Cyclin F-dependent degradation of E2F7 is critical for DNA repair and G2-phase progression.

E2F7 and E2F8 act as tumor suppressors via transcriptional repression of genes involved in S-phase entry and progression. Previously, we demonstrated that these atypical E2Fs are degraded by APC/CCdh1 during G1 phase of the cell cycle. However, the mechanism driving the downregulation of atypical E2Fs during G2 phase is unknown. Here, we show that E2F7 is targeted for degradation by the E3 ubiquitin ligase SCFcyclin F during G2. Cyclin F binds via its cyclin domain to a conserved C-terminal CY motif on E2F7. An E2F7 mutant unable to interact with SCFcyclin F remains stable during G2. Furthermore, SCFcyclin F can also interact and induce degradation of E2F8. However, this does not require the cyclin domain of SCFcyclin F nor the CY motifs in the C-terminus of E2F8, implying a different regulatory mechanism than for E2F7. Importantly, depletion of cyclin F causes an atypical-E2F-dependent delay of the G2/M transition, accompanied by reduced expression of E2F target genes involved in DNA repair. Live cell imaging of DNA damage revealed that cyclin F-dependent regulation of atypical E2Fs is critical for efficient DNA repair and cell cycle progression.

HELLP syndrome, intracerebral hemorrhage, and hemophagocytic syndrome after cesarean section in a pregnant patient with severe preeclampsia: a case report.

BACKGROUND: Pregnancy-related intracranial hemorrhage (ICH) is a rare but potentially life-threatening event with complex and varied cause, such as HELLP syndrome and hemophagocytic syndrome. CASE PRESENTATION: A 33-year-old patient underwent a cesarean section with a preliminary diagnosis of "severe preeclampsia and class3 HELLP syndrome ". The patient had poor response to language before surgery, and the catheter drainage fluid was hematuria. Later, the surgeon reported severe bleeding in the operation. Following thromboelastography (TEG) result and postoperative laboratory tests confirmed class1 HELLP syndrome and ICH occurred on the second day after the surgery, and hemophagocytic syndrome was diagnosed during subsequent treatments. CONCLUSION: For patients with HELLP syndrome, we should pay attention to their coagulation condition. The coagulation tests and platelet counts should be repeated if their clinical presentation changed. Those with neurological alarm signs should receive CT or MRI scan. If a pregnant woman had prolonged hemocytopenia and thrombocytopenia, not only the HELLP but also the hemophagocytic syndrome should be considered.

Chk1 and 14-3-3 proteins inhibit atypical E2Fs to prevent a permanent cell cycle arrest.

The atypical E2Fs, E2F7 and E2F8, act as potent transcriptional repressors of DNA replication genes providing them with the ability to induce a permanent S-phase arrest and suppress tumorigenesis. Surprisingly in human cancer, transcript levels of atypical E2Fs are frequently elevated in proliferating cancer cells, suggesting that the tumor suppressor functions of atypical E2Fs might be inhibited through unknown post-translational mechanisms. Here, we show that atypical E2Fs can be directly phosphorylated by checkpoint kinase 1 (Chk1) to prevent a permanent cell cycle arrest. We found that 14-3-3 protein isoforms interact with both E2Fs in a Chk1-dependent manner. Strikingly, Chk1 phosphorylation and 14-3-3-binding did not relocate or degrade atypical E2Fs, but instead, 14-3-3 is recruited to E2F7/8 target gene promoters to possibly interfere with transcription. We observed that high levels of 14-3-3 strongly correlate with upregulated transcription of atypical E2F target genes in human cancer. Thus, we reveal that Chk1 and 14-3-3 proteins cooperate to inactivate the transcriptional repressor functions of atypical E2Fs. This mechanism might be of particular importance to cancer cells, since they are exposed frequently to DNA-damaging therapeutic reagents.

E2F7 Is a Potent Inhibitor of Liver Tumor Growth in Adult Mice.

BACKGROUND AND AIMS: Up-regulation of the E2F-dependent transcriptional network has been identified in nearly every human malignancy and is an important driver of tumorigenesis. Two members of the E2F family, E2F7 and E2F8, are potent repressors of E2F-dependent transcription. They are atypical in that they do not bind to dimerization partner proteins and are not controlled by retinoblastoma protein. The physiological relevance of E2F7 and E2F8 remains incompletely understood, largely because tools to manipulate their activity in vivo have been lacking. APPROACH AND RESULTS: Here, we generated transgenic mice with doxycycline-controlled transcriptional activation of E2f7 and E2f8 and induced their expression during postnatal development, in adulthood, and in the context of cancer. Systemic induction of E2f7 and, to lesser extent, E2f8 transgenes in juvenile mice impaired cell proliferation, caused replication stress, DNA damage, and apoptosis, and inhibited animal growth. In adult mice, however, E2F7 and E2F8 induction was well tolerated, yet profoundly interfered with DNA replication, DNA integrity, and cell proliferation in diethylnitrosamine-induced liver tumors. CONCLUSION: Collectively, our findings demonstrate that atypical E2Fs can override cell-cycle entry and progression governed by other E2F family members and suggest that this property can be exploited to inhibit proliferation of neoplastic hepatocytes when growth and development have subsided during adulthood.

Effect of tourniquet technique on postoperative delirium in elderly patients with total knee arthroplasty: a randomized single-blind controlled trial.

BACKGROUND: The tourniquet technique is often used in total knee arthroplasty (TKA). However, its effect on postoperative delirium (POD) in elderly patients undergoing TKA is unknown.  METHODS: This prospective randomized controlled trial assessed the eligibility of 245 elderly patients. A total of 197 patients who met the inclusion criteria were randomly divided into a tourniquet group (n = 98) and a non-tourniquet group (n = 99). The primary outcome was the incidence of POD within 72 h after surgery. The secondary outcome was the quality of rehabilitation, including inflammatory reaction, postoperative pain, hypoproteinemia and anemia. RESULTS: Of 245 patients, 184 patients completed this clinical trial, with 92 cases in each group. There were 14 patients (15.22%) with POD in the tourniquet group and 5 patients (5.43%) in the non-tourniquet group (95% CI 1.076 to 9.067, P = 0.029). The changes in white blood cell count (WBC), the proportion of neutrophils (NEUT%), c-reactive protein (CRP), interleukin-6 (IL-6) and middle patellar circumference in the tourniquet group were higher than those in the non-tourniquet group (P < 0.05). The visual analog scale (VAS) at rest and activity in the tourniquet group were higher than those in the non-tourniquet group (F = 170.102, P < 0.001 F = 75.391, P < 0.001). There were 41 (44.57%) patients with hypoproteinemia in the tourniquet group and 26 (28.26%) in the non-tourniquet group (95% CI 1.106 to 3.765, P = 0.022). CONCLUSION: The application of the tourniquet technique in elderly patients with TKA procedures increased the incidence of POD. This may be attributed to the increased inflammatory reaction, severe postoperative pain and hypoproteinemia caused by the tourniquet technique. TRIAL REGISTRATION: Clinical trial registration number: ChiCTR2100045711. Full date of the first registration: 23/04/2021.

A Case-Control Study of ABCB1, ABCB6, and ABCG1 Polymorphisms and Schizophrenia in a Han Chinese Population.

BACKGROUND: Schizophrenia (SCZ) is a complex, heritable, and devastating psychiatric disorder. Mutations in the members of ABC transporters have been associated with psychiatric illnesses. AIMS: In this study, we investigated whether 9 SNPs in ABCB1 (rs6946119, rs28401781, rs4148739, and rs3747802), ABCB6 (rs1109866, rs1109867, rs3731885, and rs3755047), and ABCG1 (rs182694) contribute to the risk of SCZ in a Han Chinese population. METHODS: We conducted a case-control study in a Han Chinese population, involving 1,034 SCZ patients and 1,034 unrelated healthy controls to genotype 9 SNPs. RESULTS: The analysis demonstrated that rs182694 of ABCG1 was significantly different between SCZ patients and controls as to allele (rs182694: p = 0.0070, χ2 = 7.27) and genotype frequencies (rs182694: p = 0.0013, χ2 = 13.35). CONCLUSIONS: Our findings support an association between ABCG1 polymorphism and SCZ in a Han Chinese population.

Metabolomic profiling on rat brain of prenatal malnutrition: implicated for oxidative stress and schizophrenia.

Schizophrenia is a kind of neurodevelopmental disease. Epidemiological data associates schizophrenia with prenatal exposure to famine. Relevant prenatal protein deprivation (PPD) rodent models support this result by observing decreasing prepulse inhibition, altered hippocampal morphology and impaired memory in offspring. All these abnormalities are highly consistent with the pathophysiology of schizophrenia. We developed a prenatal famine rat model by restricting daily diet of the pregnant rat to 50% of low protein diet. A metabolomics study of prefrontal cortex was performed to integrate GC-TOFMS and UPLC-QTOFMS. Thirteen controls and thirteen famine offspring were used to differentiate in PLS-DA (partial least squares-discriminate analysis) model. Furthermore, metabolic pathways and diseases were enriched via KEGG and HMDB databases, respectively. A total of 67 important metabolites were screened out according to the multivariate analysis. Schizophrenia was the most statistical significant disease (P = 0.0016) in our famine model. These metabolites were enriched in key metabolic pathways related to energy metabolism and glutamate metabolism. Based on these important metabolites, further discussion speculated famine group was characterized by higher level of oxidized damage compared to control group. We proposed that oxidative stress might be the pathogenesis of prenatal undernutrition which is induced schizophrenia.

Feedback regulation between atypical E2Fs and APC/CCdh1 coordinates cell cycle progression.

E2F transcription factors control the oscillating expression pattern of multiple target genes during the cell cycle. Activator E2Fs, E2F1-3, induce an upswing of E2F targets, which is essential for the G1-to-S phase transition, whereas atypical E2Fs, E2F7 and E2F8, mediate a downswing of the same targets during late S, G2, and M phases. Expression of atypical E2Fs is induced by E2F1-3, but it is unknown how atypical E2Fs are inactivated in a timely manner. Here, we demonstrate that E2F7 and E2F8 are substrates of the anaphase-promoting complex/cyclosome (APC/C). Removal of CDH1, or mutating the CDH1-interacting KEN boxes, stabilized E2F7/8 from anaphase onwards and during G1. Expressing KEN mutant E2F7 during G1 impairs S phase entry and eventually results in cell death. Furthermore, we show that E2F8, but not E2F7, interacts also with APC/C(C) (dc20). Importantly, atypical E2Fs can activate APC/C(C) (dh1) by repressing its inhibitors cyclin A, cyclin E, and Emi1. In conclusion, we discovered a feedback loop between atypical E2Fs and APC/C(C) (dh1), which ensures balanced expression of cell cycle genes and normal cell cycle progression.

A Novel Immune Marker Model Predicts Oncological Outcomes of Patients with Colorectal Cancer.

BACKGROUND: The purpose of this study was to develop an in situ immune marker model to predict postoperative oncological outcomes in patients with colorectal cancer (CRC). METHODS: Immunohistochemistry for 13 immune cell markers was performed on tumor tissue microarrays from 300 CRC patients who underwent curative resection from January 2000 to January 2006. Genetic algorithm was applied for the construction of an in situ immune marker model. RESULTS: The infiltration of CD3+ cells, CD45RO+ cells, and FOXP3+ cells, but not the infiltration of Tryptase+ cells, in the tumor was significantly associated with better clinical outcome in overall survival (OS) and disease-free survival (DFS) of CRC patients, as assessed by univariate analysis (P < 0.05). Based on the genetic algorithms, a total of 6 markers, including CD3, CD45RO, IL17, CD15, Tryptase, and FOXP3, were selected to construct an immune marker model. Our model was identified to have an independent predictive capability for both OS and DFS in Cox multivariable model (P < 0.001). This was further confirmed by the ROC analysis (area under curve: OS, 0.669; DFS, 0.684). CONCLUSIONS: The in situ immune marker model constructed in this study provides a novel approach to identify CRC patients who were at an increased risk for poor oncological outcomes.

Significance of mTOR signaling and its inhibitor against cancer stem-like cells in colorectal cancer.

PURPOSE: To determine the role of the mammalian target of rapamycin (mTOR) signaling in sustaining cancer stem-like cells and its clinical values in colorectal cancer (CRC). METHODS: mTOR expression in CRC patients was analyzed by immunohistochemistry and survival analysis was used to confirm the clinical value of mTOR. Colorectal cell lines were treated by mTOR inhibitors rapamycin and PP242, and sphere formation assay and aldehyde dehydrogenase (ALDH) assay were utilized to determine the impact of mTOR inhibition in CRC stem-like cells, combined or not combined with chemotherapeutic drug (fluorouracil and oxaliplatin). RESULTS: mTOR expression was associated with outcomes of CRC patients and predicted poor prognosis in stage II CRC patients. mTOR signaling was activated in stem-like colorectal cancer cells, and mTOR inhibitors (rapamycin and PP242) decreased the capacity of sphere formation as well as ALDH activity. Furthermore, mTOR inhibitors also were demonstrated to suppress the stimulation of stem-like cells by chemotherapy. CONCLUSIONS: mTOR shared predictive significance in stage II CRC patients' outcomes and played a vital role in the maintenance of colorectal cancer stem-like cells. mTOR inhibitors might hold the potential to become a therapeutic target against CRC stem cells.

The impact of deep learning based- psychological capital with ideological and political education on entrepreneurial intentions.

The aim of this study is to investigate the influence of psychological capital on college students' entrepreneurial intentions. Through a combination of relevant analysis and linear regression, the primary focus is on exploring the relationship between psychological capital and its four dimensions with entrepreneurial intentions. Firstly, the items in the psychological capital questionnaire were revised to align more closely with entrepreneurial contexts. Subsequently, the average deviations and standard deviations of each dimension of psychological capital were analyzed. Then, the correlation between psychological capital and entrepreneurial intentions was examined to explore the extent of their relationship. Finally, regression analysis was conducted on both psychological capital and entrepreneurial intentions, and utilizing a recurrent neural network model, the covariant relationship between entrepreneurial psychological capital and intentions was explored. The results indicated that the average scores for entrepreneurial self-efficacy, optimism, hope, and resilience were 3.91, 4.27, 4.19, and 4.15, respectively. The average value of psychological capital was 4.13, indicating a moderately high level. The correlation analysis between psychological capital and entrepreneurial intentions yielded a result of 0.562, indicating a moderate degree of correlation. The correlation coefficients of the four dimensions with entrepreneurial intentions were 0.390, 0.494, 0.531, and 0.467, respectively. The standardized coefficients for psychological capital and its four dimensions were 0.564, 0.382, 0.510, 0.536, and 0.468, all of which were statistically significant. Overall, psychological capital exhibited better predictive power for entrepreneurial intentions than its individual dimensions. The results from the deep learning model similarly demonstrated the positive role of psychological capital in entrepreneurial intentions, though the influence of ideological and political education (IPE) factors was relatively weaker. In conclusion, both psychological capital and IPE have a promotive effect on entrepreneurial intentions. This study provides a reference for the accurate evaluation of college students' entrepreneurial intentions.

Transcriptome analysis to explore the mechanism of downregulated TNIK influencing the effect of risperidone.

Background: Risperidone is one of the most reliable and effective antipsychotics for schizophrenia treatment. However, the mechanism of action of risperidone is not yet fully understood. Traf2 and Nck-interacting protein kinase (TNIK), a schizophrenia susceptibility gene, is associated with risperidone treatment response. Our previous in vitro experiments confirmed that downregulated TNIK affected the effect of risperidone on downstream targets. However, the effect of downregulated TNIK on risperidone-induced molecular expression remains to be further explored. Methods: Transcriptome analysis was performed on U251 cells subjected to risperidone, TNIK siRNA, and no treatment, respectively. Compared to the no-treatment group, two groups of DEGs were screened out and then intersected with the schizophrenia-related genes to screen the cross-talk genes. Those DEGs were analyzed using GO and KEGG. STRING and Cytoscape were used to construct a protein-protein interaction (PPI) network for the cross-talk gene. Results: The results showed that the parathyroid hormone synthesis, secretion, and action were significantly enriched after risperidone treatment. Downregulated TNIK could have an impact on the collagen-containing extracellular matrix, signaling receptor activator activity, and PI3K-Akt signaling pathway. Interestingly, bone mineralization function and calcium signaling pathway were enriched in the cross-talk genes. Additionally, FGFR2, FGF1, and FGFR might be the potential targets for TNIK affecting the effects of risperidone. Conclusion: The study indicated that risperidone primarily influences functions and/or pathways associated with bone metabolism, potentially contributing to the adverse effect of osteoporosis. Our study may offer a novel perspective on investigating the mechanisms underlying the adverse effects of risperidone.

CCL18 as an independent favorable prognostic biomarker in patients with colorectal cancer.

BACKGROUND: CCL18 has been shown to have an important role in the progression of gastric and breast cancers. However, the prognostic value of CCL18 in colorectal cancer (CRC) remains unknown. MATERIALS AND METHODS: We used immunohistochemistry to examine the expression of CCL18 in CRC patients. We applied both univariate and multivariate analysis to evaluate the prognostic value of CCL18 on CRC patients' survival. We used double staining to investigate the relationship between CCL18 and macrophages. RESULTS: A total 371 CRC patient samples were enrolled in immunohistochemical analysis. According to our criteria, 118 samples (31.8%) showed a high CCL18 expression level. Clinicopathologic analysis revealed an association between the expression level of CCL18 and the preoperative carcino embryonic antigen level (P = 0.001), and the preoperative carbohydrate antigen 19-9 level (P = 0.003). Survival analysis and multivariate analysis revealed that CCL18 was an independent favorable prognostic factor in patients with CRC (P = 0.033). Double staining implied that CCL18 was expressed by macrophages. CONCLUSIONS: A high CCL18 level might be an independent biomarker for predicting better survival of patients with CRC.

QTT-DLSTM: A Cloud-Edge-Aided Distributed LSTM for Cyber-Physical-Social Big Data.

Cyber-physical-social systems (CPSS), an emerging cross-disciplinary research area, combines cyber-physical systems (CPS) with social networking for the purpose of providing personalized services for humans. CPSS big data, recording various aspects of human lives, should be processed to mine valuable information for CPSS services. To efficiently deal with CPSS big data, artificial intelligence (AI), an increasingly important technology, is used for CPSS data processing and analysis. Meanwhile, the rapid development of edge devices with fast processors and large memories allows local edge computing to be a powerful real-time complement to global cloud computing. Therefore, to facilitate the processing and analysis of CPSS big data from the perspective of multi-attributes, a cloud-edge-aided quantized tensor-train distributed long short-term memory (QTT-DLSTM) method is presented in this article. First, a tensor is used to represent the multi-attributes CPSS big data, which will be decomposed into the QTT form to facilitate distributed training and computing. Second, a distributed cloud-edge computing model is used to systematically process the CPSS data, including global large-scale data processing in the cloud, and local small-scale data processed at the edge. Third, a distributed computing strategy is used to improve the efficiency of training via partitioning the weight matrix and large amounts of input data in the QTT form. Finally, the performance of the proposed QTT-DLSTM method is evaluated using experiments on a public discrete manufacturing process dataset, the Li-ion battery dataset, and a public social dataset.

Effectiveness of pharmacogenomics on the response and remission of treatment-resistant depression: a meta-analysis of randomised controlled trials.

Background: Pharmacogenomics (PGx) is a promising tool to realise tailored drug therapy for depression. Aims: To investigate the treatment efficacy of PGx for treatment-resistant depression (TRD) compared with treatment as usual. Methods: A systematic search was conducted in PubMed, Embase, the Cochrane Library, Web of Science and PsycINFO to identify relevant studies published from inception to 15 April 2023. Two-arm randomised controlled trials (RCTs) exploring the efficacy of PGx-guided versus unguided treatment for TRD were included. The risk of bias in the included studies was evaluated using the Cochrane risk of bias assessment tool. The overall quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. Results: Seven RCTs (n=3003) comparing PGx-guided (n=1492) and unguided (n=1511) groups were identified and analysed. PGx-guided treatment was superior to treatment as usual in response (relative risk (RR)=1.31; 95% confidence interval (95% CI): 1.15 to 1.49; p<0.001) and remission (RR=1.40; 95% CI: 1.09 to 1.80; p=0.009) improvements. Effect sizes for acceptability (RR=0.90; 95% CI: 0.80 to 1.02; p=0.100) and side effect burden (RR=0.58; 95% CI: 0.29 to 1.15; p=0.120) between the two groups were not statistically different. The overall quality of evidence was rated from 'very low' (25%) to 'low' (75%) based on the GRADE criteria. Conclusions: PGx-guided treatment has shown a small overall effect in improving the response and remission rates for patients with TRD. However, these results should be interpreted cautiously because of the few included studies and the low quality of evidence. Further high-quality clinical trials are warranted to confirm the findings. PROSPERO registration number: CRD42022340182.

Chronic restraint stress-induced depression-like behavior is mediated by upregulation of melanopsin expression in C57BL/6 mice retina.

BACKGROUND: Depression is associated with circadian disturbances in which melanopsin was a key mechanism. Further studies have demonstrated that melanopsin gene variations are associated with some depressive disorders and aberrant light can impair mood through melanopsin-expressing retinal ganglion cells (mRGCs). The goal of this study was to explore the direct relationship between depression and melanopsin. METHODS: Adult C57BL/6 male mice were physically restrained for 16 h in a 50-ml polypropylene centrifuge tube and all behavioral tests were performed after CRS treatment. Western blot analysis and immunofluorescence were used to detect melanopsin expression in the retina of C57BL/6 mice. And we observed the change of the electrophysiological function and release of glutamate of mRGCs. RESULTS: The melanopsin expression upregulate in mRGCs of chronic restraint stress (CRS)-treating mice which exhibit depression-like behavior. The frequency of blue light-induced action potentials and light-induced glutamate release mediated by melanopsin also increase significantly. This change of melanopsin is mediated by the CRS-induced glucocorticoid. CONCLUSIONS: CRS may induce the depression-like behavior in mice via glucocorticoid-melanopsin pathway. Our findings provide a novel mechanistic link between CRS-induced depression and melanopsin in mice.

High expression of CD73 as a poor prognostic biomarker in human colorectal cancer.

BACKGROUND AND OBJECTIVES: To investigate the expression dynamics of CD73 and its prognostic significance in human colorectal cancer (CRC). METHODS: CD73 expression dynamics were detected by Western blotting. Immunohistochemistry was used to examine the expression of CD73 in CRC tissues from two independent cohorts by tissue microarrays. The optimal cutpoint of CD73 expression was assessed by the X-tile program. RESULTS: Western blotting analysis demonstrated that CD73 expression in CRC was significantly higher than in normal colorectal tissues. According to the X-tile program, the cutpoint for high expression of CD73 in CRC was determined when CD73 expression index was more than 5.9. High expression of CD73 was observed in 44.8% and 50.4% of CRC in the training and validation cohorts, respectively. Overexpression of CD73 was significantly correlated with tumor differentiation, nodal status, American Joint Committee on Cancer stage. Patients with high expression of CD73 had a poorer overall survival rate compared with patients with low expression of CD73 in both cohorts. In multivariate Cox regression analysis, overexpression of CD73 was proven to be an independent prognostic biomarker for CRC. CONCLUSIONS: High expression of CD73 can be an independent and useful biomarker for predicting the poor survival of patients with CRC.

Identification of Potential Key circRNAs in Aged Mice With Postoperative Delirium.

Postoperative delirium (POD) is a common postoperative complication in elderly patients and seriously affects postoperative recovery. The exact mechanism of POD is still unclear. Therefore, it is necessary to explore the mechanism of POD in transcriptional regulation. At present, circRNAs have been proven to play an important role in a variety of mental health and cognitive disorders, such as Alzheimer's disease, depression and schizophrenia. To reveal the effect of circRNA on POD, we used microarray to analyze the differential expression profiles of circRNAs in the hippocampus of 12-month-old mice between the tibial fracture and control groups. A total of 1,4236 circRNAs were identified. Compared with the control group, there were 500 circRNAs with increased expression and 187 with decreased expression. The accuracy of the microarray data was further verified by qRT-PCR. Finally, GO enrichment and KEGG pathway analyses indicated that changes in axon orientation, ubiquitin-mediated proteolysis, glutamate synapses, the estrogen signaling pathway, the RAS signaling pathway and other systems may be important potential pathological mechanisms in the progression of POD. In particular, we found that the HOMER1 gene and its transcript mmu_circRNA_26701 are specifically expressed in the glutamate synapse, which may provide new clues and intervention targets for the progression of this refractory disease.

The association between rs1260326 with the risk of NAFLD and the mediation effect of triglyceride on NAFLD in the elderly Chinese Han population.

BACKGROUND: Accumulated studies have pointed out the striking association between variants in or near APOC3, GCKR, PNPLA3, and nonalcoholic fatty liver disease (NAFLD) at various ages from multiple ethnic groups. This association remained unclear in the Chinese Han elderly population, and whether this relationship correlated to any clinical parameters was also unclear. OBJECTIVES: This study aims to decipher the complex relevance between gene polymorphisms, clinical parameters, and NAFLD by association study and mediation analysis. METHODS: Eight SNPs (rs2854116, rs2854117, rs780093, rs780094, rs1260362, rs738409, rs2294918, and rs2281135) within APOC3, GCKR, and PNPLA3 were genotyped using the MassARRAY® platform in a large Chinese Han sample comprising of 733 elderly NAFLD patients and 824 age- and ethnic-matched controls. Association and mediation analysis were employed by R. RESULTS: The genotypic frequencies of rs1260326 and rs780094 were significantly different between NAFLD and control (rs1260326: P=0.004, Pcorr=0.020, OR [95%CI]= 0.69 [0.54-0.89]; rs780094: P=0.005, Pcorr=0.025, OR [95%CI]= 0.70 [0.55-0.90]). Particularly, an increased triglyceride level was observed in carriers of rs1260326 T allele (1.94±1.19 mmol/L) compared with non-carriers (1.73±1.05 mmol/L).no significant results were observed in rs780094. Notably, triglyceride levels had considerably indirect impacts on association between NAFLD and rs1260326 (ß =0.01, 95% CI: 0.01-0.02), indicating that 12.7% of the association of NAFLD with rs1260326 was mediated by triglyceride levels. CONCLUSIONS: Our results identified a prominent relationship between GCKR rs1260326 and NAFLD, and highlighted the mediated effect of triglyceride levels on the that association in the Chinese Han elderly.