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BACKGROUNDS: Genome-wide association studies have identified multiple genetic variants associated with obesity. However, most obesity-associated loci were waiting to be translated into new biological insights. Given the critical role of brain in obesity development, we sought to explore whether obesity-associated genetic variants could be mapped to brain protein abundances. METHODS: We performed proteome-wide association studies (PWAS) and colocalization analyses to identify genes whose cis-regulated brain protein abundances were associated with obesity-related traits, including body fat percentage, trunk fat percentage, body mass index, visceral adipose tissue, waist circumference, and waist-to-hip ratio. We then assessed the druggability of the identified genes and conducted pathway enrichment analysis to explore their functional relevance. Finally, we evaluated the effects of the significant PWAS genes at the brain transcriptional level. RESULTS: By integrating human brain proteomes from discovery (ROSMAP, N = 376) and validation datasets (BANNER, N = 198) with genome-wide summary statistics of obesity-related phenotypes (N ranged from 325,153 to 806,834), we identified 51 genes whose cis-regulated brain protein abundance was associated with obesity. These 51 genes were enriched in 11 metabolic processes, e.g., small molecule metabolic process and metabolic pathways. Fourteen of the 51 genes had high drug repurposing value. Ten of the 51 genes were also associated with obesity at the transcriptome level, suggesting that genetic variants likely confer risk of obesity by regulating mRNA expression and protein abundance of these genes. CONCLUSIONS: Our study provides new insights into the genetic component of human brain protein abundance in obesity. The identified proteins represent promising therapeutic targets for future drug development.
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Age at menarche (AAM) is a sign of puberty of females. It is a heritable trait associated with various adult diseases. However, the genetic mechanism that determines AAM and links it to disease risk is poorly understood. Aiming to uncover the genetic basis for AAM, we conducted a joint association study in up to 438,089 women from 3 genome-wide association studies of European and East Asian ancestries. A series of bioinformatical analyses and causal inference were then followed to explore in-depth annotations at the associated loci and infer the causal relationship between AAM and other complex traits/diseases. This largest meta-analysis identified a total of 21 novel AAM associated loci at the genome wide significance level (P < 5.0 × 10-8), 4 of which were European ancestry-specific loci. Functional annotations prioritized 33 candidate genes at newly identified loci. Significant genetic correlations were observed between AAM and 67 complex traits. Further causal inference demonstrated the effects of AAM on 13 traits, including forced vital capacity (FVC), high blood pressure, age at first live birth, etc, indicating that earlier AAM causes lower FVC, worse lung function, hypertension and earlier age at first (last) live birth. Enrichment analysis identified 5 enriched tissues, including the hypothalamus middle, hypothalamo hypophyseal system, neurosecretory systems, hypothalamus and retina. Our findings may provide useful insights that elucidate the mechanisms determining AAM and the genetic interplay between AAM and some traits of women.
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The two-sample Mendelian randomization (MR) study revealed a causal association of plasma proteins with osteoporosis (OP) and osteoarthritis (OA). Bone mineral density (BMD) is the gold standard for the clinical assessment of OP. Recent studies have shown that plasma proteins play an essential role in the regulation of bone development. However, the causal association of plasma proteins with BMD and OA remains unclear. We estimated the effects of 2889 plasma proteins on 2 BMD phenotypes and 6 OA phenotypes using two-sample MR analysis based on the genome-wide association study summary statistics. Then, we performed sensitivity analysis and reverse-direction MR analysis to evaluate the robustness of the MR analysis results, followed by gene ontology (GO) enrichment analysis and KEGG pathway analysis to explore the functional relevance of the identified plasma proteins. Overall, we observed a total of 257 protein-estimated heel BMD associations, 17 protein-total-body BMD associations, 2 protein-all-OA associations, and 2 protein-knee-OA associations at PFDR < 0.05. Reverse-direction MR analysis demonstrated that there was little evidence of the causal association of BMD and OA with plasma proteins. GO enrichment analysis and KEGG pathway analysis identified multiple pathways, which may be involved in the development of OP and OA. Our findings recognized plasma proteins that could be used to regulate changes in OP and OA, thus, providing new insights into protein-mediated mechanisms of bone development.
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Osteoartritis de la Rodilla , Osteoporosis , Humanos , Proteoma/genética , Estudio de Asociación del Genoma Completo , Osteoporosis/metabolismo , Densidad Ósea/genética , Polimorfismo de Nucleótido SimpleRESUMEN
Carpal tunnel syndrome (CTS) is one of the most common work-related musculoskeletal disorders. The present study sought to identify putative causal proteins for CTS. We conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal association between 2859 plasma proteins (N = 35,559) and CTS (N = 1,239,680) based on the published GWAS summary statistics. Then we replicated the significant associations using an independent plasma proteome GWAS (N = 10,708). Sensitivity analyses were conducted to validate the robustness of MR results. Multivariate MR and mediation analyses were conducted to evaluate the mediation effects of body mass index (BMI), type 2 diabetes (T2D), and arm tissue composition on the association between putative causal proteins and CTS. Colocalization analysis was used to examine whether the identified proteins and CTS shared causal variant(s). Finally, we evaluated druggability of the identified proteins. Ten plasma proteins were identified as putative causal markers for CTS, including sCD14, PVR, LTOR3, CTSS, SIGIRR, IFNL3, ASPN, TM11D, ASIP, and ITIH1. Sensitivity analyses and reverse MR analysis validated the robustness of their causal effects. Arm tissue composition, BMI, and T2D may play a fully/partial mediating role in the causal relationships of ASIP, TM11D, IFNL3, PVR, and LTOR3 with CTS. The association of ASPN and sCD14 with CTS were supported by colocalization analysis. Druggability assessment demonstrated that sCD14, CTSS, TM11D, and IFNL3 were potential drug therapeutic targets. The present study identified several potential plasma proteins that were causally associated with CTS risk, providing new insights into the pathogenesis of protein-mediated CTS and offering potential targets for new therapies.
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Síndrome del Túnel Carpiano , Diabetes Mellitus Tipo 2 , Humanos , Proteínas Sanguíneas/genética , Síndrome del Túnel Carpiano/tratamiento farmacológico , Síndrome del Túnel Carpiano/genética , Síndrome del Túnel Carpiano/diagnóstico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicaciones , Receptores de Lipopolisacáridos , Análisis de la Aleatorización MendelianaRESUMEN
BACKGROUND: The increasing incidence of carbapenem-resistant Enterobacteriaceae (CRE), has resulted in a difficult problem in the current clinical anti-infective treatment. We performed a retrospective analysis of prevalence and treatment for CRE infections patients. METHODS: This study was conducted in three tertiary care hospitals from January 1, 2010 to December 30, 2016. Baseline data, treatment, and outcomes were collected in patients with ventilator-associated bacterial pneumonia (VABP), bacteremia, complicated urinary tract infection (cUTI)/acute pyelonephritis (AP), hospital-acquired bacterial pneumonia (HABP), superficial wound infection (SWI), biliary tract infection (BTI), deep wound infection (DWI) and sterile body fluids infection (SBFI) due to CRE. RESULTS: One hundred twenty-four cases of CRE infection were identified: 31 VABP, 22 bacteremia, 18 cUTI/AP, 16 HABP, 16 SWI, 9 BTI, 7 DWI and 5 SBFI. The patient population had significant immunocompromised (33 of 124, 26.6%) and severe sepsis (43 of 124, 34.7%). The most common CRE pathogens were Klebsiella pneumoniae (84 of 124, 67.7%) and Enterobacter cloacae (24 of 124, 19.4%). And the production of IMP-type carbapenemase was the main antibiotic resistance mechanism. The majority of patients to take monotherapy for empiric therapy and dual therapy for direct treatment. Outcomes were universally poor (28-day mortality was 22.6%, 28 of 124) across all sites of infection. CONCLUSIONS: We identified a large number of cases of CRE infection in 7 years from different parts, most of these pathogens have been confirmed to produce IMP-type carbapenemases. The retrospective analysis of cases of such bacterial infections will help to control future infections of these pathogens. Despite the high mortality rate, we still found that the selection of quinolone antibiotics can be effective in the treatment of CRE producing IMP type enzymes.
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Antibacterianos/uso terapéutico , Enterobacteriaceae Resistentes a los Carbapenémicos/patogenicidad , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Infecciones por Enterobacteriaceae/epidemiología , Enterobacteriaceae/efectos de los fármacos , Enterobacteriaceae/patogenicidad , Adulto , Anciano , Anciano de 80 o más Años , Bacteriemia/tratamiento farmacológico , Bacteriemia/epidemiología , Enfermedades de las Vías Biliares/tratamiento farmacológico , Enfermedades de las Vías Biliares/epidemiología , Enfermedades de las Vías Biliares/microbiología , Líquidos Corporales/microbiología , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , China , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/epidemiología , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Enterobacter cloacae/patogenicidad , Enterobacteriaceae/aislamiento & purificación , Infecciones por Enterobacteriaceae/microbiología , Escherichia coli/efectos de los fármacos , Escherichia coli/patogenicidad , Femenino , Hospitalización , Hospitales , Humanos , Unidades de Cuidados Intensivos , Klebsiella oxytoca/efectos de los fármacos , Klebsiella oxytoca/patogenicidad , Klebsiella pneumoniae/patogenicidad , Masculino , Persona de Mediana Edad , Neumonía/tratamiento farmacológico , Neumonía/epidemiología , Neumonía Asociada al Ventilador/tratamiento farmacológico , Neumonía Asociada al Ventilador/epidemiología , Neumonía Asociada al Ventilador/microbiología , Prevalencia , Pielonefritis/tratamiento farmacológico , Pielonefritis/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Sepsis/tratamiento farmacológico , Sepsis/epidemiología , Centros de Atención Terciaria , Resultado del Tratamiento , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/epidemiología , Infección de Heridas/tratamiento farmacológico , Infección de Heridas/epidemiología , Adulto JovenRESUMEN
Sarcopenic obesity (SO) is an age-related disease characterized by the coexistence of excessive adiposity and low muscle mass or function. Although obesity and sarcopenia are heritable conditions, the genetic determinants of SO have not been fully understood. We conducted a large-scale exome-wide association analysis of SO in a sequenced sample of 2 887 cases and 113 284 controls and an imputed sample of 4 003 cases and 161 990 controls in the UK Biobank cohort. Single-variant association analysis identified one locus 1q41 (lead SNP rs1417066, LYPLAL1-AS1, odds ratio [OR]â =â 1.15, 95% confidence interval [CI]â =â [1.11-1.19], pâ =â 1.75â ×â 10-14) that was significantly associated with SO at the exome-wide significance level (pâ <â 1â ×â 10-8). Colocalization analysis in the Genotype-Tissue Expression expression quantitative trait locus database showed that LYPLAL1-AS1 was colocalized with SO in multiple musculoskeletal-related tissues. Gene-based burden test of rare loss-of-function variants identified 5 genes at the gene-wise significance level (pâ <â 4.3â ×â 10-6): PDE3B (ORâ =â 2.48, pâ =â 1.10â ×â 10-6), MYOZ3 (ORâ =â 25.49, pâ =â 1.41â ×â 10-7), SLC15A3 (ORâ =â 4.75, pâ =â 6.82â ×â 10-7), RNF130 (ORâ =â 25.83, pâ =â 4.07â ×â 10-6), and TNK2 (ORâ =â 4.25, pâ =â 8.75â ×â 10-8). Overall, our study uncovered the genetic effects of both common and rare variants on SO susceptibility, expanded existing knowledge of the genetic architecture of SO, and improved understanding of the genetic mechanisms underlying SO.
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Sarcopenia , Humanos , Sarcopenia/genética , Predisposición Genética a la Enfermedad , Exoma/genética , Estudio de Asociación del Genoma Completo , Obesidad/genética , Polimorfismo de Nucleótido Simple , Proteínas Tirosina Quinasas/genéticaRESUMEN
INTRODUCTION: It has been suggested that type 1 diabetes was associated with increased COVID-19 morbidity and mortality. However, their causal relationship is still unclear. Herein, we performed a two-sample Mendelian randomization (MR) to investigate the causal effect of type 1 diabetes on COVID-19 infection and prognosis. RESEARCH DESIGN AND METHODS: The summary statistics of type 1 diabetes were obtained from two published genome-wide association studies of European population, one as a discovery sample including 15 573 cases and 158 408 controls, and the other data as a replication sample consisting of 5913 cases and 8828 controls. We first performed a two-sample MR analysis to evaluate the causal effect of type 1 diabetes on COVID-19 infection and prognosis. Then, reverse MR analysis was conducted to determine whether reverse causality exists. RESULTS: MR analysis results showed that the genetically predicted type 1 diabetes was associated with higher risk of severe COVID-19 (OR=1.073, 95% CI: 1.034 to 1.114, pFDR=1.15×10-3) and COVID-19 death (OR=1.075, 95% CI: 1.033 to 1.119, pFDR=1.15×10-3). Analysis of replication dataset showed similar results, namely a positive association between type 1 diabetes and severe COVID-19 (OR=1.055, 95% CI: 1.029 to 1.081, pFDR=1.59×10-4), and a positively correlated association with COVID-19 death (OR=1.053, 95% CI: 1.026 to 1.081, pFDR=3.50×10-4). No causal association was observed between type 1 diabetes and COVID-19 positive, hospitalized COVID-19, the time to the end of COVID-19 symptoms in the colchicine treatment group and placebo treatment group. Reverse MR analysis showed no reverse causality. CONCLUSIONS: Type 1 diabetes had a causal effect on severe COVID-19 and death after COVID-19 infection. Further mechanistic studies are needed to explore the relationship between type 1 diabetes and COVID-19 infection and prognosis.
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COVID-19 , Diabetes Mellitus Tipo 1 , Humanos , COVID-19/epidemiología , COVID-19/genética , Diabetes Mellitus Tipo 1/epidemiología , Diabetes Mellitus Tipo 1/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización MendelianaRESUMEN
BACKGROUND: The clinical symptoms and imaging manifestations of neurocysticercosis (NCC) are very different, and the difficulty and delay of clinical diagnoses may lead to an increase in mortality and disability. Rapid and accurate pathogen identification is important for the treatment of these patients. Metagenomic next-generation sequencing (mNGS) is a powerful tool to identify pathogens, especially in infections that are difficult to identify by conventional methods. CASE SUMMARY: A 43-year-old male patient was admitted due to a recurrent headache for a few months. Imaging examinations showed hydrocephalus and cystic lesions, which were considered to be a central nervous system infection, but no etiology was found by routine examination. mNGS of the cerebrospinal fluid revealed high Taenia solium reads, and the positive results of a cysticercosis antibody test confirmed the infection. Combined with the patient's clinical manifestations, the etiological evidence, and the imaging manifestation, the patient was finally diagnosed with NCC and he was prescribed dexamethasone, albendazole, neurotrophic drugs, and intracranial pressure reduction therapy. The headaches disappeared after anti-parasite treatment, and no associated symptoms recurred prior to the three- and six-month follow-up. CONCLUSION: As an accurate and sensitivity detection method, mNGS can be a reliable approach for the diagnosis of NCC.
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OBJECTIVES: The primary purpose of this study was to investigate the in vitro and in vivo effect of survivin interference RNA (siRNA) on non-small cell lung cancer. METHODS: Lentivirus was used as a vector to transfer siRNA into human lung cancer A549 cells. The proliferation of the cancer cells was assessed by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The lentivirus-mediated siRNA was also injected into the transplanted A549 tumor tissues in mice. Tumour growth was assessed after 11 injections over a period of 21 days. RESULTS: Compared with the placebo and the blank lentiviral vector groups, the siRNA treatment group had reduced cell growth rate following 4 days of the treatment (P < 0.01). The average size of the transplanted A549 tumours in the siRNA treatment group (0.75+/-0.16 cm3, n=8) was smaller than in the placebo (2.09+/-0.22 cm3, n=6) or the blank lentivrial vector groups (1.89+/-0.18 cm3, n=6) (P < 0.01). The tumour growth inhibition rate in the siRNA groups was 46.1%. CONCLUSION: Lentivirus-mediated siRNA therapy inhibits the growth of human lung cancer cells in vitro. The siRNA therapy also suppresses the growth of the transplanted lung cancer in mice.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Proteínas Asociadas a Microtúbulos/genética , Interferencia de ARN , Animales , Secuencia de Bases , Carcinoma de Pulmón de Células no Pequeñas/patología , Proliferación Celular , Cartilla de ADN , Vectores Genéticos , Humanos , Proteínas Inhibidoras de la Apoptosis , Lentivirus/genética , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Reacción en Cadena de la Polimerasa , ARN Interferente Pequeño/genética , SurvivinRESUMEN
BACKGROUND: The emergence of Enterobacteriaceae harboring IMP-4 or IMP-8 carbapenemases is rare. We report an occurrence of Enterobacteriaceae harboring IMP-4 or IMP-8 carbapenemases in a Chinese tertiary care hospital from November 2010 to December 2012. METHODS: The clinical characteristics of 30 patients were described. The genetic relationship of isolates was determined by pulsed-field gel electrophoresis (PFGE). Carbapenemases were detected by modified Hodge test (MHT) and polymerase chain reactions (PCRs). Amplicons were sequenced and blasted to determine the genotype. RESULTS: Most infected patients were from intensive care unit and had complex and serious underlying illnesses requiring mechanical ventilation. PFGE revealed that Klebsiella pneumoniae showed two major PFGE types. Two Klebsiella oxytoca had an indistinguishable PFGE pattern, while four Enterobacter cloacae were different strains. The sequencing studies showed Enterobacteriaceae harboring IMP-4 or IMP-8 carbapenemase in the 23 infected patients. The majority of patients had infections with the carbapenemase-producing Enterobacteriaceae (CPE) strain, most were successfully treated with a range of antibiotics and discharged. CONCLUSION: It is important to maintain a high index of suspicion to screen for carbapenemase-producing Enterobacteriaceae strains. Rapid identification of these strains and implementation of stringent procedures are the key to prevent major outbreaks in a hospital setting.