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2.
Neural Regen Res ; 17(4): 875-880, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34472488

RESUMO

The neutrophil-to-lymphocyte ratio (NLR) is considered a robust prognostic biomarker for predicting patient survival outcomes in many diseases. However, it remains unclear whether it can be used as a biomarker for amyotrophic lateral sclerosis (ALS). To correlate NLR with disease progression and survival in sporadic ALS, 1030 patients with ALS between January 2012 and December 2018 were included in this study. These patients were assigned into three groups according to their NLR values: Group 1 (NLR < 2, n = 544 [52.8%]), Group 2 (NLR = 2-3, n = 314 [30.5%]), and Group 3 (NLR > 3, n = 172 [16.7%]). All patients were followed up until April 2020. Patients in Group 3 had a significantly older onset age, a lower score on the Revised ALS Functional Rating Scale, and rapidly progressing disease conditions. Furthermore, faster disease progression rates were associated with higher NLR values (odds ratio = 1.211, 95% confidence interval [CI]: 1.090-1.346, P < 0.001) after adjusting for other risk factors. Compared with Groups 1 and 2, the survival time in Group 3 was significantly shorter (log-rank P = 0.002). The NLR value was considered an independent parameter for the prediction of survival in ALS patients after normalizing for all other potential parameters (hazard ratio [HR] = 1.079, 95% CI: 1.016-1.146, P = 0.014). The effects on ALS survival remained significant when adjusted for treatment (HR = 1.074, 95% CI: 1.012-1.141, Ptrend = 0.019) or when considering the stratified NLR value (HR = 1.115, 95% CI: 1.009-1.232, Ptrend = 0.033). Thus, the NLR may help to predict the rate of disease progression and survival in patients with sporadic ALS. The study was approved by the Institutional Ethics Committee of West China Hospital of Sichuan University, China (approval No. 2015 (236)) on December 23, 2015.

3.
Front Genet ; 12: 765833, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34868249

RESUMO

Background: The association between inflammation and neurodegeneration has long been observed in parkinson's disease (PD) and multiple system atrophy (MSA). Previous genome-wide association studies (GWAS) and meta-analyses have identified several risk loci in inflammation-associated genes associated with PD. Objective: To investigate whether polymorphisms in some inflammation-associated genes could modulate the risk of developing PD and MSA in a Southwest Chinese population. Methods: A total of 2,706 Chinese subjects comprising 1340 PD, 483 MSA and 883 healthy controls were recruited in the study. Three polymorphisms (rs2074404 GG/GT/TT, rs17425622 CC/CT/TT, rs34043159 CC/CT/TT) in genes linked to inflammation in all the subjects were genotyped by using the Sequenom iPLEX Assay. Results: The allele G of WNT3 rs2074404 can increase risk on PD (OR: 1.048, 95% CI: 1.182-1.333, p = 0.006), exclusively in the LOPD subgroup (OR: 1.166, 95% CI:1.025-1.327, p = 0.019), but not in EOPD or MSA. And the recessive model analysis also demonstrated an increased PD risk in GG genotype of this locus (OR = 1.331, p = 0.007). However, no significant differences were observed in the genotype distributions and alleles of HLA-DRB5 rs17425622 and IL1R2 rs34043159 between the PD patients and controls, between the MSA patients and controls, or between subgroups of PD or MSA and controls. Conclusion: Our results suggested the allele G of WNT3 rs2074404 have an adverse effect on PD and particularly, on the LOPD subgroup among a Chinese population.

4.
EBioMedicine ; 74: 103732, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34864363

RESUMO

BACKGROUND: The survival time of amyotrophic lateral sclerosis (ALS) is greatly variable and protective or risk effects of the potential survival predictors are controversial. Thus, we aim to undertake a comprehensive meta-analysis of studies investigating non-genetic prognostic and survival factors in patients with ALS. METHODS: A search of relevant literature from PubMed, Embase, Cochrane library and other citations from 1st January 1966 to 1st December 020 was conducted. Random-effects models were conducted to pool the multivariable or adjusted hazard ratios (HR) by Stata MP 16.0. PROSPERO registration number: CRD42021256923. FINDINGS: A total of 5717 reports were identified, with 115 studies meeting pre-designed inclusion criteria involving 55,169 ALS patients. Five dimensions, including demographic, environmental or lifestyle, clinical manifestations, biochemical index, therapeutic factors or comorbidities were investigated. Twenty-five prediction factors, including twenty non-intervenable and five intervenable factors, were associated with ALS survival. Among them, NFL (HR:3.70, 6.80, in serum and CSF, respectively), FTD (HR:2.98), ALSFRS-R change (HR:2.37), respiratory subtype (HR:2.20), executive dysfunction (HR:2.10) and age of onset (HR:1.03) were superior predictors for poor prognosis, but pLMN or pUMN (HR:0.32), baseline ALSFRS-R score (HR:0.95), duration (HR:0.96), diagnostic delay (HR:0.97) were superior predictors for a good prognosis. Our results did not support the involvement of gender, education level, diabetes, hypertension, NIV, gastrostomy, and statins in ALS survival. INTERPRETATION: Our study provided a comprehensive and quantitative index for assessing the prognosis for ALS patients, and the identified non-intervenable or intervenable factors will facilitate the development of treatment strategies for ALS. FUNDING: This study was supported by the National Natural Science Fund of China (Grant No. 81971188), the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (Grant No. 2019HXFH046), and the Science and Technology Bureau Fund of Sichuan Province (No. 2019YFS0216).

5.
Turk J Gastroenterol ; 32(9): 758-764, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34609305

RESUMO

BACKGROUND: Caspase-cleaved K18 (cK18) may accurately reflect hepatocyte apoptosis in patients with non-alcoholic steatohepatitis (NASH). However, NASH can also exist within the normal range of cK18. The aim of this study was to investigate the risk factors and characteristics of NASH within the normal serum levels of cK18. METHODS: In the study, 227 histopathologically confirmed non-alcoholic fatty liver disease (NAFLD) patients with normal cK18 levels (≤200 U/L), measured in serum using ELISA kits, were enrolled. The Rs738409 allele, coding patatin-like phospholipase domain-containing protein 3 (PNPLA3), was detected by MALDI-TOF mass spectrometry. Non-alcoholic steatohepatitis was defined as an NAFLD activity score (NAS) ≥5 with each part >0. RESULTS: The prevalence of NASH was 31.7% among NAFLD patients with normal serum cK18 levels. Compared with non-NASH, NASH had a higher possibility of occurrence with central obesity, insulin resistance, and the G allele of PNPLA3. The mean serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were higher in NASH patients. Moreover, ALT, AST, TC, LDL-C, central obesity, and the PNPLA3 G allele were risk factors for NASH in NAFLD patients with normal serum cK18 levels, with odds ratios of 1.01 (95% CI: 1.00, 1.02), 1.03 (95% CI: 1.01, 1.05), 1.33 (95% CI: 1.04, 1.68), 1.41 (95% CI: 1.03, 1.92), 2.19 (95% CI: 1.15, 4.18), and 2.48 (95% CI: 1.15, 5.36), respectively; all P < .05. CONCLUSIONS: The major risk factors for NASH were central obesity, AST, and the PNPLA3 G allele, in NAFLD with low hepatocyte apoptosis.

6.
J Med Genet ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34544842

RESUMO

BACKGROUND: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. METHODS: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. FINDINGS: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. CONCLUSIONS: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.

8.
J Parkinsons Dis ; 11(4): 1845-1855, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34250953

RESUMO

BACKGROUND: Genetic studies have indicated that variants in several lysosomal genes are risk factors for idiopathic Parkinson's disease (PD). However, the role of lysosomal genes in PD in Asian populations is largely unknown. OBJECTIVE: This study aimed to analyze rare variants in lysosomal related genes in Chinese population with early-onset and familial PD. METHODS: In total, 1,136 participants, including 536 and 600 patients with sporadic early-onset PD (SEOPD) and familial PD, respectively, underwent whole-exome sequencing to assess the genetic etiology. Rare variants in PD were investigated in 67 candidate lysosomal related genes (LRGs), including 15 lysosomal function-related genes and 52 lysosomal storage disorder genes. RESULTS: Compared with the autosomal dominant PD (ADPD) or SEOPD cohorts, a much higher proportion of patients with multiple rare damaging variants of LRGs were found in the autosomal recessive PD (ARPD) cohort. At a gene level, rare damaging variants in GBA and MAN2B1 were enriched in PD, but in SCARB2, MCOLN1, LYST, VPS16, and VPS13C were much less in patients. At an allele level, GBA p. Leu483Pro was found to increase the risk of PD. Genotype-phenotype correlation showed no significance in the clinical features among patients carrying a discrepant number of rare variants in LRGs. CONCLUSION: Our study suggests rare variants in LRGs might be more important in the pathogenicity of ARPD cases compared with ADPD or SEOPD. We further confirm rare variants in GBA are involve in PD pathogenecity and other genes associated with PD identified in this study should be supported with more evidence.

9.
Hepatobiliary Pancreat Dis Int ; 20(5): 416-425, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34275749

RESUMO

BACKGROUND: Although concomitant nonalcoholic steatohepatitis (NASH) is common in chronic hepatitis B (CHB), the impact of viral factors on NASH and the outcome of CHB patients concomitant with NASH remain unclear. We aimed to investigate the outcomes of NASH in CHB patients receiving antiviral treatment. METHODS: In the post-hoc analysis of a multicenter trial, naïve CHB patients receiving 72-week entecavir treatment were enrolled. We evaluated the biochemical, viral and histopathological responses of these patients. The histopathological features of NASH were also evaluated, using paired liver biopsies at baseline and week 72. RESULTS: A total of 1000 CHB patients were finally enrolled for analysis, with 18.2% of whom fulfilling the criteria of NASH. A total of 727 patients completed entecavir antiviral treatment and received the second biopsy. Serum HBeAg loss, HBeAg seroconversion and HBV-DNA undetectable rates were similar between patients with or without NASH (P > 0.05). Among patients with NASH, the hepatic steatosis, ballooning, lobular inflammation scores and fibrosis stages all improved during follow-up (all P < 0.001), 46% (63/136) achieved NASH resolution. Patients with baseline body mass index (BMI) ≥ 23 kg/m2 (Asian criteria) [odds ratio (OR): 0.414; 95% confidence interval (95% CI): 0.190-0.899; P = 0.012] and weight gain (OR: 0.187; 95% CI: 0.050-0.693; P = 0.026) were less likely to have NASH resolution. Among patients without NASH at baseline, 22 (3.7%) developed NASH. Baseline BMI ≥ 23 kg/m2 (OR: 12.506; 95% CI: 2.813-55.606; P = 0.001) and weight gain (OR: 5.126; 95% CI: 1.674-15.694; P = 0.005) were predictors of incident NASH. CONCLUSIONS: Lower BMI and weight reduction but not virologic factors determine NASH resolution in CHB. The value of weight management in CHB patients during antiviral treatment deserves further evaluation.

10.
J Gastroenterol Hepatol ; 36(10): 2925-2934, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34031913

RESUMO

BACKGROUND AND AIM: Cytochrome P450 2E1 (CYP2E1) plays a role in lipid metabolism, and by increasing hepatic oxidative stress and inflammation, the upregulation of CYP2E1 is involved in development of nonalcoholic steatohepatitis (NASH). We aimed to explore the relationship between CYP2E1-333A>T (rs2070673) and the histological severity of nonalcoholic fatty liver disease (NAFLD). METHODS: We studied 438 patients with biopsy-proven NAFLD. NASH was defined as NAFLD Activity Score ≥ 5 with existence of steatosis, ballooning, and lobular inflammation. CYP2E1-333A>T (rs2070673) was genotyped by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Serum cytokines related to inflammation were measured by the Bio-plex 200 system to investigate possible mediating factors involved in the process. RESULTS: The TA genotype of rs2070673 had a higher prevalence of moderate/severe lobular inflammation (27.6% vs 20.3% vs 13.3%, P < 0.01) and NASH (55.7% vs 42.4% vs 40.5%, P < 0.01) compared with the AA and TT genotypes, respectively. In multivariable regression modeling, the heterozygote state TA was associated with moderate/severe lobular inflammation (adjusted odds ratio: 2.31, 95% confidence interval 1.41-3.78, P < 0.01) or NASH (adjusted odds ratio: 1.82, 95% confidence interval 1.22-2.69, P < 0.01), independently of age, sex, common metabolic risk factors, and presence of liver fibrosis. Compared with no-NASH, NASH patients had significantly higher levels of serum interleukin-1 receptor antagonist, interleukin-18, and interferon-inducible protein-10 (IP-10), whereas only IP-10 was increased with the rs2070673 TA variant (P = 0.01). Mediation analysis showed that IP-10 was responsible for ~60% of the association between the rs2070672 and NASH. CONCLUSIONS: The TA allele of rs2070673 is strongly associated with lobular inflammation and NASH, and this effect appears to be largely mediated by serum IP-10 levels.

11.
Neuropsychiatr Dis Treat ; 17: 905-913, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790559

RESUMO

Background: Cumulative evidence suggests that neuronal death including autophagy, apoptosis, and necrosis is closely related to the occurrence and development of cerebral ischemia-reperfusion (I/R) injury. Moreover, vagal nerve stimulation (VNS) is involved in many different neuroprotective and neuroplasticity pathways. Thus, VNS may be a novel approach for treating various neurodegenerative diseases. The present study aims to determine whether VNS protects against cerebral I/R injury in rats by inhibiting autophagy and apoptosis. Methods: Cerebral I/R injury is induced by middle cerebral artery occlusion (MCAO) and VNS is carried out. Infarct volume, neurological deficit, autophagy, and apoptosis are examined 24 h after reperfusion. Results: Vagal nerve stimulation decreases infarct volume and suppresses neurological deficit. Moreover, obvious autophagy and apoptosis are detected in rats that have undergone I/R, and VNS inhibits autophagy and apoptosis. Conclusion: Vagal nerve stimulation exerts neuroprotective effects following I/R injury by inhibiting autophagy and apoptosis.

12.
Front Physiol ; 12: 597449, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33927635

RESUMO

Nonalcoholic fatty liver disease is the most common hepatic disease in western countries and is even more ubiquitous in Asian countries. Our study determined that TH17/Treg cells were imbalanced in animal models. Based on our interest in the mechanism underlying TH17/Treg cell imbalance in nonalcoholic fatty liver mice, we conducted a joint bioinformatics analysis to further investigate this process. Common gene sequencing analysis was based on one trial from one sequencing platform, where gene expression analysis and enrichment analysis were the only analyses performed. We compared different sequencing results from different trials performed using different sequencing platforms, and we utilized the intersection of these analytical results to perform joint analysis. We used a bioinformatics analysis method to perform enrichment analysis and map interaction network analysis and predict potential microRNA sites. Animal experiments were also designed to validate the results of the data analysis based on quantitative polymerase chain reaction (qPCR) and western blotting. Our results revealed 8 coexisting differentially expressed genes (DEGs) and 7 hinge genes. The identified DEGs may influence nonalcoholic steatosis hepatitis through the interleukin-17 pathway. We found that microRNA-29c interacts with FOS and IGFBP1. Polymerase chain reaction analyses revealed both FOS and microRNA-29c expression in NASH mice, and western blot analyses indicated the same trend with regard to FOS protein levels. Based on these results, we suggest that microRNA-29c acts on FOS via the interleukin-17 signaling pathway to regulate TH17/Treg cells in NASH patients.

13.
J Hepatobiliary Pancreat Sci ; 28(7): 593-603, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33908180

RESUMO

BACKGROUND: The presence of significant liver fibrosis is a key determinant of long-term prognosis in non-alcoholic fatty liver disease (NAFLD). We aimed to develop a novel machine learning algorithm (MLA) to predict fibrosis severity in NAFLD and compared it with the most widely used non-invasive fibrosis biomarkers. METHODS: We used a cohort of 553 adults with biopsy-proven NAFLD, who were randomly divided into a training cohort (n = 278) for the development of both logistic regression model (LRM) and MLA, and a validation cohort (n = 275). Significant fibrosis was defined as fibrosis stage F ≥ 2. MLA and LRM were derived from variables that were selected using a least absolute shrinkage and selection operator (LASSO) logistic regression algorithm. RESULTS: In the training cohort, the variables selected by LASSO algorithm were body mass index, pro-collagen type III, collagen type IV, aspartate aminotransferase and albumin-to-globulin ratio. The diagnostic accuracy of MLA showed the highest values of area under the receiver operator characteristic curve (AUROC: 0.902, 95% CI 0.869-0.904) for identifying fibrosis F ≥ 2. The LRM AUROC was 0.764, 95% CI 0.710-0.816 and significantly better than the AST-to-Platelet ratio (AUROC 0.684, 95% CI 0.605-0.762), FIB-4 score (AUROC 0.594, 95% CI 0.503-0.685) and NAFLD Fibrosis Score (AUROC 0.557, 95% CI 0.470-0.644). In the validation cohort, MLA also showed the highest AUROC (0.893, 95% CI 0.864-0.901). The diagnostic accuracy of MLA outperformed that of LRM in all subgroups considered. CONCLUSIONS: Our newly developed MLA algorithm has excellent diagnostic performance for predicting fibrosis F ≥ 2 in patients with biopsy-confirmed NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Algoritmos , Biomarcadores , Biópsia , Fibrose , Humanos , Cirrose Hepática/diagnóstico , Aprendizado de Máquina , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Valor Preditivo dos Testes , Curva ROC , Índice de Gravidade de Doença
14.
Nutr Metab Cardiovasc Dis ; 31(6): 1822-1831, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33853719

RESUMO

BACKGROUND AND AIMS: Several susceptibility gene variants predisposing to nonalcoholic fatty liver disease (NAFLD) have been identified in chronic kidney disease (CKD). Evidence supports that 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) rs72613567 plays a role in NAFLD development by affecting lipid homeostasis. Since lipid droplets may accumulate in the kidneys and contribute to renal injury, we investigated the association between the HSD17B13 rs72613567 variant and markers of renal function/injury in NAFLD. METHODS AND RESULTS: We measured estimated glomerular filtration rate (eGFR), urinary/serum neutrophil gelatinase-associated lipocalin (NGAL), and urinary albumin-to-creatinine ratio (u-ACR) in individuals with biopsy-proven NAFLD. Multivariable regression analyses were undertaken to examine the associations between the HSD17B13 rs72613567 variant and markers of renal function/injury. Individuals were stratified by HSD17B13 rs72613567 genotypes into -/-, A/- and A/A groups. HSD17B13 rs72613567 genotypes were not significantly associated with eGFR and urinary/serum NGAL levels. Conversely, the prevalence of abnormal albuminuria in the A/- + A/A group was lower than in the -/- group (4.92% vs. 19.35%, p = 0.001). Additionally, the mean u-ACR levels were lower among carriers of the A/- or A/A genotypes with coexisting hypertension or diabetes, than among those with the -/- genotype. The risk of abnormal albuminuria (adjusted-odds ratio 0.16, p = 0.001) remained significantly lower in the A/- + A/A group after adjustment for established renal risk factors and histologic severity of NAFLD. CONCLUSION: HSD17B13 rs72613567: A allele is associated with a lower risk of having abnormal albuminuria, but not with lower eGFR or urinary/serum NGAL levels, in patients with biopsy-proven NAFLD.


Assuntos
17-Hidroxiesteroide Desidrogenases/genética , Albuminúria/genética , Taxa de Filtração Glomerular , Rim/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único , Adulto , Albuminúria/diagnóstico , Albuminúria/epidemiologia , Albuminúria/fisiopatologia , Biópsia , China/epidemiologia , Estudos Transversais , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Rim/metabolismo , Lipocalina-2/sangue , Lipocalina-2/urina , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Fenótipo , Prevalência , Medição de Risco , Fatores de Risco , Adulto Jovem
15.
Mol Neurobiol ; 58(7): 3435-3442, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33723766

RESUMO

Functional and genetic studies have identified association between several Zinc finger (ZNF) proteins and Parkinson's disease (PD). However, most of them were still awaiting further replications, especially in the Asian population. Here, we systematically selected PD-relevant ZNF genes and analyzed the genetic associations between these ZNFs and PD in a large Chinese PD cohort. We identified rare variants (minor allele frequency < 0.01) in 743 unrelated patients with early-onset PD (EOPD, age at onset < 50 years) using whole exome sequencing and evaluated the association between rare variants and EOPD at both allele and gene levels. Totally 91 rare variants were identified in ZNF746, ZNF646, ZNF184, ZNF165, ZND219, and GLIS1. One variant p.R373H in ZNF219 and two variants p.G161D and p.R158H in ZNF746 were significantly associated with EOPD, and gene-based burden analysis showed enrichment of rare variants of ZNF746 in EOPD. Our findings build up the connection between ZNF746 and PD from a genetic perspective for the first time, supplement current understanding for the genetic role of ZNFs in EOPD, and broaden the mutation spectrum in PD.

16.
Front Endocrinol (Lausanne) ; 12: 604100, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33763027

RESUMO

Background and Aim: Circulating levels of interleukin (IL)-6, a well-known inflammatory cytokine, are often elevated in coronavirus disease-2019 (COVID-19). Elevated IL-6 levels are also observed in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). Our study aimed to describe the association between circulating IL-6 levels and MAFLD at hospital admission with risk of severe COVID-19. Methods: A total of 167 patients with laboratory-confirmed COVID-19 from three Chinese hospitals were enrolled. Circulating levels of IL-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were measured at admission. All patients were screened for fatty liver by computed tomography. Forty-six patients were diagnosed as MAFLD. Results: Patients with MAFLD (n = 46) had higher serum IL-6 levels (median 7.1 [interquartile range, 4.3-20.0] vs. 4.8 [2.6-11.6] pg/mL, p = 0.030) compared to their counterparts without MAFLD (n = 121). After adjustment for age and sex, patients with MAFLD had a ~2.6-fold higher risk of having severe COVID-19 than those without MAFLD. After adjustment for age, sex and metabolic co-morbidities, increased serum IL-6 levels remained associated with higher risk of severe COVID-19, especially among infected patients with MAFLD (adjusted-odds ratio 1.14, 95% CI 1.05-1.23; p = 0.002). There was a significant interaction effect between serum IL-6 levels and MAFLD for risk of severe COVID-19 (p for interaction = 0.008). Conclusions: Patients with MAFLD and elevated serum IL-6 levels at admission are at higher risk for severe illness from COVID-19.


Assuntos
COVID-19/complicações , Fígado Gorduroso/epidemiologia , Interleucina-6/sangue , Doenças Metabólicas/fisiopatologia , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , COVID-19/transmissão , COVID-19/virologia , China/epidemiologia , Fígado Gorduroso/sangue , Fígado Gorduroso/patologia , Fígado Gorduroso/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
17.
Clin Transl Gastroenterol ; 12(3): e00321, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33704100

RESUMO

INTRODUCTION: Strong evidence indicates that multiple genetic and environmental risk factors play a role in the pathogenesis of nonalcoholic steatohepatitis (NASH). We aimed to develop and validate a novel nomogram, incorporating both genetic and clinical factors, for predicting NASH. METHODS: A total of 1,070 Asian individuals with biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) from 2 countries (China and South Korea) were recruited. The histological spectrum of NAFLD was classified according to the NASH clinical research network scoring system. The nomogram was developed in the Chinese training set (n = 402), and then, it was validated in both the Chinese internal validation set (n = 136) and the external Korean validation cohort (n = 532), respectively. RESULTS: Sex, metabolic syndrome, insulin resistance, serum aspartate aminotransferase levels, and PNPLA3 (rs738409) and HSD17B13 (rs72613567) genetic variants were strongly associated with NASH. Based on their regression coefficients, we developed a nomogram with good discriminatory ability (area under the receiver operating characteristic curve: 0.81, 95% confidence interval [CI] 0.77-0.85) and good calibration (Hosmer-Lemeshow test, P = 0.794) for identifying NASH. In the 2 validation cohorts, the nomogram showed high area under the receiver operating characteristic curves (internal validation set: 0.80, 95% CI 0.72-0.88; external validation cohort: 0.76, 95% CI 0.72-0.80) and good calibration. DISCUSSION: Our newly developed and externally validated nomogram, incorporating both genetic and clinical risk factors, may be conveniently used to predict NASH. Further validation studies in other ethnic groups are warranted to confirm its diagnostic utility to identify NASH, among patients with biopsy-proven NAFLD.


Assuntos
Predisposição Genética para Doença , Fígado/patologia , Nomogramas , Hepatopatia Gordurosa não Alcoólica/epidemiologia , 17-Hidroxiesteroide Desidrogenases/genética , Adulto , Biópsia , China/epidemiologia , Estudos Transversais , Feminino , Humanos , Resistência à Insulina/genética , Lipase/genética , Masculino , Proteínas de Membrana/genética , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Polimorfismo de Nucleotídeo Único , Curva ROC , República da Coreia/epidemiologia , Medição de Risco/métodos , Fatores de Risco
18.
Mol Neurobiol ; 58(4): 1583-1592, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33219486

RESUMO

Recent genetic studies clearly indicate that variants in several lysosomal genes act as risk factors for idiopathic Parkinson's disease (PD). Variants in the co-activator of glucocerebrosidase gene (GBA) and the four active saposins (Sap A-D) which are encoded by the prosaposin gene (PSAP) are of particular interest; however, their genetic roles in PD are unknown. Whole-exome sequencing and Sanger sequencing were used to assess the genetic etiology of 400 autosomal dominant inherited PD (ADPD) and 300 sporadic PD (SPD) patients. Variants from public databases, including Genome Aggregation Database-East Asian (GnomAD_EAS) and Chinese Millionome Database (CMDB), were used as control groups. Burden analysis based on gene and domains level were performed to investigate the role of rare PSAP variants in PD. Six rare and likely pathogenic variants, located in the Sap A-D domains, were identified and accounted for 0.75% (3/400) of ADPD and 1.33% (4/300) of SPD in the Chinese population. Based on the gene or domain, burden analysis showed that damaging missense variants in SapC had statistical significance on the risk of developing PD. Interestingly, rs4747203, an intronic variant potentially linked to PSAP expression, was associated with reduced risk for PD (p = 8.6e-7 in GnomAD EAS and p = 0.002 in Chinese). Clinically, patients carrying the likely pathogenic variants presented typical PD motor symptoms and responded well to levodopa treatment. Six out of seven patients carrying the likely pathogenic variants of PSAP presented slow disease progression, and none of the patients developed cognitive impairment. Our study expands the spectrum of mutations associated with the risk of developing PD and enhances the understanding of the relationship of the clinical phenotype of PD with PSAP variants.


Assuntos
Predisposição Genética para Doença , Doenças por Armazenamento dos Lisossomos/genética , Doença de Parkinson/genética , Saposinas/genética , Idade de Início , Sequência de Aminoácidos , Sequência de Bases , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Frequência do Gene/genética , Estudos de Associação Genética , Humanos , Masculino , Mutação/genética , Linhagem , Fatores de Risco , Saposinas/química
19.
Nutr Metab Cardiovasc Dis ; 31(2): 552-560, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33250371

RESUMO

BACKGROUND AND AIMS: Some previous studies reported serum autoantibody positivity in patients with nonalcoholic fatty liver disease (NAFLD). The clinical significance of these findings remains uncertain. We aimed to investigate the association between the presence of serum autoantibodies and liver disease severity in NAFLD. METHODS AND RESULTS: A total of 388 consecutive patients with biopsy-proven NAFLD were included in the study. Various serum autoantibodies (including also anti-nuclear antibodies [ANA]) were detected by indirect immunofluorescent or immunoblotting assays. Overall, 84 (21.6%) patients with biopsy-confirmed NAFLD had positivity for at least one of the measured serum autoantibodies. ANA positivity was present in 50 (12.9%) patients, whereas anti-U1RNP or pANCA antibodies were detectable in 9 (2.3%) and 6 (1.5%) patients, respectively. Multivariate logistic regression analysis showed that ANA positivity (adjusted-odds ratio: 4.51, 95%CI: 1.77-11.5; P = 0.002) or positivity of any serum autoantibodies (adjusted-odds ratio: 3.14, 95%CI: 1.30-7.62; P = 0.01) were independently associated with advanced liver fibrosis (stages F3-F4). In serum autoantibody/ANA-positive patients, the proportion of those with advanced fibrosis was also greater among carriers of PNPLA3 rs738409 GG or CG than among those carrying PNPLA3 rs738409 CC genotype. CONCLUSIONS: Serum autoantibody positivity was independently associated with advanced liver fibrosis in patients with biopsy-proven NAFLD. The presence of serum autoantibodies in patients with advanced fibrosis occurred more frequently amongst those carrying PNPLA3 rs738409 GG or CG genotypes.


Assuntos
Autoanticorpos/sangue , Cirrose Hepática/sangue , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/sangue , Adulto , Biomarcadores/sangue , Biópsia , Estudos Transversais , Feminino , Humanos , Lipase/genética , Cirrose Hepática/genética , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/imunologia , Hepatopatia Gordurosa não Alcoólica/patologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Índice de Gravidade de Doença
20.
Br J Nutr ; 126(6): 813-824, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-33198849

RESUMO

The FNDC5 gene encodes the fibronectin type III domain-containing protein 5 that is a membrane protein mainly expressed in skeletal muscle, and the FNDC5 rs3480 polymorphism may be associated with liver disease severity in non-alcoholic fatty liver disease (NAFLD). We investigated the influence of the FNDC5 rs3480 polymorphism on the relationship between sarcopenia and the histological severity of NAFLD. A total of 370 adult individuals with biopsy-proven NAFLD were studied. The association between the key exposure sarcopenia and the outcome liver histological severity was investigated by binary logistic regression. Stratified analyses were undertaken to examine the impact of FNDC5 rs3480 polymorphism on the association between sarcopenia and the severity of NAFLD histology. Patients with sarcopenia had more severe histological grades of steatosis and a higher prevalence of significant fibrosis and definite non-alcoholic steatohepatitis than those without sarcopenia. There was a significant association between sarcopenia and significant fibrosis (adjusted OR 2·79, 95 % CI 1·31, 5·95, P = 0·008), independent of established risk factors and potential confounders. Among patients with sarcopenia, significant fibrosis occurred more frequently in the rs3480 AA genotype carriers than in those carrying the FNDC5 rs3480 G genotype (43·8 v. 17·2 %, P = 0·031). In the association between sarcopenia and liver fibrosis, there was a significant interaction between the FNDC5 genotype and sarcopenia status (P value for interaction = 0·006). Sarcopenia is independently associated with significant liver fibrosis, and the FNDC5 rs3480 G variant influences the association between sarcopenia and liver fibrosis in patients with biopsy-proven NAFLD.

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