RESUMEN
INTRODUCTION: Neoadjuvant systemic therapy (NAST) is vital in the management of HER2-positive (HER2+) breast cancer. Nevertheless, the indications for NAST in tumors <2 cm remain controversial. METHOD: A total of 7961 patients were screened from the Surveillance, Epidemiology, and End Result database. Independent prognostic factors were identified using multivariate Cox analysis. Subgroup analyses and Kaplan-Meier analyses were used to simulate whether NAST would provide a survival benefit with different high-risk characteristics. Nomograms were constructed, and an internal validation cohort was employed. RESULTS: Of the 7961 included patients, 1137 (14.3%) underwent NAST. In the total population, NAST was associated with poorer overall survival (OS) and breast cancer-specific survival (BCSS) (OS: P = 0.00093; BCSS: P < 0.0001). Multivariate Cox analysis confirmed that NAST markedly affected the prognosis of enrolled patients. Besides, a direct association between T, N, age, subtype, and prognosis was observed. Subgroup analyses yielded in these three subgroups, T1c, hormone receptor-negative, and 61-69 years of age, NAST and AST had comparable OS, while NAST possessed worse BCSS. Notably, even in the N3, we still did not observe any additional benefit of NAST. The calculated C-index of 0.72 and 0.73 confirmed the predictability of the nomograms. The AUCs exhibit consistency in the training and validation cohorts. CONCLUSION: Our findings suggest that NAST does not provide additional benefit to patients with T1 HER2+ breast cancer, even in the presence of lymph node metastasis, T1c, or hormone receptor negativity. This study facilitates the implementation of individualized management strategies.
Asunto(s)
Neoplasias de la Mama , Terapia Neoadyuvante , Nomogramas , Receptor ErbB-2 , Programa de VERF , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Neoplasias de la Mama/metabolismo , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Anciano , Pronóstico , Adulto , Estimación de Kaplan-Meier , Tasa de Supervivencia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Modelos de Riesgos Proporcionales , Estadificación de NeoplasiasRESUMEN
ABSTRACT Introduction: With the growing importance of physical training over sport training for competition, more research has been conducted. One of the least explored techniques is superisometric aquatic training. Objective: Study the application of super-isometric aquatic training to the physical training of soccer athletes. Methods: A literature review was performed to elaborate an experimental protocol. The experimental method was conducted on 24 university volunteers randomly divided into control and experimental groups. Classical training was conducted for two weeks between the groups, superisometric aquatic training was added only in the experimental group. Through the mathematical-statistical method, a comparative analysis of the research results was elaborated, and the effects of the intervention were discussed. Results: The movement time of the athletes in the experimental training group was reduced by 1.89s. The performance of running, tapping, standing jump, and weightlifting tests is not significantly different from those of the traditional strength training group. Conclusion: The application of superisometric aquatic training in the physical preparation of soccer players increased the overall strength of athletes,and also beneficially influenced specific activities of the sport. It is recommended to analyze the characteristics of the athlete and integrate superisometric training to general strength traispecificcally to the need of each athlete. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.
RESUMO Introdução: Com a crescente importância do treinamento físico sobre o treinamento esportivo para competição, um número cada vez maior de pesquisas vem sendo realizado. Uma das técnicas pouco exploradas é o treinamento aquático superisométrico. Objetivo: Estudar a aplicação do treinamento aquático superisométrico ao treinamento físico de preparo dos atletas de futebol. Métodos: Uma análise da literatura foi efetuada para elaborar um protocolo experimental. O método experimental foi conduzido sobre 24 universitários voluntários divididos aleatoriamente em grupo controle e experimental. O treinamento clássico foi conduzido por duas semanas entre os grupos, o treinamento aquático superisométrico foi adicionado apenas no grupo experimental. Através do método estatístico matemático uma análise comparativa dos resultados da pesquisa foi elaborada e os efeitos da intervenção foram discutidos. Resultados: O tempo de movimento dos atletas no grupo de treinamento experimental foi reduzido em 1,89s. O desempenho de corrida, toque, salto em pé e os resultados dos testes de levantamento de peso não foram significativamente diferentes daqueles do grupo de treinamento de força tradicional. Conclusão: A aplicação do treinamento aquático superisométrico no preparo físico de futebolistas aumentou a força geral dos atletas, também influenciou beneficamente em atividades específicas do esporte. Recomenda-se analisar as características do esportista e integrar o treinamento superisométrico ao treinamento de força geral especificamente à necessidade de cada esportista. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.
RESUMEN Introducción: Con la creciente importancia de la preparación física en el entrenamiento deportivo para la competición, se ha realizado un número cada vez mayor de investigaciones. Una de las técnicas poco exploradas es el entrenamiento acuático superisométrico. Objetivo: Estudiar la aplicación del entrenamiento acuático superisométrico a la preparación física de los deportistas de fútbol. Métodos: Se realizó una revisión de la literatura para elaborar un protocolo experimental. El método experimental se llevó a cabo con 24 voluntarios universitarios divididos aleatoriamente en grupos de control y experimentales. El entrenamiento clásico se realizó durante quince días entre los grupos, el entrenamiento acuático superisométrico se añadió sólo en el grupo experimental. Mediante el método estadístico matemático se elaboró un análisis comparativo de los resultados de la investigación y se discutieron los efectos de la intervención. Resultados: El tiempo de movimiento de los atletas del grupo de entrenamiento experimental se redujo en 1,89s. El rendimiento de la carrera, el golpeo, el salto de pie y los resultados de las pruebas de levantamiento de pesas no fueron significativamente diferentes de los del grupo de entrenamiento de fuerza tradicional. Conclusión: La aplicación del entrenamiento acuático superisométrico en la preparación física de los jugadores de fútbol aumentó la fuerza general de los atletas, también influyó beneficiosamente en las actividades específicas del deporte. Se recomienda analizar las características del deportista e integrar el entrenamiento superisométrico al entrenamiento de fuerza general de forma específica a la necesidad de cada deportista. Nivel de evidencia II; Estudios terapéuticos -investigación de los resultados del tratamiento.
RESUMEN
Abstract We aimed to compare the effects of oxycodone hydrochloride and dezocine on hemodynamics and inflammatory factors in patients receiving gynecological laparoscopic surgery under general anesthesia. A total of 246 patients were divided into group A and B (n=123). Hemorheology indices were recorded 5 min after anesthesia (T0), 1 min after pneumoperitoneum (T1), when position was changed 5 min after pneumoperitoneum (T2), 15 min after pneumoperitoneum (T3), 1 min (T4) and 5 min (T5) after position was restored. Visual analogue scale scores 1, 2, 6, 12, 24 and 48 h after operation were recorded. Postoperative adverse reactions and visceral pain were observed. The expression levels of inflammatory factors were detected by enzyme-linked immunosorbent assay 12 h after operation. Compared with group A, group B had higher heart rate and mean arterial pressure at T2, lower central venous pressure and cardiac output at T1-T3, and higher systemic vascular resistance at T1-T5 (P<0.05). The incidence rate of pain syndrome in group A was lower (P<0.05). Group A had lower tumor necrosis factor-alpha and interleukin-6 expression levels and higher interleukin-10 level than those of group B (P<0.05). For gynecological laparoscopic surgery, oxycodone preemptive analgesia has superior outcomes to those of dezocine
Asunto(s)
Humanos , Femenino , Adulto , Persona de Mediana Edad , Pacientes/clasificación , Laparoscopía/instrumentación , Anestesia General/instrumentación , Ensayo de Inmunoadsorción Enzimática/métodosAsunto(s)
Humanos , Masculino , Anomalías Cutáneas , Telangiectasia , Hepatitis B/complicaciones , China , Virus de la Hepatitis B , Pueblo AsiaticoAsunto(s)
Hepatitis B , Anomalías Cutáneas , Telangiectasia , Pueblo Asiatico , China , Hepatitis B/complicaciones , Virus de la Hepatitis B , Humanos , MasculinoRESUMEN
ABSTRACT Objective: Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic inflammatory disease that can cause bladder pain and accompanying symptoms, such as long-term urinary frequency and urgency. IC/BPS can be ulcerative or non-ulcerative. The aim of this study was to explore the core genes involved in the pathogenesis of ulcerative IC, and thus the potential biomarkers for clinical treatment. Materials and Methods: First, the gene expression dataset GSE11783 was downloaded using the Gene Expression Omnibus (GEO) database and analyzed using the limma package in R to identify differentially expressed genes (DEGs). Then, the Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for Gene Ontology (GO) functional analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) was used for pathway enrichment analysis. Finally, the protein-protein interaction (PPI) network was constructed, and key modules and hub genes were determined using the STRING and Cytoscape software. The resulting key modules were then analyzed for tissue-specific gene expression using BioGPS. Results: A total of 216 up-regulated DEGs and 267 down-regulated genes were identified, and three key modules and nine hub genes were obtained. Conclusion: The core genes (CXCL8, CXCL1, IL6) obtained in this study may be potential biomarkers of interstitial cystitis with guiding significance for clinical treatment.
Asunto(s)
Humanos , Cistitis Intersticial/genética , Programas Informáticos , Perfilación de la Expresión Génica , Mapas de Interacción de Proteínas/genética , Ontología de GenesRESUMEN
OBJECTIVE: Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic inflammatory disease that can cause bladder pain and accompanying symptoms, such as long-term urinary frequency and urgency. IC/BPS can be ulcerative or non-ulcerative. The aim of this study was to explore the core genes involved in the pathogenesis of ulcerative IC, and thus the potential biomarkers for clinical treatment. MATERIALS AND METHODS: First, the gene expression dataset GSE11783 was downloaded using the Gene Expression Omnibus (GEO) database and analyzed using the limma package in R to identify differentially expressed genes (DEGs). Then, the Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for Gene Ontology (GO) functional analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) was used for pathway enrichment analysis. Finally, the protein-protein interaction (PPI) network was constructed, and key modules and hub genes were determined using the STRING and Cytoscape software. The resulting key modules were then analyzed for tissue-specific gene expression using BioGPS. RESULTS: A total of 216 up-regulated DEGs and 267 down-regulated genes were identified, and three key modules and nine hub genes were obtained. CONCLUSION: The core genes (CXCL8, CXCL1, IL6) obtained in this study may be potential biomarkers of interstitial cystitis with guiding significance for clinical treatment.
Asunto(s)
Cistitis Intersticial , Cistitis Intersticial/genética , Perfilación de la Expresión Génica , Ontología de Genes , Humanos , Mapas de Interacción de Proteínas/genética , Programas InformáticosAsunto(s)
Hipertensión Portal/diagnóstico , Vena Porta/anomalías , Malformaciones Vasculares/diagnóstico , Procedimientos Quirúrgicos Vasculares/métodos , Angiografía por Tomografía Computarizada , Humanos , Hipertensión Portal/etiología , Hipertensión Portal/cirugía , Lactante , Masculino , Ultrasonografía , Malformaciones Vasculares/complicaciones , Malformaciones Vasculares/cirugíaRESUMEN
Epoxide hydrolases (EHs) are present in all living organisms and catalyze the hydrolysis of epoxides to the corresponding vicinal diols. EH are involved in the metabolism of endogenous and exogenous epoxides, and thus have application in pharmacology and biotechnology. In this work, we describe the substrates and inhibitors selectivity of an epoxide hydrolase recently cloned from the filamentous fungus Trichoderma reesei QM9414 (TrEH). We also studied the TrEH urea-based inhibitors effects in the fungal growth. TrEH showed high activity on radioative and fluorescent surrogate and natural substrates, especially epoxides from docosahexaenoic acid. Using a fluorescent surrogate substrate, potent inhibitors of TrEH were identified. Interestingly, one of the best compounds inhibit up to 60% of T. reesei growth, indicating an endogenous role for TrEH. These data make TrEH very attractive for future studies about fungal metabolism of fatty acids and possible development of novel drugs for human diseases.
Asunto(s)
Epóxido Hidrolasas/fisiología , Trichoderma/metabolismo , Catálisis , Epóxido Hidrolasas/antagonistas & inhibidores , Epóxido Hidrolasas/metabolismo , Compuestos Epoxi/metabolismo , Ácidos Grasos/fisiología , Hidrólisis , Trichoderma/fisiologíaRESUMEN
Our recent studies have shown that cross-talk between histone deacetylase 5 (HDAC5) and lysine-specific demethylase 1 (LSD1) facilitates breast cancer progression. In this work, we demonstrated that regulatory activity at -356 to -100 bp promoter element plays a critical role in governing HDAC5 transcription. By using DNA affinity precipitation and mass spectrometry, we identified a group of factors that bind to this element. Among these factors, Upstream Transcription Factor 1 (USF1) was shown to play a critical role in controlling HDAC5 transcription. Through screening a panel of epigenetic modifying drugs, we showed that a natural bioactive HDAC inhibitor, sulforaphane, downregulated HDAC5 transcription by blocking USF1 activity. Sulforaphane facilitated LSD1 ubiquitination and degradation in an HDAC5-dependent manner. A comparative microarray analysis demonstrated a genome wide cooperative effect of HDAC5 and LSD1 on cancer-related gene expression. shRNA knockdown and sulforaphane inhibition of HDAC5/LSD1 exhibited similar effects on expression of HDAC5/LSD1 target genes. We also showed that coordinated cross-talk of HDAC5 and LSD1 is essential for the antitumor efficacy of sulforaphane. Combination treatment with sulforaphane and a potent LSD1 inhibitor resulted in synergistic growth inhibition in breast cancer cells, but not in normal breast epithelial cells. Furthermore, combined therapy with sulforaphane and LSD1 inhibitor exhibited superior inhibitory effect on MDA-MB-231 xenograft tumor growth. Taken together, our work demonstrates that HDAC5-LSD1 axis is an effective drug target for breast cancer. Inhibition of HDAC5-LSD1 axis with sulforaphane blocks breast cancer growth and combined treatment with LSD1 inhibitor improves the therapeutic efficacy of sulforaphane.
Asunto(s)
Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histona Desacetilasas/metabolismo , Histona Demetilasas/metabolismo , Isotiocianatos/farmacología , Animales , Biomarcadores de Tumor/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Proliferación Celular/efectos de los fármacos , Epigénesis Genética , Femenino , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/química , Histona Desacetilasas/genética , Histona Demetilasas/antagonistas & inhibidores , Histona Demetilasas/genética , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , ARN Interferente Pequeño/genética , Sulfóxidos , Células Tumorales Cultivadas , Factores Estimuladores hacia 5'/genética , Factores Estimuladores hacia 5'/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Background: Ginsenoside is the most important secondary metabolite in ginseng. Natural sources of wild ginseng have been overexploited. Although root culture can reduce the length of the growth cycle of ginseng, the number of species of ginsenosides is reduced and their contents are lower in the adventitious roots of ginseng than in the roots of ginseng cultivated in the field. Results: In this study, 147 strains of ß-glucosidase-producing microorganisms were isolated from soil. Of these, strain K35 showed excellent activity for converting major ginsenosides into rare ginsenosides, and a NCBI BLAST of its 16S rDNA gene sequence showed that it was most closely related to Penicillium sp. (HQ608083.1). Strain K35 was used to ferment the adventitious root extract, and the fermentation products were analyzed by high-performance liquid chromatography. The results showed that the content of the rare ginsenoside CK was 0.253 mg mL-1 under the optimal converting conditions of 9 d of fermentation at pH 7.0 in LL medium, which was significantly higher than that in the adventitious roots of ginseng. Conclusion: These findings may not only solve the problem of low productivity of metabolite in ginseng root culture but may also result in the development of a new valuable method of manufacturing ginsenoside CK.
Asunto(s)
beta-Glucosidasa/metabolismo , Raíces de Plantas/metabolismo , Ginsenósidos/metabolismo , Panax/metabolismo , Penicillium , Biotransformación , Cromatografía Líquida de Alta Presión , Raíces de Plantas/química , Reactores Biológicos , Ginsenósidos/aislamiento & purificación , Fermentación , Panax/crecimiento & desarrollo , Panax/químicaRESUMEN
Brazilein is an active small molecular compound extracted from Caesalpinia sappan L. with favorable pharmacological properties on immune system, cardiovascular system, and nervous system. C. sappan has been used as a traditional medicine in China for hundreds of years for various diseases. However, the general reproductive toxicity of brazilein is still unknown. The purpose of the present study was to thoroughly evaluate the general reproductive toxicity of brazilein in ICR mice to support the future drug development and modernization of this potent traditional Chinese medicine. The results showed that, although no apparent toxicity on the reproducibility of the male was observed, brazilein might cause considerable risks to the fetuses and females as indicated by the ratios of dead fetuses and reabsorptions. In conclusion, our results from the present study provided some useful insights about the safety profile of brazilein, suggesting that brazilein should be used with caution in pregnant women.
Asunto(s)
Benzopiranos/toxicidad , Caesalpinia/toxicidad , Medicamentos Herbarios Chinos/toxicidad , Indenos/toxicidad , Reproducción/efectos de los fármacos , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos ICR , EmbarazoRESUMEN
The specifications of state space model for some principal component-related models are described, including the independent-group common principal component (CPC) model, the dependent-group CPC model, and principal component-based multivariate analysis of variance. Some derivations are provided to show the equivalence of the state space approach and the existing Wishart-likelihood approach. For each model, a numeric example is used to illustrate the state space approach. In addition, a simulation study is conducted to evaluate the standard error estimates under the normality and nonnormality conditions. In order to cope with the nonnormality conditions, the robust standard errors are also computed. Finally, other possible applications of the state space approach are discussed at the end.
Asunto(s)
Evaluación Educacional , Funciones de Verosimilitud , Salud Mental , Análisis de Componente Principal , Estadística como Asunto , Análisis de Varianza , Humanos , Análisis Multivariante , Países Bajos , Psicometría , SurinameRESUMEN
There is evidence that both smartphone and tablet integration into medical education has been lacking. At the same time, there is a niche for augmented reality (AR) to improve this process through the enhancement of textbook learning. Gunner Goggles is an attempt to enhance textbook learning in shelf exam preparatory review with augmented reality. Here we describe our initial prototype and detail the process by which augmented reality was implemented into our textbook through Layar. We describe the unique functionalities of our textbook pages upon augmented reality implementation, which includes links, videos and 3D figures, and surveyed 24 third year medical students for their impression of the technology. Upon demonstrating an initial prototype textbook chapter, 100% (24/24) of students felt that augmented reality improved the quality of our textbook chapter as a learning tool. Of these students, 92% (22/24) agreed that their shelf exam review was inadequate and 19/24 (79%) felt that a completed Gunner Goggles product would have been a viable alternative to their shelf exam review. Thus, while students report interest in the integration of AR into medical education test prep, future investigation into how the use of AR can improve performance on exams is warranted.
Asunto(s)
Instrucción por Computador/métodos , Educación Médica/métodos , Evaluación Educacional/métodos , Instrucciones Programadas como Asunto , Teléfono Inteligente , Interfaz Usuario-Computador , Instrucción por Computador/instrumentación , Aplicaciones MóvilesRESUMEN
OBJECTIVE: To explore the effects of obstructive sleep apnea syndrome (OSAS) on children's growth by the study of identical twins. STUDY DESIGN: Seventeen cases of nonobese children with OSAS were included in this study. The control group was their identical twin sibling, who had no signs of OSAS. Data including height, weight, and serum insulin-like growth factor 1 levels were analyzed before tonsillectomy and adenoidectomy (T&A) and at 3, 6, and 12 months after surgery. RESULTS: The mean apnea hyponea index was 3.9 times/hour in patients with OSAS and became normal after surgery. Minimum oxygen saturation gradually increased after T&A. The height and weight of the OSAS group before T&A was lower than the control group. During the follow-up period, height and weight increased but were lower than the control group. Serum insulin-like growth factor 1 levels in the OSAS group before T&A were lower than the control group. The level was significantly increased 3 months after T&A. CONCLUSION: OSAS impairs growth and development. Significant growth recovery occurs after T&A, and early surgical intervention is an important factor for improvement in growth.
Asunto(s)
Desarrollo Infantil/fisiología , Enfermedades en Gemelos , Apnea Obstructiva del Sueño/fisiopatología , Gemelos , Adenoidectomía , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Masculino , Polisomnografía , Pronóstico , Estudios Retrospectivos , Apnea Obstructiva del Sueño/cirugía , TonsilectomíaRESUMEN
Aim: To analyze the changes in surface characteristics of moderately roughened grade IV titanium discs following a standardized implantoplasty protocol. Materials and Method: Nine moderately roughened titanium discs (ø9.0 mm; 2-mm thickness) with a comparable surface to commercially available oral implants (Southern Implants (Pty) Ltd, Irene, South Africa) were used. One disc was used as a control sample while the remaining 8 discs were modified using a standardized technique. Each disc was divided into 4 sections of which each quadrant was instrumented in the same manner. Regular grit and superfine grit diamond burs were used for 10s each, followed by brown and green silicone burs for 15s respectively. The surface characteristics of all samples were analysed using scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM), and energy dispersive x-ray spectroscopy (EDS). Results: SEM analysis of the surfaces showed that as the instrumentation progressed from diamond burs to silicone burs, surface irregularities began to diminish. However, using silicone burs tended to increase the amount of surface debris and the roughness still remained significantly higher than the control sample. EDS identified some foreign elements originating from the silicone burs that were used. Conclusion: The proposed standardized implantoplasty protocol did not decrease the roughness of the surface below that of the control disc. The clinical implications of foreign elements remaining on the titanium surfaces need further investigation.
Asunto(s)
Implantes Dentales , Microscopía Confocal , Periimplantitis , Titanium Metallicum , Técnicas In VitroRESUMEN
BACKGROUND: More than 200 asthma candidate genes have been examined in human association studies or identified with knockout mouse approaches. However, many have not been systematically replicated in human populations, especially those containing a large number of tagging single nucleotide polymorphisms (SNPs). OBJECTIVE: We comprehensively evaluated the association of previously implicated asthma candidate genes with childhood asthma in a Mexico City population. METHODS: From the literature, we identified candidate genes with at least 1 positive report of association with asthma phenotypes in human subjects or implicated in asthma pathogenesis using knockout mouse experiments. We performed a genome-wide association study in 492 asthmatic children aged 5 to 17 years and both parents using the Illumina HumanHap 550v3 BeadChip. Separate candidate gene analyses were performed for 2933 autosomal SNPs in the 237 selected genes by using the log-linear method with a log-additive risk model. RESULTS: Sixty-one of the 237 genes had at least 1 SNP with a P value of less than .05 for association with asthma. The 9 most significant results were observed for rs2241715 in the gene encoding TGF-beta1 (TGFB1; P = 3.3 x 10(-5)), rs13431828 and rs1041973 in the gene encoding IL-1 receptor-like 1 (IL1RL1; P = 2 x 10(-4) and 3.5 x 10(-4)), 5 SNPs in the gene encoding dipeptidyl-peptidase 10 (DPP10; P = 1.6 x 10(-4) to 4.5 x 10(-4)), and rs17599222 in the gene encoding cytoplasmic FMR1 interacting protein 2 (CYFIP2; P = 4.1 x 10(-4)). False discovery rates were less than 0.1 for all 9 SNPs. Multimarker analysis identified TGFB1, IL1RL1, the gene encoding IL-18 receptor 1 (IL18R1), and DPP10 as the genes most significantly associated with asthma. CONCLUSIONS: This comprehensive analysis of literature-based candidate genes suggests that SNPs in several candidate genes, including TGFB1, IL1RL1, IL18R1, and DPP10, might contribute to childhood asthma susceptibility in a Mexican population.
Asunto(s)
Asma/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Adolescente , Niño , Preescolar , Femenino , Genotipo , Humanos , Masculino , MéxicoRESUMEN
Many candidate genes have been studied for asthma, but replication has varied. Novel candidate genes have been identified for various complex diseases using genome-wide association studies (GWASs). We conducted a GWAS in 492 Mexican children with asthma, predominantly atopic by skin prick test, and their parents using the Illumina HumanHap 550 K BeadChip to identify novel genetic variation for childhood asthma. The 520,767 autosomal single nucleotide polymorphisms (SNPs) passing quality control were tested for association with childhood asthma using log-linear regression with a log-additive risk model. Eleven of the most significantly associated GWAS SNPs were tested for replication in an independent study of 177 Mexican case-parent trios with childhood-onset asthma and atopy using log-linear analysis. The chromosome 9q21.31 SNP rs2378383 (p = 7.10x10(-6) in the GWAS), located upstream of transducin-like enhancer of split 4 (TLE4), gave a p-value of 0.03 and the same direction and magnitude of association in the replication study (combined p = 6.79x10(-7)). Ancestry analysis on chromosome 9q supported an inverse association between the rs2378383 minor allele (G) and childhood asthma. This work identifies chromosome 9q21.31 as a novel susceptibility locus for childhood asthma in Mexicans. Further, analysis of genome-wide expression data in 51 human tissues from the Novartis Research Foundation showed that median GWAS significance levels for SNPs in genes expressed in the lung differed most significantly from genes not expressed in the lung when compared to 50 other tissues, supporting the biological plausibility of our overall GWAS findings and the multigenic etiology of childhood asthma.
Asunto(s)
Asma/genética , Cromosomas Humanos Par 9/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino , México , Adulto JovenRESUMEN
BACKGROUND: Polymorphisms in the proinflammatory cytokine genes tumor necrosis factor-alpha (TNF) and lymphotoxin-alpha (LTA, also called TNF-beta) have been associated with asthma and atopy in some studies. Parental smoking is a consistent risk factor for childhood asthma. Secondhand smoke and ozone both stimulate TNF production. OBJECTIVES: Our goal was to investigate whether genetic variation in TNF and LTA is associated with asthma and atopy and whether the association is modified by parental smoking in a Mexican population with high ozone exposure. METHODS: We genotyped six tagging single nucleotide polymorphisms (SNPs) in TNF and LTA, including functional variants, in 596 nuclear families consisting of asthmatics 4-17 years of age and their parents in Mexico City. Atopy was determined by skin prick tests. RESULTS: The A allele of the TNF-308 SNP was associated with increased risk of asthma [relative risk (RR) = 1.54; 95% confidence interval (CI), 1.04-2.28], especially among children of non-smoking parents (RR = 2.06; 95% CI, 1.19-3.55; p for interaction = 0.09). Similarly, the A allele of the TNF-238 SNP was associated with increased asthma risk among children of nonsmoking parents (RR = 2.21; 95% CI, 1.14-4.30; p for interaction = 0.01). LTA SNPs were not associated with asthma. Haplotype analyses reflected the single SNP findings in magnitude and direction. TNF and LTA SNPs were not associated with the degree of atopy. CONCLUSIONS: Our results suggest that genetic variation in TNF may contribute to childhood asthma and that associations may be modified by parental smoking.
Asunto(s)
Asma/epidemiología , Linfotoxina-alfa/genética , Contaminación por Humo de Tabaco/efectos adversos , Factor de Necrosis Tumoral alfa/genética , Adolescente , Adulto , Asma/genética , Niño , Preescolar , Exposición a Riesgos Ambientales , Femenino , Genotipo , Humanos , Hipersensibilidad Inmediata , Masculino , México/epidemiología , Ozono , Relaciones Padres-Hijo , Polimorfismo de Nucleótido Simple , Factores de RiesgoRESUMEN
Transforming growth factor beta-1 (TGFB1) may influence asthma by modulating allergic airway inflammation and airway remodeling. The role of single nucleotide polymorphisms (SNPs) of TGFB1 in asthma remains inconclusive. We examined TGFB1 SNPs in relation to asthma risk and degree of atopy among 546 case-parent triads, consisting of asthmatics aged 4-17 years and their parents in Mexico City. Atopy to 24 aeroallergens was determined by skin prick tests. We genotyped five TGFB1 SNPs, including two known functional SNPs [C-509T (rs1800469), T869C (rs1982073)] and three others (rs7258445, rs1800472, rs8179181), using TaqMan and Masscode assays. We analyzed the data using log-linear and polytomous logistic methods. Three associated SNPs, including the two known functional SNPs, were statistically significantly related to asthma risk. Individuals carrying the T allele of C-509T had an increased risk of asthma [relative risk (RR)=1.42, 95% confidence interval (CI)=1.08-1.87 for one copy; RR (95%CI)=1.95 (1.36-2.78) for two copies]. For T869C, the RRs (95%CI) were 1.47 (1.09-1.98) for one and 2.00 (1.38-2.90) for two copies of the C allele. Similar results were found for rs7258445. The haplotype containing all three risk alleles conferred an increased risk of asthma (RR=1.48, 95% CI=1.11-1.95 for one copy; RR=1.77, 95% CI=1.22-2.57 for two copies). These three SNPs were also related to the degree of atopy. This largest study to date of genetic variation in TGFB1 and asthma and atopy adds to increasing evidence for a role in these disorders.