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1.
Medicine (Baltimore) ; 99(5): e18921, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32000403

RESUMEN

BACKGROUND: Recent studies have suggested that the potential functional polymorphism R47H in triggering receptors expressed on myeloid cells 2 (TREM2) is associated with several neurodegenerative diseases, however, the results remain inconclusive. This meta-analysis aimed to investigate the association between TREM2 R47H and the risk for 3 typical neurodegenerative diseases: Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). METHODS: A literature review was carried out using PubMed, Medline, and Embase. Data analysis was conducted using Stata 15.0 software. The pooled odds ratio (ORs) and 95% confidence interval (CIs) were calculated. RESULTS: A total of 35 articles were identified as eligible: 22 on AD, 3 on ALS, 7 on PD, 2 on AD and ALS, and 1 on ALS and PD. The AD set included 23,092 cases and 30,920 controls, the ALS set included 7391 cases and 12,442 controls, and the PD set included 8498 patients and 9161 controls. We found that R47H was associated with an increased risk of AD in the total pooled population (P < .001, OR = 4.02, 95% CI = 3.15-5.13). However, this significant difference existed for Caucasian people (OR = 4.16, 95% CI = 3.24-5.33) but not for Asian or African people. Moreover, we did not find any significant differences in minor allele frequency distribution between the PD and control groups or between the ALS and control groups, not only for the total pooled population but also for the subgroups of different ethnicities. CONCLUSION: Our study suggested that R47H in the TREM2 gene leads to an increased risk for developing AD, but not for ALS and PD, which adds evidence to the notion that diverse pathogenesis may be involved in different neurogenerative diseases.


Asunto(s)
Enfermedad de Alzheimer/genética , Esclerosis Amiotrófica Lateral/genética , Glicoproteínas de Membrana/genética , Enfermedad de Parkinson/genética , Receptores Inmunológicos/genética , Predisposición Genética a la Enfermedad , Humanos , Polimorfismo Genético
2.
Medicine (Baltimore) ; 99(4): e18914, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31977906

RESUMEN

BACKGROUND: Previous studies demonstrated that ADRB3, beta-3 adrenergic receptor, participated in lipolysis and thermogenesis in adipose tissue. Consequently, this gene has attracted an increasing number of genetic studies examining its association with coronary artery disease (CAD) in different ethnicities in recent years, but no conclusion has been reached so far. The aim of this study was to explore whether the well-studied locus ADRB3 Trp64Arg in this gene confers a race-specific effect to CAD by conducting a stratified meta-analysis involving 15 independent studies and 11,802 subjects. METHODS: Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of association. Publication bias was quantified and examined with Begg's funnel plot test and Egger's linear regression method. The overall meta-analysis or stratified meta-analysis by ethnicity was performed by using STATA 12.0 software. RESULTS: A total of 15 eligible studies involving 5779 CAD cases and 6023 health controls were included in this meta-analysis. The pooled results indicated that ADRB3 Trp64Arg polymorphism was significantly associated with an increased risk of CAD. Further stratified analysis by ethnicity revealed that ADRB3 Trp64Arg polymorphism was significantly associated with CAD in Asians (allelic: OR = 1.48, 95%CI 1.13-1.94, P = .005; homozygous: OR = 2.66, 95%CI 1.87-3.77, P < .001; recessive: OR = 2.46, 95%CI 1.74-3.47, P < .001), but not in Caucasians (allelic: OR = 1.09, 95%CI 0.93-1.27, P = .290; homozygous: OR = 1.31, 95%CI 0.61-2.86, P = .490; recessive: OR = 1.31, 95%CI 0.60-2.84, P = 2.494). CONCLUSIONS: This meta-analysis suggests that ADRB3 Trp64Arg polymorphism confers a race-specific effect to CAD.


Asunto(s)
Enfermedad de la Arteria Coronaria/genética , Predisposición Genética a la Enfermedad , Receptores Adrenérgicos beta 3 , Grupo de Ascendencia Continental Asiática/estadística & datos numéricos , Estudios de Casos y Controles , Enfermedad de la Arteria Coronaria/etnología , Grupo de Ascendencia Continental Europea/estadística & datos numéricos , Humanos , Polimorfismo de Nucleótido Simple
3.
Cancer Immunol Immunother ; 69(2): 285-292, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31897662

RESUMEN

The wide-ranging collection of malignancies arising at the upper aerodigestive tract is categorized as head and neck cancer (HNC), the sixth most prevalent cancer worldwide. Infection with human papillomavirus (HPV) or exposure to carcinogens is the leading causes of HPV+ and HPV- HNCs development, respectively. HPV+ and HPV- HNCs are different in clinical and molecular aspects. Specifically, HPV- HNCs tightly associate with missense mutants of the TP53 gene (encoding for the p53 protein), suggesting a central role for mutant p53 gain-of-function (GOF) in driving tumorigenesis. In contrast, in HPV + HNC, the sequence of TP53 typically remains intact, while the protein is degraded. In tumor cells, the status of the TP53 gene affects the cargo of secreted exosomes. In this review, we describe the accumulated knowledge regarding the involvement of exosomes and p53 on cellular interactions between HPV+ and HPV- HNC cells, and the surrounding tumor microenvironment (TME). Moreover, we envision how TP53 status may determine exosomes cargo in HNC, and, consequently, modify the TME. The potential roles of exosomes described herein are based on both our studies and the studies of others on mutant p53-derived exosomes. Specifically, we showed how exosomes are shed by cancer cells harboring mutant p53 communicate with tumor-associated macrophages in the colon as well as with cancer-associated fibroblasts in the lung, creating immunosuppressive conditions and promoting invasiveness. Altogether, exosomes in HNC in the context of TP53 status are understudied and extensive research is required to shed light on the biology of HPV+ and HPV- HNC.


Asunto(s)
Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Exosomas/metabolismo , Neoplasias de Cabeza y Cuello/etiología , Neoplasias de Cabeza y Cuello/metabolismo , Mutación , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Animales , Susceptibilidad a Enfermedades , Matriz Extracelular/metabolismo , Predisposición Genética a la Enfermedad , Neoplasias de Cabeza y Cuello/patología , Humanos
4.
Anticancer Res ; 40(1): 97-100, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31892557

RESUMEN

BACKGROUND/AIM: Chronic expanding hematoma is defined as a hematoma that gradually expands over 1 month or longer, is without neoplastic features on histological sections, and does not occur in the setting of coagulopathy. The pathogenetic mechanism behind its development is unknown, nor is anything known about its genetic features. CASE REPORT: A 49-year-old man noted a tender lump close to the right femoral trochanter. Examination of a core needle biopsy showed a fibrous capsule with fibrinoid material on one side. The patient underwent surgery with removal of a cystic, encapsulated structure with central bleeding and proliferating vessels in the fibrous capsule. The reactive fibroblasts were without any sign of atypia. Genetic analyses were performed on this chronic expanding hematoma. RESULTS: G-Banding analysis of short-term cultured cells from the chronic expanding hematoma yielded a karyotype with a single clonal chromosome abnormality: 46,XY,t(11;19)(q13;q13)[8]/46,XY[10]. RNA sequencing and examination of the sequencing data using five different programs did not identify fusion genes related to the translocation. CONCLUSION: The acquired translocation t(11;19)(q13;q13) suggested that chronic expanding hematoma is a neoplastic lesion. Since the translocation did not lead to any fusion genes, one can speculate that it causes deregulation of gene expression.


Asunto(s)
Cromosomas Humanos Par 11 , Cromosomas Humanos Par 19 , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Hematoma/diagnóstico , Hematoma/genética , Translocación Genética , Biopsia , Bandeo Cromosómico , Enfermedad Crónica , Progresión de la Enfermedad , Humanos , Cariotipificación , Masculino , Persona de Mediana Edad
5.
Zhonghua Er Ke Za Zhi ; 58(1): 35-40, 2020 Jan 02.
Artículo en Chino | MEDLINE | ID: mdl-31905474

RESUMEN

Objective: To investigate the genotype and phenotype of children with KCNA2 gene related developmental and epileptic encephalopathy (DEE). Methods: Clinical data including the manifestations and electroencephalogram of 8 children with KCNA2 variants treated in the Department of Pediatrics, Peking University First Hospital from March 2017 to June 2019 were collected and analyzed retrospectively. Results: Among the 8 epileptic patients with KCNA2 variants, 5 were males and 3 were females. The age of onset was from 1 day to 11 months. The age at last follow-up ranged from 4 months to 86 months. Two variants including c.1214C>T (loss-of-function) and c.1120A>G (gain-and loss-of-function) were identified. The variant of c.1214C>T was found in six patients (case 1-6). For these patients, the age of onset was from 5 to 11 months and they were characterized by multiple seizure types. All had focal seizures and had normal development before seizure onset with developmental regression after seizure onset. The first electroencephalogram showed epileptic discharges in Rolandic region in two, epileptic discharges in Rolandic region combined with generalized discharge in one, generalized discharge with posterior predominance in two (combined with or transferred to Rolandic region during the course) and epileptic discharges in posterior region combined with generalized discharge in one. And in 5 of them the Rolandic discharges developed into epileptic electrical status (ESES) during sleep. All the six patients were still treated with a combination of multiple antiepileptic drugs. Two of them had seizure controlled at 80 months and 68 months, respectively. The variant of c.1120A>G were identified in two of eight patients (case 7 and 8) and they had seizure onset on the 1st day after birth. Their epileptic seizures were frequent and difficult to control. They had remarkably developmental delay and microcephaly since birth. One case (case 8) had a wide forehead. They had frequent seizures up to the last follow-up. In case 7, the early electroencephalogram showed epileptic discharges in temporal region, and interictal electroencephalogram at 3 months of age showed multifocal discharge with posterior and temporal region predominance. In case 8, the early electroencephalogram was normal and electroencephalogram showed burst suppression at 2 months of age, and it developed epileptiform discharge in posterior region at 1 year of age. Conclusions: KCNA2 gene variants can lead to DEE with multiple seizures types. Among them, loss-of-function c.1214C>T is the most common, and these patients have seizure onset at infancy with Rolandic discharges tended to develop into to ESES pattern. The variant of c.1120A>G is a gain-of- and loss-of-function variant, patients with c.1120A>G have seizure onset in neonatal period, the phenotype overlaps with the former but is more severe.


Asunto(s)
Encefalopatías/genética , Epilepsia/diagnóstico , Canal de Potasio Kv.1.2/genética , Convulsiones , Edad de Inicio , Encéfalo/fisiopatología , Encefalopatías/fisiopatología , Niño , Preescolar , Discapacidades del Desarrollo/fisiopatología , Epilepsia/complicaciones , Epilepsia/genética , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Fenotipo , Estudios Retrospectivos
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(1): 1-4, 2020 Jan 10.
Artículo en Chino | MEDLINE | ID: mdl-31922584

RESUMEN

OBJECTIVE: To explore susceptibility genes for autism spectrum disorders (ASD). METHODS: Whole-exome sequencing was carried out for 60 family trios affected with sporadic ASD. Genetic variants discovered in over 10% of the patients were selected for genotype-phenotype correlation and pathway enrichment analysis using Phenolyzer software and metascape database. Combining gene-phenotypic scores, pathway-related genes associated with neural and neurite triggering were screened for the candidates. RESULTS: A total of 170 common variants were found to be associated with the ASD phenotype. Among these, there was only one high-confidence gene [SHANK2(0.8146)] and four medium-confidence genes [ERBB2(0.1322), LAMC3(0.1117), PPFIA4(0.1059), DISC1(0.1002)]. Twenty-pathways and four biological processes were found to be statistically significant by pathway enrichment analysis, which included neuron projection morphogenesis (GO: 0048812), regulation of neuroblast proliferation (GO: 1902692), modulation of excitatory postsynaptic potential (GO: 0098815), and dendrite morphogenesis (GO: 0048813). Twenty-one genes were found to be closely associated with neurological and neurite triggering, among which only SHANK2, ERBB2, and DISC1 had above-medium confidence correlation scores with the ASD phenotypes. CONCLUSION: Abnormal neuron projection morphogenesis (GO: 0048812) may be closely related to the occurrence of ASD. SHANK2, ERBB2, and DISC1 are susceptibility genes for ASD.


Asunto(s)
Trastorno del Espectro Autista , Variación Genética , Trastorno del Espectro Autista/genética , Predisposición Genética a la Enfermedad , Humanos , Fenotipo , Sinapsis/genética , Secuenciación del Exoma Completo
7.
BMC Med Genet ; 21(1): 17, 2020 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-31996156

RESUMEN

BACKGROUND: Several reports were published on the relationship between the vascular endothelial growth factor (VEGF) -2578C > A gene polymorphism and lung cancer risk; however, the results are debatable. This meta-analysis was conducted to assess the relationship between VEGF -2578C > A gene polymorphism and lung cancer risk. METHODS: The associated literatures were identified on the 1st of September 2018 from CBM-disc (China Biological Medicine Database) and PubMed. RESULT: A total of 14 reports were recruited into our meta-analysis to assess the association between VEGF -2578C > A gene polymorphism and lung cancer susceptibility. There was a marked association between VEGF -2578C > A A allele / CC genotype and lung cancer risk in overall and Asian populations (overall populations: A allele: OR = 1.26, 95% CI: 1.08-1.46, P = 0.003; CC genotype: OR = 0.72, 95% CI: 0.54-0.95, P = 0.02; Asians: A allele: OR = 1.33, 95% CI: 1.15-1.55, P = 0.0002; CC genotype: OR = 0.68, 95% CI: 0.50-0.93, P = 0.01). However, VEGF -2578C > A gene polymorphism was not associated with the risk of lung cancer in Caucasians. CONCLUSION: VEGF -2578C > A A allele / CC genotype is associated with the lung cancer susceptibility in Asians and in overall populations.


Asunto(s)
Neoplasias Pulmonares/genética , Factor A de Crecimiento Endotelial Vascular/genética , Alelos , Grupo de Ascendencia Continental Asiática/genética , Bases de Datos Factuales , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Neoplasias Pulmonares/etnología , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Factor C de Crecimiento Endotelial Vascular/genética
9.
Mymensingh Med J ; 29(1): 108-114, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31915345

RESUMEN

The MDM2 gene is a negative regulator of p53, which has been linked to lung cancer. Here, we have evaluated the association of MDM2 SNP 285 G>C (rs117039649) and SNP 354 A>G (rs769412) with lung cancer risk in Bangladeshi population at the National Institute of Cancer Research and Hospital, Dhaka, Bangladesh from July 2015 to June 2017. We have genotyped 126 lung cancer patients and 133 healthy controls from Bangladesh by PCR-RFLP method for this study. Statistical analyses were performed to define the associations. Multivariate logistic regression revealed that MDM2 SNP 285 decreases the risk of lung cancer (GC+CC vs. GG: OR = 0.29, 95% CI = 0.15-0.56, p<0.005). A stratification analysis confirmed that this protective status is extended to younger people, male, overweight people, and smokers (GC+CC vs. GG: OR = 0.25-0.29, 95% CI = 0.11-0.69, p<0.01). However, we did not find any association of SNP 354 with lung cancer risk in Bangladeshi population (p>0.05). The present data indicated that MDM2 SNP 285 G>C (rs117039649) reduces the chance of lung cancer development in Bangladeshi population. However, MDM2 SNP 354 A>G (rs769412) has no such association in the same population.


Asunto(s)
Grupo de Ascendencia Continental Asiática , Predisposición Genética a la Enfermedad , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteína p53 Supresora de Tumor/genética , Grupo de Ascendencia Continental Asiática/etnología , Grupo de Ascendencia Continental Asiática/genética , Bangladesh , Estudios de Casos y Controles , Humanos , Masculino , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , Factores de Riesgo
10.
Medicine (Baltimore) ; 99(4): e18662, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31977856

RESUMEN

BACKGROUND: As a key gene in the reverse transport pathway of cholesterol, ABCA1 (ATP-binding cassette transporter A1) plays an important role in the pathogenesis of coronary artery disease (CAD). In the ABCA1, rs2230806 is the most widely studied polymorphism and its role has been controversial. METHODS: We performed an updated meta-analysis by searching online electronic databases using the PubMed, Web of Science, Embase, Cochrane Library, EMBASE, Google Scholar, China National Knowledge Infrastructure, and Wan Fang databases before June 28, 2019. STATA12.0 software was used to perform a series of analyses on the data, including genetic effect model, heterogeneity, sensitivity, and publication bias analysis. RESULTS: Based on our inclusion and exclusion criteria, finally 43 articles including a total of 34,348 subjects (14,085 CAD cases and 20,263 healthy controls) were investigated. Results showed that carrying the K allele in rs223086 in the overall population significantly reduced the risk of CAD (OR = 0.745, 95% CI = 0.687-0.809, P < .001). After the ethnicity stratification analysis, the above phenomenon was found to be significant in Asian populations (OR = 0.686, 95% CI = 0.633-0.744, P < .001), marginally significant in Caucasians (OR = 0.887, 95% CI = 0.786-1.001, P = .051), and not significant in other populations (OR = 0.851, 95% CI = 0.558-1.297, P = .452). Further stratified according to the sample size in the Asian and Caucasian populations, in the Asian the K allele is more protective in small samples than large samples; however, in the Caucasian small samples carrying the K allele play a protective role while large samples are negative. In addition, according to the source of the control population and the geographical location in China, the results showed that rs2230806 was significantly associated with CAD in any group. Five genetic models (allelic, recessive, dominant, homozygote, and heterozygote) were analyzed in the above analysis. CONCLUSION: The K allele of rs2230806 was significantly associated with decreased risk of CAD, especially in Asian populations and small sample Caucasians.


Asunto(s)
Transportador 1 de Casete de Unión a ATP/genética , Enfermedad de la Arteria Coronaria/genética , Alelos , Grupo de Ascendencia Continental Asiática/genética , Enfermedad de la Arteria Coronaria/etnología , Grupo de Ascendencia Continental Europea/genética , Predisposición Genética a la Enfermedad , Humanos , Polimorfismo de Nucleótido Simple
11.
Medicine (Baltimore) ; 99(4): e18720, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31977861

RESUMEN

The methylenetetrahydrofolate reductase (MTHFR) may play a pathological role in polycystic ovary syndrome (PCOS). However, the conclusions of published reports on the relationship between the MTHFR C677T polymorphism and PCOS risk remain controversial.To derive a more precise estimation we performed a metaanalysis based on 22 studies that together included 2405 cases and 2419 controls. PubMed, EMBASE, WanFang and the Chinese National Knowledge Infrastructure databases were used to retrieve articles up to up to October 28, 2019. The crude odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated to evaluate the association.Metaanalysis results showed a significant association between the MTHFR C677T polymorphism and PCOS risk in 3 genetic models (allele model: OR = 1.40, 95% CI = 1.27-1.53; dominant model: OR = 1.47, 95% CI = 1.17-1.85); homozygous model: OR = 1.90, 95% CI = 1.55-2.32). Moreover, significant associations were observed when stratified by ethnicity, source of controls, etiology, and genotype methods.This metaanalysis suggests that the T-allele of the MTHFR C677T polymorphism is associated with an increased risk of PCOS, especially in Asians further studies with larger population sizes are needed to confirm these results.


Asunto(s)
Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Síndrome del Ovario Poliquístico/genética , Grupos de Población Continentales , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Polimorfismo de Nucleótido Simple
13.
Medicine (Baltimore) ; 99(2): e18725, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31914088

RESUMEN

The NOTCH signaling pathway plays a crucial role in cell phenotype and transformation. Single nucleotide polymorphisms (SNPs) may regulate gene expression to trigger bladder cancer susceptibility. Here, we aimed to explore the relationships between genetic variants in the NOTCH pathway and bladder cancer progression.We screened SNPs located in NOTCH pathway genes using the 1000 Genomes Project dataset (CHB). A case-control cohort study including 580 bladder cancer cases and 1101 controls was conducted to genotype the candidate SNPs. The expression quantitative trait locus (eQTL) and bioinformatics analyses were performed to explore the biological function of the SNPs' host gene and their relationship. Kaplan-Meier analysis was performed to assess the association between host gene expression and bladder cancer patient prognosis.The rs7944701 in the intron of mastermind-like 2 (MAML2) had the strongest signal and was related to bladder cancer risk (OR = 1.329, 95% CI = 1.115-1.583, P = .001). eQTL analysis showed that rs7944701 with a C allele was negatively associated with mastermind-like 2 (MAML2) expression (TT versus TC/CC). Bioinformatics analysis indicated that MAML2expression was lower in bladder cancer tissues than in non-tumor tissues (P = 5.46 × 10). Additionally, bladder cancer patients with high MAML2 expression had a significantly poorer prognosis (HR = 1.53, 95% CI = 1.29-1.82, P = .010).The rs7944701 in MAML2 was strongly associated with bladder cancer susceptibility in a Chinese population. This genetic variant and its host gene could be a potential novel biomarker for individuals suffering from bladder cancer.


Asunto(s)
Transactivadores/genética , Neoplasias de la Vejiga Urinaria/genética , China , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Intrones , Estimación de Kaplan-Meier , Masculino , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Transducción de Señal
14.
Lancet Haematol ; 7(1): e73-e81, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31810765

RESUMEN

Diagnosing, surveilling, and understanding the biological consequences of clonal haematopoiesis poses a clinical challenge for both patients and clinicians. The relationship between peripheral blood cytopenias and myeloid neoplasms-such as myelodysplastic syndrome-is an area of active research, and understanding of clonal haematopoiesis has developed markedly on the basis of findings concerning somatic mutations in genes known to be associated with myelodysplastic syndrome. These findings have raised the conundrum of how to appropriately define and follow myelodysplastic syndrome precursor states, such as clonal haematopoiesis of indeterminate potential (CHIP) and clonal cytopenias of undetermined significance (CCUS). Identifying these conditions could allow earlier diagnosis of myelodysplastic syndrome, modify surveillance for myelodysplastic syndrome, and possibly guide therapies, but this information also comes at a cost to patients that might or might not be justified by our present understanding of clonal haematopoiesis. When faced with a diagnosis of clonal haematopoiesis, some patients and providers might be content to let the events unfold naturally, whereas others may insist on intense follow-up and early interventions. This Viewpoint assesses recent developments in clonal haematopoiesis and the related implications for affected patients and their providers.


Asunto(s)
Hematopoyesis , Síndromes Mielodisplásicos/diagnóstico , Transformación Celular Neoplásica/genética , Predisposición Genética a la Enfermedad , Humanos , Mutación , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/fisiopatología
15.
J Cancer Res Clin Oncol ; 146(1): 273-285, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31641854

RESUMEN

PURPOSE: The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway plays a vital role in cancer development and progression. This study aimed to investigate the relationship between genotype variants in mTORC1 pathway and the risk of brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC). METHODS: We extracted genomic DNA from blood samples of 501 NSCLC patients and genotyped eight single-nucleotide polymorphisms (SNPs) in three core genes [mammalian target of rapamycin (mTOR), mammalian lethal with sec-13 protein 8 (mLST8) and regulatory-associated protein of mTOR (RPTOR)] of the mTORC1 pathway. The associations between these SNPs and the risk of BM development were assessed. RESULTS: The AG/GG genotype of mLST8:rs26865 and TC/CC genotype of mLST8:rs3160 were associated with an increased risk of BM [hazard ratios (HR) 2.938, 95% confidence interval (CI) 1.664-5.189, p < 0.001 and HR = 2.490, 95% CI = 1.543-4.016, p < 0.001, respectively]. These risk polymorphisms had a cumulative effect on BM risk, with two risk genotypes exhibiting the highest increased risk (p < 0.001). Furthermore, these risk SNPs were associated with the lymph node metastasis (N2/3), body mass index (BMI) (≥ 25 kg/m2), high level of squamous cell carcinoma (SCC) antigen and Ki-67 proliferation index. Moreover, patients with AG/GG genotype of mLST8:rs26865 had significantly lower median overall survival than those with AA genotype (12.1 months versus 21.6 months, p = 0.04). CONCLUSIONS: Our results indicate that polymorphisms in mTORC1 pathway were significantly associated with increased risk of BM and may be valuable biomarkers to identify NSCLC patients with a high risk of BM.


Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , ADN de Neoplasias/sangre , ADN de Neoplasias/genética , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Persona de Mediana Edad , Mutación , Polimorfismo de Nucleótido Simple , Estudios Retrospectivos , Transducción de Señal
16.
Gene ; 726: 144147, 2020 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-31629822

RESUMEN

BACKGROUND: Suicidal ideation (SI) is the most serious symptom of major depressive disorder (MDD) and considered an extreme state. The serotonin transporter gene (SLC6A4) plays a significant role in MDD and suicide pathophysiology. Previous studies have revealed an association between common variants of SLC6A4 with the risk of MDD and suicide. However, very few studies have so far focused on the degree to which rare variants of SLC6A4 are responsible for the depression observed in adolescent and young adult suicide patients. The aim of this study was to examine the impact of common and rare variants of SLC6A4 on the risk of Han Chinese adolescents and young adults suffering MDD with SI. METHODS: Targeted sequencing of the SLC6A4 gene was conducted using FastTarget technology in Han Chinese adolescents and young adults, of which 74 were MDD patients with SI and 150 were healthy controls. Gene-based association analyses of rare variants were performed using enrichment analysis and a cumulative allele test. An allele association study was performed against common variants. RESULTS: After sequencing and bioinformatics analysis, a total of 15 single nucleotide variants (SNVs) were detected in the targeted regions from all participants, including 9 common and 6 rare variants. Among these, 5 rare variants were identified within the study group. Enrichment analysis of rare variants demonstrated a statistical difference (p = 0.042) between the study and control groups. Using cumulative allele analysis, alternative alleles in the SLC6A4 gene exhibited an association with MDD patients with SI (cumulative allele: OR = 10.18, 95% CI = 1.18-87.32, p = 0.017). No significant association was found between the 9 common SLC6A4 variants and MDD patients with SI. CONCLUSIONS: Our results suggest that rare variants of SLC6A4 may contribute to a genetic risk of adolescents and young adults suffering MDD with SI.


Asunto(s)
Grupo de Ascendencia Continental Asiática/genética , Trastorno Depresivo Mayor/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Adolescente , Adulto , Alelos , Femenino , Pruebas Genéticas/métodos , Humanos , Masculino , Factores de Riesgo , Ideación Suicida , Suicidio , Adulto Joven
17.
Gene ; 726: 144165, 2020 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-31726085

RESUMEN

GWAS studies have identified variant rs 17810546 in a non-coding region on chromosome 3 as a risk factor for several auto-immune diseases, including Celiac Disease. In silico analysis reveals that this variant is located in a transcription regulatory site. By means of reporter constructs we show that this region can override the expression rate of a gene as determined by its native promoter and that this modulation is influenced by the genetic composition of the haplotype which rs17810546 forms with a nearby other variant, rs761008. Secondly, we present data that this genetically imprinted modulation could be involved in Celiac Disease through the IL12A gene which is located 40 Kb downstream of this regulatory region. Based on our findings it is most likely that the IL12A gene does so as part of the cytokine IL-35.


Asunto(s)
Enfermedad Celíaca/genética , Silenciador del Gen/fisiología , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Línea Celular , Estudio de Asociación del Genoma Completo/métodos , Células HEK293 , Haplotipos/genética , Humanos , Interleucinas/genética , Regiones Promotoras Genéticas/genética , Transcripción Genética/genética
18.
Hum Genet ; 139(1): 85-94, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31520123

RESUMEN

In recent years, genome-wide association study (GWAS) sample sizes have become larger, the statistical power has improved and thousands of trait-associated variants have been uncovered, offering new insights into the genetic etiology of complex human traits and disorders. However, a large fraction of the polygenic architecture underlying most complex phenotypes still remains undetected. We here review the conditional false discovery rate (condFDR) method, a model-free strategy for analysis of GWAS summary data, which has improved yield of existing GWAS and provided novel findings of genetic overlap between a wide range of complex human phenotypes, including psychiatric, cardiovascular, and neurological disorders, as well as psychological and cognitive traits. The condFDR method was inspired by Empirical Bayes approaches and leverages auxiliary genetic information to improve statistical power for discovery of single-nucleotide polymorphisms (SNPs). The cross-trait condFDR strategy analyses separate GWAS data, and leverages overlapping SNP associations, i.e., cross-trait enrichment, to increase discovery of trait-associated SNPs. The extension of the condFDR approach to conjunctional FDR (conjFDR) identifies shared genomic loci between two phenotypes. The conjFDR approach allows for detection of shared genomic associations irrespective of the genetic correlation between the phenotypes, often revealing a mixture of antagonistic and agonistic directional effects among the shared loci. This review provides a methodological comparison between condFDR and other relevant cross-trait analytical tools and demonstrates how condFDR analysis may provide novel insights into the genetic relationship between complex phenotypes.


Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genómica/métodos , Herencia Multifactorial , Polimorfismo de Nucleótido Simple , Humanos , Fenotipo
19.
BJOG ; 127(3): 364-375, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31507061

RESUMEN

OBJECTIVE: Unselected population-based BRCA testing provides the opportunity to apply genomics on a population-scale to maximise primary prevention for breast-and-ovarian cancer. We compare long-term outcomes of population-based and family-history (FH)/clinical-criteria-based BRCA testing on psychological health and quality of life. DESIGN: Randomised controlled trial (RCT) (ISRCTN73338115) GCaPPS, with two-arms: (i) population-screening (PS); (ii) FH/clinical-criteria-based testing. SETTING: North London Ashkenazi-Jewish (AJ) population. POPULATION/SAMPLE: AJ women/men. METHODS: Population-based RCT (1:1). Participants were recruited through self-referral, following pre-test genetic counselling from the North London AJ population. INCLUSION CRITERIA: AJ women/men >18 years old; exclusion-criteria: prior BRCA testing or first-degree relatives of BRCA-carriers. INTERVENTIONS: Genetic testing for three Jewish BRCA founder-mutations: 185delAG (c.68_69delAG), 5382insC (c.5266dupC) and 6174delT (c.5946delT), for (i) all participants in PS arm; (ii) those fulfilling FH/clinical criteria in FH arm. Linear mixed models and appropriate contrast tests were used to analyse the impact of BRCA testing on psychological and quality-of-life outcomes over 3 years. MAIN OUTCOME MEASURES: Validated questionnaires (HADS/MICRA/HAI/SF12) used to analyse psychological wellbeing/quality-of-life outcomes at baseline/1-year/2-year/3-year follow up. RESULTS: In all, 1034 individuals (691 women, 343 men) were randomised to PS (n = 530) or FH (n = 504) arms. There was a statistically significant decrease in anxiety (P = 0.046) and total anxiety-&-depression scores (P = 0.0.012) in the PS arm compared with the FH arm over 3 years. No significant difference was observed between the FH and PS arms for depression, health-anxiety, distress, uncertainty, quality-of-life or experience scores associated with BRCA testing. Contrast tests showed a decrease in anxiety (P = 0.018), health-anxiety (P < 0.0005) and quality-of-life (P = 0.004) scores in both PS and FH groups over time. Eighteen of 30 (60%) BRCA carriers identified did not fulfil clinical criteria for BRCA testing. Total BRCA prevalence was 2.9% (95% CI 1.97-4.12%), BRCA1 prevalence was 1.55% (95% CI 0.89-2.5%) and BRCA2 prevalence was 1.35% (95% CI 0.74-2.26%). CONCLUSION: Population-based AJ BRCA testing does not adversely affect long-term psychological wellbeing or quality-of-life, decreases anxiety and could identify up to 150% additional BRCA carriers. TWEETABLE ABSTRACT: Population BRCA testing in Ashkenazi Jews reduces anxiety and does not adversely affect psychological health or quality of life.


Asunto(s)
Ansiedad , Detección Precóz del Cáncer , Genes BRCA1 , Genes BRCA2 , Síndrome de Cáncer de Mama y Ovario Hereditario , Calidad de Vida , Adulto , Ansiedad/fisiopatología , Ansiedad/prevención & control , Detección Precóz del Cáncer/métodos , Detección Precóz del Cáncer/psicología , Femenino , Predisposición Genética a la Enfermedad/psicología , Pruebas Genéticas/métodos , Pruebas Genéticas/estadística & datos numéricos , Síndrome de Cáncer de Mama y Ovario Hereditario/diagnóstico , Síndrome de Cáncer de Mama y Ovario Hereditario/etnología , Síndrome de Cáncer de Mama y Ovario Hereditario/genética , Síndrome de Cáncer de Mama y Ovario Hereditario/psicología , Humanos , Judíos/genética , Judíos/estadística & datos numéricos , Londres/epidemiología , Masculino , Anamnesis/estadística & datos numéricos , Incertidumbre
20.
Mol Genet Genomics ; 295(1): 23-30, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31410611

RESUMEN

P2RX7 (purinergic receptor P2X 7) is an important membrane ion channel and involved in multiple physiological processes. One non-synonymous SNP on P2RX7, rs3751143, had been proven to reduce ion channel function and further associated with multiple diseases. However, it was still unclear whether there were other cis-regulatory elements for P2RX7, which might further contribute to related diseases. Allele-specific expression (ASE) is a robust and sensitive approach to identify the potential functional region in human genome. In the current study, we measured ASE on rs3751143 in lung tissues and observed a consistent excess of A allele over C (P = 0.001), which indicated that SNP(s) in linkage disequilibrium (LD) could regulate P2RX7 expression. By analyzing the 1000 genomes project data for Chinese, one SNP locating ~ 5 kb away and downstream of P2RX7, rs11615992, was disclosed to be in strong LD with rs3751143. The dual-luciferase assay confirmed that rs11615992 could alter target gene expression in lung cell line. Through chromosome conformation capture, it was verified that the region surrounding rs11615992 could interact with P2RX7 promoter and effect as an enhancer. By chromatin immunoprecipitation, the related transcription factor POU2F1 (POU class 2 homeobox 1) was recognized to bind the region spanning rs11615992. Our work identified a novel long-distance cis-regulatory SNP for P2RX7, which might contribute to multiple diseases.


Asunto(s)
Polimorfismo de Nucleótido Simple/genética , Receptores Purinérgicos P2X7/genética , Alelos , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Genoma Humano/genética , Haplotipos/genética , Humanos , Desequilibrio de Ligamiento/genética , Regiones Promotoras Genéticas/genética
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