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1.
Nat Commun ; 15(1): 1908, 2024 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-38459023

RESUMEN

Liver injury is a core pathological process in the majority of liver diseases, yet the genetic factors predisposing individuals to its initiation and progression remain poorly understood. Here we show that asialoglycoprotein receptor 1 (ASGR1), a lectin specifically expressed in the liver, is downregulated in patients with liver fibrosis or cirrhosis and male mice with liver injury. ASGR1 deficiency exacerbates while its overexpression mitigates acetaminophen-induced acute and CCl4-induced chronic liver injuries in male mice. Mechanistically, ASGR1 binds to an endoplasmic reticulum stress mediator GP73 and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73 levels and promotes the interaction between GP73 and BIP to activate endoplasmic reticulum stress, leading to liver injury. Neutralization of GP73 not only attenuates ASGR1 deficiency-induced liver injuries but also improves survival in mice received a lethal dose of acetaminophen. Collectively, these findings identify ASGR1 as a potential genetic determinant of susceptibility to liver injury and propose it as a therapeutic target for the treatment of liver injury.


Asunto(s)
Acetaminofén , Hígado , Animales , Humanos , Masculino , Ratones , Acetaminofén/toxicidad , Receptor de Asialoglicoproteína/genética , Receptor de Asialoglicoproteína/metabolismo , Estrés del Retículo Endoplásmico , Fibrosis , Hígado/metabolismo , Cirrosis Hepática/patología
2.
Curr Med Sci ; 42(3): 561-568, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35678917

RESUMEN

OBJECTIVE: To evaluate the impact of hypertension on the clinical outcome of COVID-19 patients aged 60 years old and older. METHODS: This single-center retrospective cohort study enrolled consecutive COVID-19 patients aged 60 years old and older, who were admitted to Liyuan Hospital from January 1, 2020 to April 25, 2020. All included patients were divided into two groups: hypertension and nonhypertension group. The baseline demographic characteristics, laboratory test results, chest computed tomography (CT) images and clinical outcomes were collected and analyzed. The prognostic value of hypertension was determined using binary logistic regression. RESULTS: Among the 232 patients included in the analysis, 105 (45.3%) patients had comorbid hypertension. Compared to the nonhypertension group, patients in the hypertension group had higher neutrophil-to-lymphocyte ratios, red cell distribution widths, lactate dehydrogenase, high-sensitivity C-reactive protein, D-dimer and severity of lung lesion, and lower lymphocyte counts (all P<0.05). Furthermore, the hypertension group had a higher proportion of intensive care unit admissions [24 (22.9%) vs. 14 (11.0%), P=0.02) and deaths [16 (15.2%) vs. 3 (2.4%), P<0.001] and a significantly lower probability of survival (P<0.001) than the nonhypertension group. Hypertension (OR: 4.540, 95% CI: 1.203-17.129, P=0.026) was independently correlated with all-cause in-hospital death in elderly patients with COVID-19. CONCLUSION: The elderly COVID-19 patients with hypertension tend to have worse conditions at baseline than those without hypertension. Hypertension may be an independent prognostic factor of poor clinical outcome in elderly COVID-19 patients.


Asunto(s)
COVID-19 , Hipertensión , Anciano , COVID-19/complicaciones , Mortalidad Hospitalaria , Humanos , Hipertensión/complicaciones , Hipertensión/epidemiología , Persona de Mediana Edad , Estudios Retrospectivos , SARS-CoV-2
3.
Front Immunol ; 9: 1775, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30123216

RESUMEN

The thymic stromal lymphopoietin (TSLP)/TSLP receptor (TSLPR) axis is involved in multiple inflammatory immune diseases, including coronary artery disease (CAD). To explore the causal relationship between this axis and CAD, we performed a three-stage case-control association analysis with 3,628 CAD cases and 3,776 controls using common variants in the genes TSLP, interleukin 7 receptor (IL7R), and TSLPR. Three common variants in the TSLP/TSLPR axis were significantly associated with CAD in a Chinese Han population [rs3806933T in TSLP, Padj = 4.35 × 10-5, odds ratio (OR) = 1.18; rs6897932T in IL7R, Padj = 1.13 × 10-7, OR = 1.31; g.19646A>GA in TSLPR, Padj = 2.04 × 10-6, OR = 1.20]. Reporter gene analysis demonstrated that rs3806933 and rs6897932 could influence TSLP and IL7R expression, respectively. Furthermore, the "T" allele of rs3806933 might increase plasma TSLP levels (R2 = 0.175, P < 0.01). In a stepwise procedure, the risk for CAD increased by nearly fivefold compared with the maximum effect of any single variant (Padj = 6.99 × 10-4, OR = 4.85). In addition, the epistatic interaction between TSLP and IL33 produced a nearly threefold increase in the risk of CAD in the combined model of rs3806933TT-rs7025417TT (Padj = 3.67 × 10-4, OR = 2.98). Our study illustrates that the TSLP/TSLPR axis might be involved in the pathogenesis of CAD through upregulation of mRNA or protein expression of the referenced genes and might have additive effects on the CAD risk when combined with IL-33 signaling.


Asunto(s)
Enfermedad de la Arteria Coronaria/etiología , Enfermedad de la Arteria Coronaria/metabolismo , Citocinas/genética , Epistasis Genética , Regulación de la Expresión Génica , Interleucina-33/genética , Receptores de Citocinas/genética , Anciano , Alelos , Estudios de Casos y Controles , China , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/mortalidad , Citocinas/sangre , Citocinas/metabolismo , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Interleucina-33/metabolismo , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Modelos de Riesgos Proporcionales , Receptores de Citocinas/metabolismo , Receptores de Interleucina-7/genética , Transducción de Señal , Linfopoyetina del Estroma Tímico
4.
Sci Rep ; 8(1): 6182, 2018 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-29670225

RESUMEN

Interleukin-13 (IL-13) has important functions in atherosclerosis, but its role in coronary artery disease (CAD) is unclear. Here, we studied the genetic role of IL-13 in CAD in a Chinese Han population using tag SNPs covering the whole IL13 gene (i.e., rs1881457, rs2069744 and rs20541) and a two-stage cohort containing 1863 CAD cases and 1841 controls. Traditional risk factors for CAD, such as age, BMI, and other factors, were used as covariates in logistic regression analysis. In the total population, we found that two haplotypes of IL13 (ATG and ATA, ordered rs1881457C-rs2069744T-rs20541A) significantly contributed to the risk of CAD with adjusted p values less than 0.05 (padj = 0.019 and padj = 0.042, respectively). In subgroup population analyses, the variant rs1881457C was found to significantly contribute to a nearly two fold increase in the risk of CAD in men (padj = 0.023, OR = 1.91, 95% CI: 1.09-3.33). The variant rs1881457C also significantly contributed to a nearly twofold risk of late-onset CAD (padj = 0.024, OR = 1.93, 95% CI: 1.09-3.42). In conclusion, IL13 might be involved in CAD via different mechanisms under different conditions in the Chinese Han population.


Asunto(s)
Pueblo Asiatico/genética , Enfermedad de la Arteria Coronaria/etiología , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Interleucina-13/genética , Adulto , Alelos , Estudios de Casos y Controles , China/epidemiología , Comorbilidad , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/metabolismo , Femenino , Humanos , Interleucina-13/metabolismo , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Medición de Riesgo
5.
Oncotarget ; 8(64): 107678-107684, 2017 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-29296197

RESUMEN

Stroke is one of the most common causes of death worldwide. Genetic risk factors have been found to play important roles in the pathology of ischemic stroke. In a previous genome-wide association study, a functional variant (rs9943582, -154G/A) in the 5' flanking region of the apelin receptor gene (APLNR) was shown to be significantly associated with stroke in the Japanese population. However, the association required validation in other ethnicities. To validate the genetic relationship between APLNR and ischemic stroke in the Chinese Han population, we genotyped rs9943582 in a case-control population containing 1,158 ischemic stroke patients and 1,265 common controls enrolled from the GeneID database, and performed a genetic association study. We detected no allelic or genotypic associations between rs9943582 and ischemic stroke in the Chinese Han GeneID population, although the study population provided sufficient statistical power. This finding indicates that the association between the APLNR variant and ischemic stroke or atherosclerosis may need further validation.

6.
J Leukoc Biol ; 97(4): 797-805, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25722319

RESUMEN

There has been increasing evidence that chronic immune activation plays critical roles in the pathogenesis of DCM. CD4(+) LAP(+) Tregs are a newly identified T cell subset with suppressive function on the immune response. This study was designed to investigate whether the circulating frequency and function of CD4(+)LAP(+) Tregs would be impaired in patients with DCM. The results demonstrated that DCM patients had a significantly lower frequency of circulating CD4(+)LAP(+) Tregs compared with control donors. CD4(+)LAP(+) Tregs from DCM patients showed compromised function to suppress proliferation of CD4(+) LAP(-)CD25(int/low) T cells and proliferation and IgG production of B cells. Moreover, B cell proliferation and IgG subset production could be directly suppressed by CD4(+) LAP(+) Tregs. TGF-ß and contact-dependent mechanisms were involved in CD4(+)LAP(+) Treg-mediated suppression. Correlation analysis suggested that CD4(+)LAP(+) Treg frequency was positively correlated with LVEF and negatively correlated with serum IgG3 and NT-proBNP concentration in patients with DCM. Our results are the first to demonstrate that the frequencies of CD4(+)LAP(+) Tregs in patients with DCM are reduced and that their suppressive function is compromised. Defective CD4(+) LAP(+) Tregs may be an underlying mechanism of immune activation in DCM patients.


Asunto(s)
Cardiomiopatía Dilatada/inmunología , Subgrupos de Linfocitos T/patología , Linfocitos T Reguladores/patología , Factor de Crecimiento Transformador beta1/sangre , Adulto , Anciano , Linfocitos B/inmunología , Recuento de Linfocito CD4 , Cardiomiopatía Dilatada/sangre , Cardiomiopatía Dilatada/diagnóstico por imagen , Cardiomiopatía Dilatada/fisiopatología , Citometría de Flujo , Humanos , Tolerancia Inmunológica , Inmunoglobulina G/sangre , Activación de Linfocitos/inmunología , Cooperación Linfocítica/inmunología , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Volumen Sistólico , Subgrupos de Linfocitos T/química , Linfocitos T Reguladores/química , Factor de Crecimiento Transformador beta/farmacología , Ultrasonografía
7.
Nat Genet ; 43(4): 345-9, 2011 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-21378986

RESUMEN

Coronary artery disease (CAD) causes more than 700,000 deaths each year in China. Previous genome-wide association studies (GWAS) in populations of European ancestry identified several genetic loci for CAD, but no such study has yet been reported in the Chinese population. Here we report a three-stage GWAS in the Chinese Han population. We identified a new association between rs6903956 in a putative gene denoted as C6orf105 on chromosome 6p24.1 and CAD (P = 5.00 × 10⁻³, stage 2 validation; P = 3.00 × 10⁻³, P = 1.19 × 10⁻8 and P = 4.00 × 10⁻³ in three independent stage 3 replication populations; P = 4.87 × 10⁻¹², odds ratio = 1.51 in the combined population). The minor risk allele A of rs6903956 is associated with decreased C6orf105 mRNA expression. We report the first GWAS for CAD in the Chinese Han population and identify a SNP, rs6903956, in C6orf105 associated with susceptibility to CAD in this population.


Asunto(s)
Pueblo Asiatico/genética , Enfermedad de la Arteria Coronaria/genética , Alelos , Estudios de Casos y Controles , China , Cromosomas Humanos Par 6/genética , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Desequilibrio de Ligamiento , Masculino , Polimorfismo de Nucleótido Simple , ARN Mensajero/genética , Factores de Riesgo
8.
Yi Chuan Xue Bao ; 33(8): 685-91, 2006 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16939002

RESUMEN

Congenital fibrosis of the extraocular muscles type 1 (CFEOM1) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. In this study, we identified a Chinese family with CFEOMI for four generations. Linkage analysis mapped the causative gene of the family to 12q with a Lod score 2.1 for polymorphic marker D12S85, where KIF21A is located. Direct DNA sequence analysis identified a 2860C-->T change in exon 21, resulting in a tryptophan substitution for arginine in codon 954 of KIF21A. SSCP (single-stranded conformational polymorphism) analysis showed that mutation p.Arg954Trp of KIF21A co-segregated with the affected members, but was absent in the unaffected individuals in the family and 150 normal controls. Our results indicate that mutation p.Arg954Trp of the KIF21A is the genetic basis of the Chinese family with CFEOM1.


Asunto(s)
Fibrosis/genética , Cinesinas/genética , Mutación , Oftalmoplejía/genética , Sustitución de Aminoácidos , Arginina/genética , Pueblo Asiatico/genética , Femenino , Humanos , Cinesinas/fisiología , Masculino , Músculos Oculomotores/fisiopatología , Linaje , Triptófano/genética , Adulto Joven
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