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BACKGROUND: Although the inherited risk factors associated with fatty liver disease are well understood, little is known about the genetic background of metabolic dysfunction-associated steatotic liver disease (MASLD) and its related health impacts. Compared to non-alcoholic fatty liver disease (NAFLD), MASLD presents significantly distinct diagnostic criteria, and epidemiological and clinical features, but the related genetic variants are yet to be investigated. Therefore, we conducted this study to assess the genetic background of MASLD and interactions between MASLD-related genetic variants and metabolism-related outcomes. METHODS: Participants from the UK Biobank were grouped into discovery and replication cohorts for an MASLD genome-wide association study (GWAS), and base and target cohorts for polygenic risk score (PRS) analysis. Autosomal genetic variants associated with NAFLD were compared with the MASLD GWAS results. Kaplan-Meier and Cox regression analyses were used to assess associations between MASLD and metabolism-related outcomes. RESULTS: Sixteen single-nucleotide polymorphisms (SNPs) were identified at genome-wide significance levels for MASLD and duplicated in the replication cohort. Differences were found after comparing these SNPs with the results of NAFLD-related genetic variants. MASLD cases with high PRS had a multivariate-adjusted hazard ratio of 3.15 (95% confidence interval, 2.54-3.90) for severe liver disease (SLD), and 2.81 (2.60-3.03) for type 2 diabetes mellitus. The high PRS amplified the impact of MASLD on SLD and extrahepatic outcomes. CONCLUSIONS: High PRS of MASLD GWAS amplified the impact of MASLD on SLD and metabolism-related outcomes, thereby refining the process of identification of individuals at high risk of MASLD. Supplementation of this process with relevant genetic backgrounds may lead to more effective MASLD prevention and management.
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Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Herencia Multifactorial , Polimorfismo de Nucleótido Simple , Humanos , Polimorfismo de Nucleótido Simple/genética , Masculino , Femenino , Herencia Multifactorial/genética , Factores de Riesgo , Persona de Mediana Edad , Hígado Graso/genética , Hígado Graso/complicaciones , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedades Metabólicas/genética , Enfermedades Metabólicas/complicaciones , Estudios de Cohortes , Estimación de Kaplan-Meier , Anciano , Modelos de Riesgos Proporcionales , Puntuación de Riesgo GenéticoRESUMEN
OBJECTIVE: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects many populations, and screening out the high-risk populations at an early stage is a challenge. As a sarcopenia index, the relationship between creatinine to cystatin C ratio (CCR) and MASLD remains unclear. This cross-sectional, prospective study aimed to explore the relationship between CCR and MASLD. Design Firstly, explored the correlation between CCR and MASLD in cross-sectional analyses. Then excluded the population with baseeline diagnosis of MASLD and analyzed the association with baseline CCR levels and the onset of MASLD in the population with available follow-up data. Univariate and multivariate logistic regression analyses were used to calculate odds ratios (ORs) to evaluate the association between CCR levels and MASLD. PATIENTS AND MEASUREMENTS: This study included 368,634 participants from the UK Biobank for cross-sectional and prospective analyses. The demographic characteristics and laboratory measurements of all participants were obtained from the UK Biobank. MASLD was diagnosed according to the multi-society consensus nomenclature. Hepatic steatosis was defined as FLI â¯≥60. RESULTS: We grouped the study participants according to CCR tertiles. In cross-sectional analyses, participants in CCR tertile 1 had the highest MASLD risk (OR: 1.070, 95% CI: 1.053-1.088, p < .001). And the similar association was observed in the prospective analyses (CCR tertile 1 OR: 1.340, 95% CI: 1.077-1.660, p = .009; CCR tertile 2 OR: 1.217, 95% CI: 1.021-1.450, p = .029, respectively). After stratification by gender, the significant association between CCR and the onset of MASLD was only observed in males (CCR tertile 1 OR: 1.639, 95% CI: 1.160-2.317, p = .005; CCR tertile 2 OR: 1.322, 95% CI: 1.073-1.628, p = .005, respectively). CONCLUSION: Our results indicated that lower CCR was significantly associated with higher risk of MASLD, based on which predictive models can be developed to screen populations at high risk of developing MASLD.
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Cistatina C , Hígado Graso , Masculino , Humanos , Estudios Prospectivos , Creatinina , Estudios Transversales , Bancos de Muestras Biológicas , Biobanco del Reino UnidoRESUMEN
Previously observational studies did not draw a clear conclusion on the association between fatty liver diseases and bone mineral density (BMD). Our large-scale studies revealed that MAFLD and hepatic steatosis had no causal effect on BMD, while some metabolic factors were correlated with BMD. The findings have important implications for the relationship between fatty liver diseases and BMD, and may help direct the clinical management of MAFLD patients who experience osteoporosis and osteopenia. PURPOSE: Liver and bone are active endocrine organs with several metabolic functions. However, the link between metabolic dysfunction-associated fatty liver disease (MAFLD) and bone mineral density (BMD) is contradictory. METHODS: Using the UK Biobank and National Health and Nutrition Examination Survey (NHANES) dataset, we investigated the association between MAFLD, steatosis, and BMD in the observational analysis. We performed genome-wide association analysis to identify single-nucleotide polymorphisms associated with MAFLD. Large-scale two-sample Mendelian randomization (TSMR) analyses examined the potential causal relationship between MAFLD, hepatic steatosis, or major comorbid metabolic factors, and BMD. RESULTS: After adjusting for demographic factors and body mass index, logistic regression analysis demonstrated a significant association between MAFLD and reduced heel BMD. However, this association disappeared after adjusting for additional metabolic factors. MAFLD was not associated with total body, femur neck, and lumbar BMD in the NHANES dataset. Magnetic resonance imaging-measured steatosis did not show significant associations with reduced total body, femur neck, and lumbar BMD in multivariate analysis. TSMR analyses indicated that MAFLD and hepatic steatosis were not associated with BMD. Among all MAFLD-related comorbid factors, overweight and type 2 diabetes showed a causal relationship with increased BMD, while waist circumference and hyperlipidemia had the opposite effect. CONCLUSION: No causal effect of MAFLD and hepatic steatosis on BMD was observed in this study, while some metabolic factors were correlated with BMD. This has important implications for understanding the relationship between fatty liver disease and BMD, which may help direct the clinical management of MAFLD patients with osteoporosis.
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Diabetes Mellitus Tipo 2 , Diagnóstico por Imagen de Elasticidad , Enfermedad del Hígado Graso no Alcohólico , Osteoporosis , Humanos , Densidad Ósea/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Encuestas Nutricionales , Osteoporosis/genéticaRESUMEN
Cholelithiasis is a common digestive disease that drives a myriad of adverse complications. The correlation between sarcopenia and various digestive disorders has been extensively researched, whereas its association with cholelithiasis remains unreported. We aimed to investigate the association through prospective and Mendelian randomization (MR) analyses and establish a quantitative score reflecting the impact of sarcopenia-related markers on cholelithiasis. The prospective study involved 448 627 participants from the UK Biobank. Cox proportional hazard models were employed to investigate the correlation between sarcopenia-related markers and cholelithiasis. To quantitatively assess cholelithiasis risk, the SARCHO score was derived from a multivariable Cox model. Bidirectional two-sample MR analysis was conducted to validate the causal association. A total of 16 738 individuals developed cholelithiasis during a median follow-up of 12 years. Hazard ratios (HRs) of cholelithiasis decreased stepwise over skeletal muscle index tertiles (highest tertile: reference; middle tertile: 1.23, p < .001; lowest tertile: 1.33, p < .001). The tertiles of grip strength showed a similar pattern. Individuals with slow walking pace had a higher risk of cholelithiasis compared to those with normal walking pace (HR 1.23; p < .001). Our SARCHO score better quantifies the risk of cholelithiasis. MR analysis showed a causal relationship between muscle mass and cholelithiasis (OR 0.81; p < .001). No causal effect of cholelithiasis on lean mass was observed. Prospective and MR analyses have consistently demonstrated an increased risk of cholelithiasis in individuals with decreased muscle mass. Additionally, SARCHO score further quantified the cholelithiasis occurrence risk. These findings provide compelling evidence for muscle strengthening in preventing cholelithiasis.
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Colelitiasis , Análisis de la Aleatorización Mendeliana , Sarcopenia , Humanos , Sarcopenia/epidemiología , Colelitiasis/epidemiología , Estudios Prospectivos , Femenino , Masculino , Persona de Mediana Edad , Biomarcadores/sangre , Anciano , Adulto , Modelos de Riesgos Proporcionales , Factores de RiesgoRESUMEN
BACKGROUND: There is still no specific real-world data regarding the clinical activity of immune checkpoint inhibitors in the elderly with liver cancer. Our study aimed to compare the efficacy and safety of immune checkpoint inhibitors between patients aged ≥ 65 years and the younger group, while exploring their differences in genomic background and tumor microenvironment. METHODS: This retrospective study was conducted at two hospitals in China and included 540 patients treated with immune checkpoint inhibitors for primary liver cancer between January 2018 and December 2021. Patients' medical records were reviewed for clinical and radiological data and oncologic outcomes. The genomic and clinical data of patients with primary liver cancer were extracted and analyzed from TCGA-LIHC, GSE14520, and GSE140901 datasets. RESULTS: Ninety-two patients were classified as elderly and showed better progression-free survival (P = 0.027) and disease control rate (P = 0.014). No difference was observed in overall survival (P = 0.69) or objective response rate (P = 0.423) between the two age groups. No significant difference was reported concerning the number (P = 0.824) and severity (P = 0.421) of adverse events. The enrichment analyses indicated that the elderly group was linked to lower expression of oncogenic pathways, such as PI3K-Akt, Wnt, and IL-17. The elderly had a higher tumor mutation burden than younger patients. CONCLUSIONS: Our results indicated that immune checkpoint inhibitors might exhibit better efficacy in the elderly with primary liver cancer, with no increased adverse events. Differences in genomic characteristics and tumor mutation burden may partially explain these results.
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Antineoplásicos Inmunológicos , Neoplasias Hepáticas , Anciano , Humanos , Estudios Retrospectivos , Estudios de Cohortes , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Fosfatidilinositol 3-Quinasas , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Microambiente TumoralRESUMEN
Hyperuricemia (HUA) has emerged as the second most prevalent metabolic disorder characterized by prolonged and asymptomatic period, triggering gout and metabolism-related outcomes. Early detection and prognosis prediction for HUA and gout are crucial for pre-emptive interventions. Integrating genetic and clinical data from 421287 UK Biobank and 8900 Nanfang Hospital participants, a stacked multimodal machine learning model is developed and validated to synthesize its probabilities as an in-silico quantitative marker for hyperuricemia (ISHUA). The model demonstrates satisfactory performance in detecting HUA, exhibiting area under the curves (AUCs) of 0.859, 0.836, and 0.779 within the train, internal, and external test sets, respectively. ISHUA is significantly associated with gout and metabolism-related outcomes, effectively classifying individuals into low- and high-risk groups for gout in the train (AUC, 0.815) and internal test (AUC, 0.814) sets. The high-risk group shows increased susceptibility to metabolism-related outcomes, and participants with intermediate or favorable lifestyle profiles have hazard ratios of 0.75 and 0.53 for gout compared with those with unfavorable lifestyles. Similar trends are observed for other metabolism-related outcomes. The multimodal machine learning-based ISHUA marker enables personalized risk stratification for gout and metabolism-related outcomes, and it is unveiled that lifestyle changes can ameliorate these outcomes within high-risk group, providing guidance for preventive interventions.
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Immune checkpoint inhibitors (ICIs) are safe and efficacious treatments for advanced primary liver cancer (PLC). The efficacy of different ICIs in the treatment of liver cancer remains unclear. The purpose of this study was to explore whether there is a difference in the efficacy and safety of various programmed cell death protein 1 (PD-1) inhibitors in combination with lenvatinib in the treatment of unresectable PLC. Patients with PLC treated with lenvatinib in combination with PD-1 inhibitors (camrelizumab, tislelizumab, sintilimab, or pembrolizumab) between January 2018 and December 2021 were retrospectively enrolled. Tumor response, adverse events, and grades were evaluated. Kaplan-Meier analysis and log-rank test were used to compare the overall survival and progression-free survival of patients treated with different PD-1 inhibitors. Cox regression analysis was used for univariate and multivariate analyses to identify clinical variables related to treatment efficacy. This study included a total of 176 patients who received a combination of lenvatinib and PD-1 inhibitors. Of these, 103 patients received camrelizumab, 44 received tislelizumab, 20 received sintilimab, and 9 received pembrolizumab. There was no significant difference in the pairwise comparison of camrelizumab, tislelizumab, sintilimab, and pembrolizumab using Kaplan-Meier survival analysis. Adverse events occurred in 40 (22.7%) patients (grade ≥ 3, 2.3%). The incidence of grade 3 adverse events among the four PD-1 inhibitor groups was below 5%. Camrelizumab, tislelizumab, sintilimab, and pembrolizumab are viable options for patients with unresectable PLC. These PD-1 inhibitors in combination with lenvatinib showed good safety profiles. The results guide selecting treatment for patients with unresectable PLC.
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Fe-Cu-kaolinites were prepared by co-precipitation and hydrothermal methods, and characterized by X-ray diffraction (XRD) and scanning electron microscope (SEM), where 2 wt.% natural kaolinite was dispersed, and the ratios of (Al + Fe + Cu)/clay = 10 mmol/g and Al/(Fe + Cu) = 5/1 were maintained. The effect of different drying methods (vacuum drying, ethanol exchange drying, freeze-drying, microwave drying, normal oven drying) and different Fe/Cu molar ratio (0/2, 0.4/1.6, 0.8/1.2, 1/1, 1.2/0.8, 1.6/0.4, 2/0) was also assessed. Catalytic wet peroxide oxidation (CWPO) reaction of 4-chlorophenol (4-CP) was used to probe the reactivity and activity of the materials prepared. The results showed that Fe and Cu could be successfully intercalated into the interlayer of kaolinite by hydrothermal method, where specific surface area and pore volume increased by 19 times and 7 times, respectively; the intensity of basal space (001) reflection peak was reduced by 80%, and tip width was doubly increased. The catalyst possessed higher reactivity, with 85.5% of 4-CP conversion being observed, whereas only 15.2% of 4-CP was removed over raw kaolinite. High-power microwave drying (720 W) was the best drying method, because it resulted in greater microstructure and thus higher reactivity (85.3% of 4-CP conversion), with lower active metal (Fe or Cu) leaching (3.96 mg L-1). Fe/Cu molar ratio of 0.8-1.0/1.2-1.0 was considered as the optimum ratio in pillaring solution, for maintaining higher catalytic activity (85-90% of 4-CP conversion) and lower metal (Fe or Cu) leaching (7-9.3 mg L-1).