Receptor‐interacting protein kinase 3 (RIP3) is a key determinant of necroptosis and participates in ischaemia—and oxidative stress‐induced necroptosis, myocardial remodelling and heart failure (HF). In this study, we tested the hypothesis that common variants in RIP3 gene were associated with the risk and prognosis of HF in the Chinese Han population. By re‐sequencing and luciferase assays, we identified a common functional variant in the RIP3 promoter region. The rs3212247‐T allele suppressed RIP3 promoter activity by facilitating transcription factor SOX17 binding, but not the C allele. We further recruited 2961 control participants and 3194 HF patients who underwent a mean follow‐up of 19 months (6‐31 months) for this study. Rs3212247 and another missense variant rs3212254 were genotyped. Although rs3212247 did not significantly associate with increased risk of HF (odds ratio = 1.00, 95% CI = 0.92‐1.08, P = 0.91), it raised the risk for cardiovascular death and cardiac transplantation (hazard ratio = 1.47, 95% CI = 1.13‐1.91, P = 0.004). Moreover, participants carrying the rs3212247 CC genotype had higher plasma levels of RIP3 than those carrying the TT or TC genotype (p for trend = 0.02) in New York Heart Association class III HF group. No association was found between the RIP3 missense variant rs3212254 and risk or prognosis of HF after adjustment for traditional risk factors. In conclusion, genetic variant in RIP3 promoter region is associated with increased RIP3 transcription, thus contributed to the poor prognosis of HF patients. Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT03461107?term=03461107&cond=Heart+Failure&cntry=CN&rank=1. Unique identifier: NCT03461107.

Chronic heart failure (CHF) has poor prognosis and polygenic heritability, and the genetic risk score (GRS) to predict CHF outcome has not yet been researched comprehensively. In this study, we sought to establish GRS to predict the outcomes of CHF. We re‐analysed the proteomics data of failing human heart and combined them to filter the data of high‐throughput sequencing in 1000 Chinese CHF cohort. Cox hazards models were used based on single nucleotide polymorphisms (SNPs) to estimate the association of GRS with the prognosis of CHF, and to analyse the difference between individual SNPs and tertiles of genetic risk. In the cohort study, GRS encompassing eight SNPs harboured in seven genes were significantly associated with the prognosis of CHF (P = 2.19 × 10⁻¹⁰ after adjustment). GRS was used in stratifying individuals into significantly different CHF risk, with those in the top tertiles of GRS distribution having HR of 3.68 (95% CI: 2.40‐5.65 P = 2.47 × 10⁻¹⁰) compared with those in the bottom. We developed GRS and demonstrated its association with first event of heart failure endpoint. GRS might be used to stratify individuals for CHF prognostic risk and to predict the outcomes of genomic screening as a complement to conventional risk and NT‐proBNP.

Phosphoinositide 3‐kinase γ (PI3Kγ) is G‐protein‐coupled receptor‐activated lipid kinase with both kinase‐dependent and kinase‐independent activity. Plenty of evidence have demonstrated that PI3Kγ participated in TAC and I/R‐induced myocardial remodelling and heart failure (HF). In this study, we tested the hypothesis that common variants in the PI3Kγ gene (PIK3CG) were associated with the prognosis of HF in the Chinese Han population. Through re‐sequencing and genotyping, we finally identified a common variant in the 3′UTR of PIK3CG strongly associated with the prognosis of HF in two‐stage population: adjusted p = 0.007, hazard ratio = 0.56 (0.36–0.85) in the first cohort and adjusted p = 0.024, hazard ratio = 0.39 (0.17–0.88) in the replicated cohort. A series of functional assays revealed that rs10215499‐A allele suppressed PIK3CG translation by facilitating has‐miR‐133a‐3p binding, but not the G allele. Subjects carrying the GG genotype showed higher mRNA and protein level than those with AA and AG genotype. Furthermore, overexpression of PIK3CG could protect AC16 from hypoxia/reoxygenation (H/R)‐induced apoptosis, while the case was opposite for PIK3CG silencing. In conclusion, common variant rs10215499 in the 3′‐UTR of PIK3CG might affect the prognosis of HF by interfering with miR‐133a‐3p binding and PIK3CG is a promising target for HF treatment in the future.

Aims: The prognosis of heart failure (HF) depends on genetic predisposition, and recent studies have shown that impaired autophagy is involved in HF. This study was aimed to construct a prognostic model combining polygenetic background based on the autophagy pathway and other traditional risk factors (TRF) of HF prognosis. Methods and results: Via re-analysing the transcriptomic data of 50 failing and 14 non-failing donors, differentially expressed autophagy-related genes (ARGs) were chosen for further comparison and analysis with whole exome sequencing and follow-up data of 1000 HF patients. By searching from reported articles, prognosis-related polymorphisms were identified. ARGs and prognosis-related polymorphisms were used to develop genetic risk score (GRS) and genetic risk factor (GRF), respectively. We compared the predictive power of five models [Model 1, GRS; Model 2, composite of TRF and N-terminal B-type natriuretic peptide (NT-proBNP); Model 3, composite of TRF, NT-proBNP, and GRS; Model 4, composite of TRF, NT-proBNP, and GRF; and Model 5, composite of TRF, NT-proBNP, GRF, and GRS] by applying receiver operating characteristic curves. Twenty-four prognosis-related polymorphisms were used to construct GRF and 11 variants among 48 differentially expressed ARGs associated with clinical outcomes of HF patients were applied for GRS. GRS was strongly associated with cardiac mortality of HF patients, independent of TRF and GRF (95% confidence interval 1.273–1.739, P = 5.78 × 10−7). Comparing with patients with lowest GRS tertile, those with highest tertile had higher risks of developing worse clinical outcomes (hazard ratio = 1.866; 95% confidence interval 1.352–2.575, P = 1.47 × 10−4). The discrimination power of the model including GRS, TRF, GRF, and NT-proBNP is most considerable (area under curve = 0.777), especially in men, patients over 60, patients with hypertension, patients without diabetes or hyperlipidaemia. Conclusions: The model combining autophagy-related GRS, TRF, GRF, and NT-proBNP performs well in distinguishing between worse-prognosis and better-prognosis HF patients, leading a promising strategy for HF treatment and HF prevention.

Background: Endometrial cancer (EC) is a common malignant tumor in women with increasing mortality. The prognosis of EC is highly heterogeneous which needs more effective biomarkers for clinical decision. Here, we reported the effect of autophagy-related genes (ARGs) on the prognosis of EC. Methods: The expression data of EC tissues and adjacent non-tumor samples were available from the TCGA dataset and 232 autophagy-related genes were from The Human Autophagy Database. A prognostic ARGs risk model was further constructed by using LASSO-Cox regression, and its prognostic and predictive value were evaluated by nomogram. Further functional analysis was conducted to reveal a significant signaling pathway. Results: A total of 45 differentially expressed ARGs were obtained, including 18 upregulated and 27 downregulated genes. Eleven ARGs (BID, CAPN2, CDKN2A, DLC1, GRID2, IFNG, MYC, NRG3, P4HB, PTK6, and TP73) were finally selected to build ARGs risk. This signature could well distinguish between the high- and low-risk patients (survival analysis: P = 1.18E-10; AUC: 0.733 at 1 year, 0.795 at 3 years, and 0.823 at 5 years). Furthermore, a nomogram was plotting to predict the possibility of overall survival and suggested good value for clinical utility. Conclusion: We established an eleven-ARG signature, which was probably effective in the prognostic prediction of patients with EC.

Background: The monocyte-to-lymphocyte ratio (MLR) has emerged as a novel marker of inflammation. Nevertheless, its potential utility in predicting the development of left ventricular aneurysm (LVA) remains unexplored. This study aims to investigate the association between MLR and the risk of LVA in patients presenting with acute ST segment elevation myocardial infarction (STEMI). Methods: A total of 551 patients were enrolled in the first cohort, and 471 patients were included in the validation cohort. To evaluate the predictive value of MLR for LVA, multivariable logistic regression analysis, restricted cubic splines (RCS) analysis, and receiver operating characteristic (ROC) analysis were employed. Results: The prevalence of LVA was 14.5% in the first cohort and 13.6% in the validation cohort. The multivariable logistic regression analysis revealed that individuals in the highest quartile of MLR (Q4) exhibited a significantly increased risk of LVA formation compared to those in the lowest quartile (Q1) in both cohorts (first cohort: OR = 3.07, 95% CI = 1.33–7.08, P = 0.009; validation cohort: OR = 3.55, 95% CI = 1.34–9.42, P = 0.011). The RCS analysis identified a positively nonlinear association in the first cohort and a positively linear association in the validation cohort between MLR and the risk of LVA (overall P < 0.05). Furthermore, the discriminative ability of MLR for LVA is 0.69 in the first cohort and 0.71 in the validation cohort, exceeding that of both monocyte and lymphocyte alone. The subgroup analyses further substantiated the robustness of our findings. Conclusion: An elevated MLR was independently linked to an increased risk of LVA development in patients with STEMI who received primary PCI. This readily available inflammatory index may offer supplementary prognostic information and could be considered for inclusion in future risk stratification models.