higher in T2DM (17%) compared to controls (8%) with an odd ratio of 2.16 and 95% CI of 1.34 to 4.56. With respect to -420(C>G) SNP, no significant association was found with the risk of T2DM (P=0.128). The haplotype analysis of the examined SNPs indicated that the CA haplotype of the -420 and +299 SNPs in RETN was associated with T2DM risk (P=0.004; odd ration 4.0, 95% CI: 1.56-10.0). In conclusion, the present findings suggest a role of the RETN locus in modulating the risk of T2DM.


Assuntos
Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único , Resistina/genética , Adulto , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados/métodos , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Feminino , Frequência do Gene , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Retrospectivos , Risco
16.
Med Sci Monit ; 27: e930591, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33723203

RESUMO

BACKGROUND Cytochrome P450 (CYP) genes are necessary for the production or metabolism of fetal sex hormones during pregnancy. The second-to-fourth digit ratio (2D: 4D) is formed in the early stage of human fetal development and considered an indicator reflecting prenatal sex steroids levels. We explored the association between 2D: 4D and single-nucleotide polymorphisms (SNPs) of CYP. MATERIAL AND METHODS Correlation analysis between 2D: 4D and 8 SNPs, rs2687133 (CPY3A7), rs7173655 (CYP11A1), rs1004467, rs17115149, and rs2486758 (CYP17A1), and rs4646, rs2255192, rs4275794 (CYP19A1), was performed using data from 426 female and 412 male Chinese university students. SNP genotyping was conducted using PCR. Digit lengths were photographed and measured by image processing software. RESULTS rs2486758 (CYP17A1) correlated with left hand 2D: 4D in men (P=0.026), and rs1004467 (CYP17A1) correlated with right hand 2D: 4D in men (P=0.008) and the whole population (P=0.032). In men, allele G rs1004467 decreased right hand 2D: 4D, while allele C of rs2486758 increased left hand 2D: 4D. In women, left hand 2D: 4D was higher in genotypes with allele A of SNP rs4646 (CYP19A1) under the dominant genetic model; female DR-L was higher in genotypes with allele T of rs17115149 (CYP11A1). SNPs rs2687133 (CYP3A7) and rs1004467 (CYP17A1) were significantly correlated with right hand 2D: 4D (P=0.0107). CONCLUSIONS SNPs rs1004467 and rs2486758 of CYP17A1 are significant in the relationship between 2D: 4D and CYP gene polymorphisms under different conditions. SNP interactions between CYP genes probably impact 2D: 4D. The correlation between 2D: 4D and some sex hormone-related diseases may be due to the effect of CYP variants on the 2 phenotypes.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Dedos/anatomia & histologia , Alelos , Aromatase/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Citocromo P-450 CYP3A/genética , Feminino , Frequência do Gene/genética , Estudos de Associação Genética/métodos , Genótipo , Humanos , Masculino , Nucleotídeos/genética , Polimorfismo de Nucleotídeo Único/genética , Esteroide 17-alfa-Hidroxilase/genética , Estudantes , Universidades , Adulto Jovem
17.
Nat Commun ; 12(1): 1964, 2021 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-33785739

RESUMO

Genome-wide association meta-analysis (GWAMA) is an effective approach to enlarge sample sizes and empower the discovery of novel associations between genotype and phenotype. Independent replication has been used as a gold-standard for validating genetic associations. However, as current GWAMA often seeks to aggregate all available datasets, it becomes impossible to find a large enough independent dataset to replicate new discoveries. Here we introduce a method, MAMBA (Meta-Analysis Model-based Assessment of replicability), for assessing the "posterior-probability-of-replicability" for identified associations by leveraging the strength and consistency of association signals between contributing studies. We demonstrate using simulations that MAMBA is more powerful and robust than existing methods, and produces more accurate genetic effects estimates. We apply MAMBA to a large-scale meta-analysis of addiction phenotypes with 1.2 million individuals. In addition to accurately identifying replicable common variant associations, MAMBA also pinpoints novel replicable rare variant associations from imputation-based GWAMA and hence greatly expands the set of analyzable variants.


Assuntos
Algoritmos , Biologia Computacional/métodos , Estudo de Associação Genômica Ampla/métodos , Metanálise como Assunto , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Estudos de Associação Genética/métodos , Genótipo , Fenótipo , Reprodutibilidade dos Testes , Tamanho da Amostra , Software
18.
Genes (Basel) ; 12(2)2021 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672558

RESUMO

CDC42 (cell division cycle protein 42) belongs to the Rho GTPase family that is known to control the signaling axis that regulates several cellular functions, including cell cycle progression, migration, and proliferation. However, the functional characterization of the CDC42 gene in mammalian physiology remains largely unclear. Here, we report the genetic and functional characterization of a non-consanguineous Saudi family with a single affected individual. Clinical examinations revealed poor wound healing, heterotopia of the brain, pancytopenia, and recurrent infections. Whole exome sequencing revealed a de novo missense variant (c.101C > A, p.Pro34Gln) in the CDC42 gene. The functional assays revealed a substantial reduction in the growth and motility of the patient cells as compared to the normal cells control. Homology three-dimensional (3-D) modeling of CDC42 revealed that the Pro34 is important for the proper protein secondary structure. In conclusion, we report a candidate disease-causing variant, which requires further confirmation for the etiology of CDC42 pathogenesis. This represents the first case from the Saudi population. The current study adds to the spectrum of mutations in the CDC42 gene that might help in genetic counseling and contributes to the CDC42-related genetic and functional characterization. However, further studies into the molecular mechanisms that are involved are needed in order to determine the role of the CDC42 gene associated with aberrant cell migration and immune response.


Assuntos
Encéfalo/anormalidades , Estudos de Associação Genética , Predisposição Genética para Doença , Pancitopenia/genética , Reinfecção/etiologia , Cicatrização/genética , Proteína cdc42 de Ligação ao GTP/deficiência , Biópsia , Encéfalo/diagnóstico por imagem , Biologia Computacional/métodos , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética/métodos , Humanos , Imageamento por Ressonância Magnética , Modelos Moleculares , Mutação , Pancitopenia/diagnóstico , Linhagem , Conformação Proteica , Reinfecção/diagnóstico , Relação Estrutura-Atividade , Sequenciamento Completo do Exoma , Adulto Jovem , Proteína cdc42 de Ligação ao GTP/química
19.
Genes (Basel) ; 12(2)2021 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672602

RESUMO

Xeroderma pigmentosum is a rare autosomal recessive skin disorder characterized by freckle-like dry pigmented skin, photosensitivity, and photophobia. Skin and ocular symptoms are confined to sun exposed areas of the body. Patients have markedly increased risk for UV-induced skin, ocular, and oral cancers. Some patients develop neurodegenerative symptoms, including diminished tendon reflexes and microcephaly. In this study, we describe clinical and genetic findings of 36 XP patients from Egypt, a highly consanguineous population from North Africa. Thorough clinical evaluation followed by Sanger sequencing of XPA and XPC genes were done. Six novel and seven previously reported mutations were identified. Phenotype-genotype correlation was investigated. We report clinical and molecular findings consistent with previous reports of countries sharing common population structure, and geographical and historical backgrounds with implications on common ancestral origins and historical migration flows. Clinical and genetic profiling improves diagnosis, management, counselling, and implementation of future targeted therapies.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Mutação , Fenótipo , Xeroderma Pigmentoso/diagnóstico , Xeroderma Pigmentoso/genética , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Dano ao DNA/efeitos da radiação , Análise Mutacional de DNA , Egito/epidemiologia , Feminino , Estudos de Associação Genética/métodos , Genótipo , Humanos , Lactente , Masculino , Xeroderma Pigmentoso/epidemiologia , Adulto Jovem
20.
Gene ; 786: 145585, 2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-33753148

RESUMO

OBJECTIVES: This study aimed to investigate the association of FTO methylation level with type 2 diabetes mellitus (T2DM) in a nested case-control study. METHODS: This nested case-control study included 287 pairs of T2DM cases and controls identified from a rural Chinese cohort study with a 6-year follow-up. Controls were matched to the cases on a 1:1 basis by age, sex, ethnicity, marital status, and residence. Conditional multivariate logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of cytosine guanine (CpG) locus and tag-single nucleotide polymorphisms (Tag-SNPs) with T2DM. Spearman correlation analysis was used to evaluate the association between FTO methylation and possible risk factors for T2DM in the control group. RESULTS: The methylation level on the CpG9 site significantly differs between cases and controls, with a significant association between the CpG9 site methylation and probability of T2DM: OR 2.19 (95%CI: 1.31-3.65) after adjusting for potential confounders. The Tag-SNPs (rs72803657, rs1558902, rs17817449, rs11076023) were not associated with T2DM. Further, FTO methylation was associated with some risk factors for T2DM. CONCLUSIONS: A CpG locus of FTO was positively associated with T2DM, but SNPs were not. FTO methylation were also associated with some T2DM risk factors. Further study with a large sample size and data on metabolic product are needed to confirm the association.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Metilação de DNA , Diabetes Mellitus Tipo 2/genética , Estudos de Associação Genética/métodos , Adulto , Estudos de Casos e Controles , Ilhas de CpG , Epigênese Genética , Feminino , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
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