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1.
PLoS Genet ; 16(6): e1008775, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32492070

RESUMO

Late-Onset Alzheimer's disease (LOAD) is a common, complex genetic disorder well-known for its heterogeneous pathology. The genetic heterogeneity underlying common, complex diseases poses a major challenge for targeted therapies and the identification of novel disease-associated variants. Case-control approaches are often limited to examining a specific outcome in a group of heterogenous patients with different clinical characteristics. Here, we developed a novel approach to define relevant transcriptomic endophenotypes and stratify decedents based on molecular profiles in three independent human LOAD cohorts. By integrating post-mortem brain gene co-expression data from 2114 human samples with LOAD, we developed a novel quantitative, composite phenotype that can better account for the heterogeneity in genetic architecture underlying the disease. We used iterative weighted gene co-expression network analysis (WGCNA) to reduce data dimensionality and to isolate gene sets that are highly co-expressed within disease subtypes and represent specific molecular pathways. We then performed single variant association testing using whole genome-sequencing data for the novel composite phenotype in order to identify genetic loci that contribute to disease heterogeneity. Distinct LOAD subtypes were identified for all three study cohorts (two in ROSMAP, three in Mayo Clinic, and two in Mount Sinai Brain Bank). Single variant association analysis identified a genome-wide significant variant in TMEM106B (p-value < 5×10-8, rs1990620G) in the ROSMAP cohort that confers protection from the inflammatory LOAD subtype. Taken together, our novel approach can be used to stratify LOAD into distinct molecular subtypes based on affected disease pathways.


Assuntos
Doença de Alzheimer/genética , Genes Modificadores , Transcriptoma , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Feminino , Perfilação da Expressão Gênica/métodos , Heterogeneidade Genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único
2.
PLoS One ; 15(4): e0231285, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32302349

RESUMO

Cystic fibrosis (CF) is a rare genetic disease that affects the respiratory and digestive systems. Lung disease is variable among CF patients and associated with the development of comorbidities and chronic infections. The rate of lung function deterioration depends not only on the type of mutations in CFTR, the disease-causing gene, but also on modifier genes. In the present study, we aimed to identify genes and pathways that (i) contribute to the pathogenesis of cystic fibrosis and (ii) modulate the associated comorbidities. We profiled blood samples in CF patients and healthy controls and analyzed RNA-seq data with Weighted Gene Correlation Network Analysis (WGCNA). Interestingly, lung function, body mass index, the presence of diabetes, and chronic P. aeruginosa infections correlated with four modules of co-expressed genes. Detailed inspection of networks and hub genes pointed to cell adhesion, leukocyte trafficking and production of reactive oxygen species as central mechanisms in lung function decline and cystic fibrosis-related diabetes. Of note, we showed that blood is an informative surrogate tissue to study the contribution of inflammation to lung disease and diabetes in CF patients. Finally, we provided evidence that WGCNA is useful to analyze-omic datasets in rare genetic diseases as patient cohorts are inevitably small.


Assuntos
Fibrose Cística/epidemiologia , Fibrose Cística/genética , Diabetes Mellitus/genética , Genes Modificadores , Adulto , Comorbidade , Fibrose Cística/sangue , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Diabetes Mellitus/sangue , Feminino , Humanos , Pulmão/metabolismo , Masculino , Mutação , Infecções por Pseudomonas/patologia , Transcriptoma
3.
BMC Med Genet ; 21(1): 54, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32183743

RESUMO

BACKGROUND: The ABCG2 rs2231142 single nucleotide polymorphism (SNP) is one of the most significant genetic variants associated with hyperuricemia (HUA) in Asian populations. However, the risk of ABCG2 rs2231142 variants for HUA could interact with other important HUA risk variants and cardiovascular factors. This study investigated the effects of the combined association among ABCG2 rs2231142 and multiple HUA genetic variants or cardiovascular risk factors on HUA risk and serum uric acid (sUA) levels in an elderly Chinese population. METHODS: A total of 1206 participants over 65 years old were enrolled in this study. Physical and laboratory examinations were performed for all participants. The ABCG2 rs2231142, SLC2A9 rs3733591, and SLC22A12 rs893006 SNPs were assayed using a standardized protocol. Logistic regression analysis and liner regression were adjusted respectively to account for the association between ABCG2 rs2231142 and other genetic variants, as well as between cardiovascular risk factors and HUA risk and sUA levels. RESULTS: The prevalence of HUA was 14.71% in the elderly community-dwelling population. The ABCG2 rs2231142 risk T allele was associated with HUA risk (odds ratio (OR) = 1.63, 95% confidence interval (CI): 1.27-2.11; p = 1.65 × 10- 4) and with increased sUA levels (Beta = 0.16, p = 6.75 × 10- 9) in the whole study population. Linear regression analysis showed that the mean sUA level increased linearly with the number of risk alleles of the three candidate genetic variants (Beta = 0.18, p = 1.94 × 10- 12) The joint effect of the ABCG2 rs2231142 T allele and cardiovascular risk factors (obesity, hypertension and dyslipidemia) was also associated with increased HUA risk and sUA levels. Each copy of the risk T allele was significantly associated with enhanced HUA risk in patients with hypertriglyceridemia (OR = 2.52, 95% CI: 1.33-4.60; p = 0.003) compared to controls. CONCLUSION: Our findings reinforce the importance of the ABCG2 rs2231143 variant as a crucial genetic locus for HUA in Chinese populations and demonstrated the combined effects of multiple genetic risk variants and cardiovascular risk exposures on HUA risk and increased sUA level.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Doenças Cardiovasculares/etiologia , Genes Modificadores , Proteínas Facilitadoras de Transporte de Glucose/genética , Hiperuricemia/genética , Proteínas de Neoplasias/genética , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Envelhecimento/fisiologia , Doenças Cardiovasculares/epidemiologia , China/epidemiologia , Estudos de Coortes , Modificador do Efeito Epidemiológico , Epistasia Genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Hiperuricemia/sangue , Hiperuricemia/epidemiologia , Vida Independente/estatística & dados numéricos , Masculino , Fatores de Risco , Ácido Úrico/sangue
4.
PLoS One ; 15(1): e0227067, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31931521

RESUMO

BACKGROUND: Cystic fibrosis (CF) is characterized by a progressive decline in lung function due to airway obstruction, infection, and inflammation. CF patients are particularly susceptible to respiratory infection by a variety of pathogens, and the inflammatory response in CF is dysregulated and prolonged. BPI fold containing family A, member 1 (BPIFA1) and BPIFB1 are proteins expressed in the upper airways that may have innate immune activity. We previously identified polymorphisms in the BPIFA1/BPIFB1 region associated with CF lung disease severity. METHODS: We evaluated whether the BPIFA1/BPIFB1 associations with lung disease severity replicated in individuals with CF participating in the International CF Gene Modifier Consortium (n = 6,365). Furthermore, we investigated mechanisms by which the BPIFA1 and BPIFB1 proteins may modify lung disease in CF. RESULTS: The association of the G allele of rs1078761 with reduced lung function was replicated in an independent cohort of CF patients (p = 0.001, n = 2,921) and in a meta-analysis of the full consortium (p = 2.39x10-5, n = 6,365). Furthermore, we found that rs1078761G which is associated with reduced lung function was also associated with reduced BPIFA1, but not BPIFB1, protein levels in saliva from CF patients. Functional assays indicated that BPIFA1 and BPIFB1 do not have an anti-bacterial role against P. aeruginosa but may have an immunomodulatory function in CF airway epithelial cells. Gene expression profiling using RNAseq identified Rho GTPase signaling pathways to be altered in CF airway epithelial cells in response to treatment with recombinant BPIFA1 and BPIFB1 proteins. CONCLUSIONS: BPIFA1 and BPIFB1 have immunomodulatory activity and genetic variation associated with low levels of these proteins may increase CF lung disease severity.


Assuntos
Fibrose Cística/genética , Genes Modificadores , Glicoproteínas/genética , Fosfoproteínas/genética , Pneumonia/genética , Autoantígenos/genética , Autoantígenos/metabolismo , Linhagem Celular , Fibrose Cística/complicações , Fibrose Cística/imunologia , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Glicoproteínas/metabolismo , Humanos , Fosfoproteínas/metabolismo , Pneumonia/etiologia , Pneumonia/imunologia , Polimorfismo de Nucleotídeo Único , Mucosa Respiratória/imunologia
5.
Nucleic Acids Res ; 48(D1): D977-D982, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31642469

RESUMO

From clinical observations to large-scale sequencing studies, the phenotypic impact of genetic modifiers is evident. To better understand the full spectrum of the genetic contribution to human disease, concerted efforts are needed to construct a useful modifier resource for interpreting the information from sequencing data. Here, we present the PhenoModifier (https://www.biosino.org/PhenoModifier), a manually curated database that provides a comprehensive overview of human genetic modifiers. By manually curating over ten thousand published articles, 3078 records of modifier information were entered into the current version of PhenoModifier, related to 288 different disorders, 2126 genetic modifier variants and 843 distinct modifier genes. To help users probe further into the mechanism of their interested modifier genes, we extended the yeast genetic interaction data and yeast quantitative trait loci to the human and we also integrated GWAS data into the PhenoModifier to assist users in evaluating all possible phenotypes associated with a modifier allele. As the first comprehensive resource of human genetic modifiers, PhenoModifier provides a more complete spectrum of genetic factors contributing to human phenotypic variation. The portal has a broad scientific and clinical scope, spanning activities relevant to variant interpretation for research purposes as well as clinical decision making.


Assuntos
Biologia Computacional , Bases de Dados Genéticas , Genes Modificadores , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Fenótipo , Biologia Computacional/métodos , Curadoria de Dados , Estudos de Associação Genética/métodos , Humanos , Software , Interface Usuário-Computador , Navegador
6.
Int J Cancer ; 146(5): 1457-1467, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31344264

RESUMO

It remains unclear whether there is a relationship between therapeutic effects of hypomethylating agents (HMAs) and epigenetic modifier gene mutations (EMMs) in patients with cytogenetically intermediate-risk acute myeloid leukemia (IR-AML). Based on targeted-capture sequencing, we retrospectively analyzed the correlation between EMMs and prognosis in 83 IR-AML patients treated with decitabine in combination with cytarabine, aclarubicin hydrochloride and granulocyte colony-stimulating factor (DCAG, n = 35) or "7 + 3" induction regimens (n = 48). In the multivariate analyses, EMM (+) patients did not show any statistically significant difference in remission rates from EMM (-) patients in the DCAG group (p > 0.05), but achieved inferior complete remission (CR; p = 0.03) and overall remission rates (ORR; p = 0.04) after the first course of standard induction regimens (p < 0.05). In the EMM (-) cohort, the DCAG group showed the tendency of adverse total CR (p = 0.06). Besides, DCAG group with EMMs achieved the best survival outcome independent of baseline characteristics, whereas it was opposite in EMM (+) patients receiving standard induction regimens (p < 0.05). Additionally, in the EMM (+) cohort, the survival rate of isolated DCAG group was statistically similar to that of the combination of standard chemotherapies and allogeneic hematopoietic stem cell transplantation (allo-HSCT) (p > 0.40), whereas patients who received only standard regimens had the worst survival rate (0.0%, p < 0.01). It can be concluded that the EMMs might be regarded as the potentially predictive biomarkers of better response to DCAG in IR-AML patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Epigênese Genética/genética , Genes Modificadores/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Aclarubicina/farmacologia , Aclarubicina/uso terapêutico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/farmacologia , Citarabina/uso terapêutico , Metilação de DNA/efeitos dos fármacos , Decitabina/farmacologia , Decitabina/uso terapêutico , Intervalo Livre de Doença , Feminino , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Estimativa de Kaplan-Meier , Cariotipagem , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Indução de Remissão/métodos , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
7.
Proc Natl Acad Sci U S A ; 117(2): 1113-1118, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31879347

RESUMO

Genetic and phenotypic heterogeneity and the lack of sufficiently large patient cohorts pose a significant challenge to understanding genetic associations in rare disease. Here we identify Bsnd (alias Barttin) as a genetic modifier of cystic kidney disease in Joubert syndrome, using a Cep290-deficient mouse model to recapitulate the phenotypic variability observed in patients by mixing genetic backgrounds in a controlled manner and performing genome-wide analysis of these mice. Experimental down-regulation of Bsnd in the parental mouse strain phenocopied the severe cystic kidney phenotype. A common polymorphism within human BSND significantly associates with kidney disease severity in a patient cohort with CEP290 mutations. The striking phenotypic modifications we describe are a timely reminder of the value of mouse models and highlight the significant contribution of genetic background. Furthermore, if appropriately managed, this can be exploited as a powerful tool to elucidate mechanisms underlying human disease heterogeneity.


Assuntos
Anormalidades Múltiplas/genética , Cerebelo/anormalidades , Canais de Cloreto/genética , Canais de Cloreto/metabolismo , Anormalidades do Olho/genética , Genes Modificadores , Doenças Renais Císticas/genética , Retina/anormalidades , Animais , Antígenos de Neoplasias/genética , Proteínas de Ciclo Celular/genética , Proteínas do Citoesqueleto/genética , Modelos Animais de Doenças , Predisposição Genética para Doença/genética , Nefropatias , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Fenótipo , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença
8.
Genes (Basel) ; 10(11)2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703244

RESUMO

Nonsyndromic familial non-medullary thyroid cancer (FNMTC) represents 3-9% of thyroid cancers, but the susceptibility gene(s) remain unknown. We designed this multicenter study to analyze families with nonsyndromic FNMTC and identify candidate susceptibility genes. We performed exome sequencing of DNA from four affected individuals from one kindred, with five cases of nonsyndromic FNMTC. Single Nucleotide Variants, and insertions and deletions that segregated with all the affected members, were analyzed by Sanger sequencing in 44 additional families with FNMTC (37 with two affected members, and seven with three or more affected members), as well as in an independent control group of 100 subjects. We identified the germline variant p. Asp31His in NOP53 gene (rs78530808, MAF 1.8%) present in all affected members in three families with nonsyndromic FNMTC, and not present in unaffected spouses. Our functional studies of NOP53 in thyroid cancer cell lines showed an oncogenic function. Immunohistochemistry exhibited increased NOP53 protein expression in tumor samples from affected family members, compared with normal adjacent thyroid tissue. Given the relatively high frequency of the variant in the general population, these findings suggest that instead of a causative gene, NOP53 is likely a low-penetrant gene implicated in FNMTC, possibly a modifier.


Assuntos
Genes Modificadores , Polimorfismo de Nucleotídeo Único , Neoplasias da Glândula Tireoide/genética , Proteínas Supressoras de Tumor/genética , Linhagem Celular Tumoral , Feminino , Mutação em Linhagem Germinativa , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , Penetrância , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia
9.
Genetics ; 213(3): 1047-1063, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31562180

RESUMO

F1 hybrids between mouse inbred strains PWD and C57BL/6 represent the most thoroughly genetically defined model of hybrid sterility in vertebrates. Hybrid male sterility can be fully reconstituted from three components of this model, the Prdm9 gene, intersubspecific homeology of Mus musculus musculus and Mus musculus domesticus autosomes, and the X-linked Hstx2 locus. Hstx2 modulates the extent of Prdm9-dependent meiotic arrest and harbors two additional factors responsible for intersubspecific introgression-induced oligospermia (Hstx1) and meiotic recombination rate (Meir1). To facilitate positional cloning and to overcome the recombination suppression within the 4.3 Mb encompassing the Hstx2 locus, we designed Hstx2-CRISPR and SPO11/Cas9 transgenes aimed to induce DNA double-strand breaks specifically within the Hstx2 locus. The resulting recombinant reduced the Hstx2 locus to 2.70 Mb (chromosome X: 66.51-69.21 Mb). The newly defined Hstx2 locus still operates as the major X-linked factor of the F1 hybrid sterility, and controls meiotic chromosome synapsis and meiotic recombination rate. Despite extensive further crosses, the 2.70 Mb Hstx2 interval behaved as a recombination cold spot with reduced PRDM9-mediated H3K4me3 hotspots and absence of DMC1-defined DNA double-strand-break hotspots. To search for structural anomalies as a possible cause of recombination suppression, we used optical mapping and observed high incidence of subspecies-specific structural variants along the X chromosome, with a striking copy number polymorphism of the microRNA Mir465 cluster. This observation together with the absence of a strong sterility phenotype in Fmr1 neighbor (Fmr1nb) null mutants support the role of microRNA as a likely candidate for Hstx2.


Assuntos
Genes Modificadores , Histona-Lisina N-Metiltransferase/genética , Infertilidade Masculina/genética , Polimorfismo Genético , Animais , Recombinação Homóloga , Masculino , Meiose , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Cromossomo X/genética
10.
Nature ; 572(7767): 125-130, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31341277

RESUMO

Neuromuscular disorders are often caused by heterogeneous mutations in large, structurally complex genes. Targeting compensatory modifier genes could be beneficial to improve disease phenotypes. Here we report a mutation-independent strategy to upregulate the expression of a disease-modifying gene associated with congenital muscular dystrophy type 1A (MDC1A) using the CRISPR activation system in mice. MDC1A is caused by mutations in LAMA2 that lead to nonfunctional laminin-α2, which compromises the stability of muscle fibres and the myelination of peripheral nerves. Transgenic overexpression of Lama1, which encodes a structurally similar protein called laminin-α1, ameliorates muscle wasting and paralysis in mouse models of MDC1A, demonstrating its importance as a compensatory modifier of the disease1. However, postnatal upregulation of Lama1 is hampered by its large size, which exceeds the packaging capacity of vehicles that are clinically relevant for gene therapy. We modulate expression of Lama1 in the dy2j/dy2j mouse model of MDC1A using an adeno-associated virus (AAV9) carrying a catalytically inactive Cas9 (dCas9), VP64 transactivators and single-guide RNAs that target the Lama1 promoter. When pre-symptomatic mice were treated, Lama1 was upregulated in skeletal muscles and peripheral nerves, which prevented muscle fibrosis and paralysis. However, for many disorders it is important to investigate the therapeutic window and reversibility of symptoms. In muscular dystrophies, it has been hypothesized that fibrotic changes in skeletal muscle are irreversible. However, we show that dystrophic features and disease progression were improved and reversed when the treatment was initiated in symptomatic dy2j/dy2j mice with apparent hindlimb paralysis and muscle fibrosis. Collectively, our data demonstrate the feasibility and therapeutic benefit of CRISPR-dCas9-mediated upregulation of Lama1, which may enable mutation-independent treatment for all patients with MDC1A. This approach has a broad applicability to a variety of disease-modifying genes and could serve as a therapeutic strategy for many inherited and acquired diseases.


Assuntos
Genes Modificadores/genética , Terapia Genética/métodos , Laminina/genética , Laminina/metabolismo , Distrofias Musculares/genética , Distrofias Musculares/terapia , Regulação para Cima , Animais , Proteína 9 Associada à CRISPR/genética , Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas , Progressão da Doença , Feminino , Fibrose/metabolismo , Fibrose/patologia , Edição de Genes , Masculino , Camundongos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Mutação
11.
Neurol Sci ; 40(12): 2537-2540, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31286297

RESUMO

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons. The hexanucleotide repeat expansion in C9orf72 gene (C9orf72-HRE) is the most frequent genetic cause of ALS. Since many ALS pedigrees showed incomplete penetrance, several genes have been analyzed as possible modifiers. Length of the GCG repeat tract in NIPA1 (non-imprinted in Prader-Willi/Angelman syndrome 1) gene has been recently investigated as a possible modifier factor for C9orf72-HRE patients with contrasting findings. To disclose the possible role of NIPA1 GCG repeat length as modifier of the disease risk in C9orf72-HRE carriers, we analyzed a large cohort of 532 Italian ALS cases enriched in C9orf72-HRE carriers (172 cases) and 483 Italian controls. This sample size is powered (92% power, p = 0.05) to replicate the modifier effect observed in literature. We did not observe higher frequency of NIPA1 long alleles (> 8 GCG) in C9orf72-HRE carriers (3.5%) compared with C9orf72-HRE negative patients (4.1%) and healthy controls (5%). For the latter comparison, we meta-analyzed our data with currently available literature data, and no statistically significant effect was observed (p = 0.118). In conclusion, we did not confirm a role of NIPA1 repeat length as a modifier of the C9orf72 ALS disease risk.


Assuntos
Esclerose Amiotrófica Lateral/genética , Proteína C9orf72/genética , Genes Modificadores/genética , Predisposição Genética para Doença/genética , Proteínas de Membrana/genética , Estudos de Coortes , Humanos , Itália , Expansão das Repetições de Trinucleotídeos
12.
Exp Mol Pathol ; 110: 104286, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31323190

RESUMO

Psoriasis (PS) is a common inflammatory and incurable skin disease affecting 2-3% of the human population. Although genome-wide association studies implicate more than 60 loci, the full complement of genetic factors leading to disease is not known. Rare, highly penetrant, gain-of-function, dominantly acting mutations within the human caspase recruitment domain family, member 14 (CARD14) gene lead to the development of PS and psoriatic arthritis (PSA) (a familial p.G117S and de-novo p.E138A alteration). These residues are conserved in mouse and orthologous Knock-In (KI) mutations within Card14 were created. The Card14tm.1.1Sun allele (G117S) resulted in no clinically or histologically evident phenotype of the skin or joints in young adult or old mice. However, mice carrying the Card14tm2.1Sun mutant allele (E138A) were runted and developed thick, white, scaly skin soon after birth, dying within two weeks or less. The skin hyperplasia and inflammation was remarkable similarity to human PS at the clinical, histological, and transcriptomic levels. For example, the skin was markedly acanthotic and exhibited orthokeratotic hyperkeratosis with minimal inflammation and no pustules and transcripts affecting critical pathways of epidermal differentiation and components of the IL17 axis (IL23, IL17A, IL17C, TNF and IL22) were altered. Similar changes were seen in a set of orthologous microRNAs previously associated with PS suggesting conservation across species. Crossing the Card14tm2.1Sun/WT mice to C57BL/6NJ, FVB/NJ, CBA/J, C3H/HeJ, and 129S1/SvImJ generated progeny with epidermal acanthosis and marked orthokeratotic hyperkeratosis regardless of the hybrid strain. Of these hybrid lines, only the FVB;B6N(129S4) mice survived to 250 days of age or older and has led to recombinant inbred lines homozygous for Card14E138A that are fecund and have scaly skin disease. This implicates that modifiers of PS severity exist in mice, as in the familial forms of the disease in humans.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/fisiologia , Mutação com Ganho de Função , Genes Modificadores , Guanilato Ciclase/genética , Guanilato Quinases/fisiologia , Inflamação/genética , Proteínas de Membrana/genética , Psoríase/genética , Dermatopatias/genética , Animais , Feminino , Técnicas de Introdução de Genes , Humanos , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Knockout , Psoríase/patologia , Índice de Gravidade de Doença , Dermatopatias/patologia , Transcriptoma
13.
Breast Cancer Res Treat ; 177(1): 77-91, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31165373

RESUMO

PURPOSE: Understanding the molecular mediators of breast cancer survival is critical for accurate disease prognosis and improving therapies. Here, we identified Neuronatin (NNAT) as a novel antiproliferative modifier of estrogen receptor-alpha (ER+) breast cancer. EXPERIMENTAL DESIGN: Genomic regions harboring breast cancer modifiers were identified by congenic mapping in a rat model of carcinogen-induced mammary cancer. Tumors from susceptible and resistant congenics were analyzed by RNAseq to identify candidate genes. Candidates were prioritized by correlation with outcome, using a consensus of three breast cancer patient cohorts. NNAT was transgenically expressed in ER+ breast cancer lines (T47D and ZR75), followed by transcriptomic and phenotypic characterization. RESULTS: We identified a region on rat chromosome 3 (142-178 Mb) that modified mammary tumor incidence. RNAseq of the mammary tumors narrowed the candidate list to three differentially expressed genes: NNAT, SLC35C2, and FAM210B. NNAT mRNA and protein also correlated with survival in human breast cancer patients. Quantitative immunohistochemistry of NNAT protein revealed an inverse correlation with survival in a univariate analysis of patients with invasive ER+ breast cancer (training cohort: n = 444, HR = 0.62, p = 0.031; validation cohort: n = 430, HR = 0.48, p = 0.004). NNAT also held up as an independent predictor of survival after multivariable adjustment (HR = 0.64, p = 0.038). NNAT significantly reduced proliferation and migration of ER+ breast cancer cells, which coincided with altered expression of multiple related pathways. CONCLUSIONS: Collectively, these data implicate NNAT as a novel mediator of cell proliferation and migration, which correlates with decreased tumorigenic potential and prolonged patient survival.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Genes Modificadores , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Receptores Estrogênicos/genética , Animais , Biomarcadores Tumorais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Incidência , Estimativa de Kaplan-Meier , Proteínas de Membrana/metabolismo , Estadiamento de Neoplasias , Proteínas do Tecido Nervoso/metabolismo , Avaliação de Resultados da Assistência ao Paciente , Prognóstico , Ratos , Receptores Estrogênicos/metabolismo , Transdução de Sinais
14.
Pediatr Blood Cancer ; 66(8): e27807, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31094093

RESUMO

BACKGROUND: The Uganda Sickle Surveillance Study provided evidence for a large sickle burden among HIV-exposed infants in Uganda. To date, however, no large scale screening program has been developed for Central or East Africa. METHODS: A 3-year targeted sickle cell screening project in Uganda was designed by the Ministry of Health to (1) determine sickle cell trait and disease prevalence within high-burden districts, (2) document the prevalence among HIV-exposed and nonexposed children, (3) confirm previously suggested HIV comorbidity, and (4) estimate the co-inheritance of known genetic modifiers of sickle cell disease. RESULTS: A total of 163 334 dried blood spot samples collected between April 2015 and March 2018 were analyzed, including 112 352 samples within the HIV Early Infant Diagnosis program. A high burden with >1% sickle cell disease was found within targeted East Central and Mid-Northern districts, in both HIV-exposed and nonexposed children. Based on crude birth-rate data, 236 905 sickle cell trait births and 16 695 sickle cell disease births will occur annually in Uganda. Compared to sickle cell disease without HIV, the odds ratio of having sickle cell disease plus HIV was 0.50 (95% confidence interval = 0.40-0.64, P < .0001). Alpha-thalassemia trait and G6PD deficiency were common with sickle cell disease, but with different geospatial distribution. CONCLUSIONS: High sickle cell burden and potential HIV comorbidity are confirmed in Uganda. Genetic modifiers are common and likely influence laboratory and clinical phenotypes. These prospective data document that targeted sickle cell screening is feasible and effective in Uganda, and support development of district-level comprehensive care programs.


Assuntos
Anemia Falciforme/diagnóstico , Genes Modificadores , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Infecções por HIV/diagnóstico , Programas de Rastreamento/métodos , Talassemia alfa/diagnóstico , Anemia Falciforme/complicações , Anemia Falciforme/epidemiologia , Anemia Falciforme/genética , Pré-Escolar , Comorbidade , Feminino , Seguimentos , Deficiência de Glucosefosfato Desidrogenase/complicações , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Deficiência de Glucosefosfato Desidrogenase/genética , HIV/genética , HIV/isolamento & purificação , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Infecções por HIV/genética , Humanos , Lactente , Recém-Nascido , Masculino , Prevalência , Prognóstico , Estudos Prospectivos , Talassemia alfa/complicações , Talassemia alfa/epidemiologia , Talassemia alfa/genética
15.
Hemoglobin ; 43(1): 73-75, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31104519

RESUMO

A regulatory single nucleotide polymorphism (rSNP), the Aγ (+25 G>A) (rs368698783) (NG_000007.3: g47783G>A) located in the HBG1 proximal promoter, is a significant predictor of clinical severity by elevating Hb F levels in ß-thalassemia (ß-thal). In this study, the presence of the Aγ (+25 G>A) and Aγ (+25 A>A) genotypes was investigated in four subgroups from a total of 611 subjects, including 88 α-thalassemia (α-thal) carriers (group A), 162 ß-thal carriers of point mutations (group B), 57 carriers of ß-thal deletions (group C) and 152 non thalassemic individuals (group D). The result is that the genotypes G>A and A>A exhibit significantly high levels of Hb F compared with the genotype G>G in both groups B and C, while no significant difference was observed in both groups A and D. We assume that the effect of Aγ (+25 G>A) polymorphism on Hb F production is only under erythropoietic stress characteristic for ß-globin chain deficiency.


Assuntos
Alelos , Eritropoese/genética , Hemoglobina Fetal/genética , Genes Modificadores , Polimorfismo de Nucleotídeo Único , Globinas beta/genética , Talassemia beta/diagnóstico , Talassemia beta/genética , Índices de Eritrócitos , Feminino , Genótipo , Humanos , Fatores de Transcrição Kruppel-Like/genética , Masculino , Análise de Sequência de DNA , Talassemia alfa/diagnóstico , Talassemia alfa/genética
16.
Neurosci Lett ; 706: 75-80, 2019 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-31082450

RESUMO

BACKGROUND: Parkinson's disease (PD) is the debilitating movement disorder, distinguished by dopaminergic and norepinephrinergic neurodegeneration. Apart from candidate gene mutations, several modifier loci have been reported to be associated with the disease manifestation. The Dopamine ß-Hydroxylase (DBH) maintains cellular dopamine content and regulates dopamine turn over in neurons. Genetic polymorphisms of DBH are associated with PD and are found to alter plasma DBH activity in patients compared to healthy controls. Therefore, DBH activity in plasma could be a potential and easily detectable biomarkers for alteration of dopaminergic neuronal function in PD. METHODS: Plasma DBH activity has been assessed among PD cases and age-matched controls to identify correlation with PD. To elucidate the role of DBH polymorphisms in Eastern Indian PD patients, three SNPs (rs1611115, rs1108580 and rs129882) were selected and screened by PCR-RFLP and DNA sequencing analysis. RESULTS: The T-allele of rs129882 was more prevalent among patients than controls posing risk (p-value = 0.02, OR = 1.404, 95% CI = 1.047-1.883) towards PD. The dual-Luciferase assay in SHSY5Y cell line revealed that the T-allele of rs129882 increases Luciferase signal (p = 0.0269). However, the rs1611115 and rs1108580 did not show association with PD; plasma DBH activity was not significantly different between patients and controls (p-value > 0.05). Haplotypes constructed with three SNPs showed that the CAT haplotype to pose risk, TAC haplotype to provide protection against early disease onset and CGT being protective against non-motor symptoms. CONCLUSION: These data suggest that DBH might influence the susceptibility of PD.


Assuntos
Dopamina beta-Hidroxilase/genética , Genes Modificadores , Predisposição Genética para Doença , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Feminino , Frequência do Gene , Estudos de Associação Genética , Haplótipos , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas
17.
J Neuromuscul Dis ; 6(2): 201-211, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30958311

RESUMO

BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a uniform 1.5-Mb duplication on chromosome 17p, which includes the PMP22 gene. Patients often present the classic neuropathy phenotype, but also with high clinical variability. OBJECTIVE: We aimed to identify genetic variants that are potentially associated with specific clinical outcomes in CMT1A. METHODS: We genotyped over 600,000 genomic markers using DNA samples from 971 CMT1A patients and performed a case-only genome-wide association study (GWAS) to identify potential genetic association in a subset of 644 individuals of European ancestry. A total of 14 clinical outcomes were analyzed in this study. RESULTS: The analyses yielded suggestive association signals in four clinical outcomes: difficulty with eating utensils (lead SNP rs4713376, chr6 : 30773314, P = 9.91×10-7, odds ratio = 3.288), hearing loss (lead SNP rs7720606, chr5 : 126551732, P = 2.08×10-7, odds ratio = 3.439), decreased ability to feel (lead SNP rs17629990, chr4 : 171224046, P = 1.63×10-7, odds ratio = 0.336), and CMT neuropathy score (lead SNP rs12137595, chr1 : 4094068, P = 1.14×10-7, beta = 3.014). CONCLUSIONS: While the results require validation in future genetic and functional studies, the detected association signals may point to novel genetic modifiers in CMT1A.


Assuntos
Doença de Charcot-Marie-Tooth/genética , Genes Modificadores/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos
18.
EBioMedicine ; 43: 553-561, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30922962

RESUMO

BACKGROUND: Neonatal screening for Pompe disease is complicated by difficulties in predicting symptom onset in patients with the common c.-32-13T>G (IVS1) variant/null (i.e. fully deleterious) acid α-glucosidase (GAA) genotype. This splicing variant occurs in 90% of Caucasian late onset patients, and is associated with a broad range of symptom onset. METHODS: We analyzed a cohort of 143 compound heterozygous and 10 homozygous IVS1 patients, and we assessed ages at symptom onset, the presence of cis-acting single nucleotide variants (SNVs), and performed splicing analysis and enzyme activity assays. FINDINGS: In compound heterozygous IVS1 patients, the synonymous variant c.510C>T was uniquely present on the IVS1 allele in 9/33 (27%) patients with childhood onset, but was absent from 110 patients with onset in adulthood. GAA enzyme activity was lower in fibroblasts from patients who contained c.510C>T than it was in patients without c.510C>T. By reducing the extent of leaky wild-type splicing, c.510C>T modulated aberrant splicing caused by the IVS1 variant. The deleterious effect of c.510C>T was also found in muscle cells, the main target cells in Pompe disease. In homozygous IVS1 patients, the c.510C>T variant was absent in 4/4 (100%) asymptomatic individuals and present in 3/6 (50%) symptomatic patients. In cells from homozygous IVS1 patients, c.510C>T caused reduced leaky wild-type splicing. INTERPRETATION: c.510C>T is a genetic modifier in compound heterozygous and homozygous IVS1 patients. This finding is important for neonatal screening programs for Pompe disease. FUND: This work was funded by grants from Sophia Children's Hospital Foundation (SSWO, grant S17-32) and Metakids (2016-063).


Assuntos
Genes Modificadores , Estudos de Associação Genética , Predisposição Genética para Doença , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/genética , Fenótipo , Adolescente , Adulto , Idade de Início , Alelos , Criança , Pré-Escolar , Frequência do Gene , Genótipo , Doença de Depósito de Glicogênio Tipo II/metabolismo , Humanos , Lactente , Íntrons , Pessoa de Meia-Idade , Mutação , Processamento de RNA , Avaliação de Sintomas , Adulto Jovem , alfa-Glucosidases/genética , alfa-Glucosidases/metabolismo
19.
Am J Physiol Heart Circ Physiol ; 316(6): H1267-H1280, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30848680

RESUMO

Radiation therapy is used in ~50% of cancer patients to reduce the risk of recurrence and in some cases improve survival. Despite these benefits, doses can be limited by toxicity in multiple organs, including the heart. The underlying causes and biomarkers of radiation-induced cardiotoxicity are currently unknown, prompting the need for experimental models with inherent differences in sensitivity and resistance to the development of radiation-induced cardiotoxicity. We have identified the parental SS (Dahl salt-sensitive/Mcwi) rat strain to be a highly-sensitized model of radiation-induced cardiotoxicity. In comparison, substitution of rat chromosome 3 from the resistant BN (Brown Norway) rat strain onto the SS background (SS-3BN consomic) significantly attenuated radiation-induced cardiotoxicity. SS-3BN rats had less radiation-induced cardiotoxicity than SS rats, as measured by survival, pleural and pericardial effusions, echocardiogram parameters, and histological damage. Mast cells, previously shown to have predominantly protective roles in radiation-induced cardiotoxicity, were increased in the more resistant SS-3BN hearts postradiation. RNA sequencing from SS and SS-3BN hearts at 1 wk postradiation revealed 5,098 differentially expressed candidate genes across the transcriptome and 350 differentially expressed genes on rat chromosome 3, which coincided with enrichment of multiple pathways, including mitochondrial dysfunction, sirtuin signaling, and ubiquitination. Upstream regulators of enriched pathways included the oxidative stress modulating transcription factor, Nrf2, which is located on rat chromosome 3. Nrf2 target genes were also differentially expressed in the SS vs. SS-3BN consomic hearts postradiation. Collectively, these data confirm the existence of heritable modifiers in radiation-induced cardiotoxicity and provide multiple biomarkers, pathways, and candidate genes for future analyses. NEW & NOTEWORTHY This novel study reveals that heritable genetic factors have the potential to modify normal tissue sensitivity to radiation. Gene variant(s) on rat chromosome 3 can contribute to enhanced cardiotoxicity displayed in the SS rats vs. the BN and SS-3BN consomic rats. Identifying genes that lead to understanding the mechanisms of radiation-induced cardiotoxicity represents a novel method to personalize radiation treatment, as well as predict the development of radiation-induced cardiotoxicity.


Assuntos
Mapeamento Cromossômico , Cromossomos de Mamíferos , Genes Modificadores , Variação Genética , Cardiopatias/genética , Lesões por Radiação/genética , Animais , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Cardiopatias/metabolismo , Cardiopatias/patologia , Masculino , Mastócitos/metabolismo , Mastócitos/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Lesões por Radiação/metabolismo , Lesões por Radiação/patologia , Ratos Endogâmicos BN , Ratos Endogâmicos Dahl , Transdução de Sinais
20.
J Pak Med Assoc ; 69(2): 241-243, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30804591

RESUMO

Phenotype varies among the various types of Charcot Marie Tooth Neuropathies(CMT), However the problem arises in cases of same gene but gives a huge variety of phenotype in terms of early and late onset and severity of the disease. To check the impact of rs139723190 SNP on severity of the CMT 2k patients; being a genetic modifier of GDAP1. In the current study CMT 2k patients with early and late onset were analyzed for association of rs139723190 SNP in JPH1 gene responsible for CMT type severe and mild phenotypes. Single nucleotide polymorphisms (SNPs) lead to genetic differences in CMT patients on the basis of severity of the disease. The results of the present study suggest that variants of JPH1 may contribute to the genetic susceptibility as it plays a vital role as genetic modifier in CMT 2K. Candidates risk variants should be further evaluated in studies with a larger sample size.


Assuntos
Doença de Charcot-Marie-Tooth , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Adolescente , Adulto , Idade de Início , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/epidemiologia , Doença de Charcot-Marie-Tooth/genética , Pré-Escolar , Feminino , Genes Modificadores , Estudos de Associação Genética , Humanos , Masculino , Paquistão , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença
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