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To establish a short-term high-fat/high-cholesterol (HFHC) diet-induced Metabolic dysfunction-associated steatotic liver disease (MASLD) mouse model, and evaluate the effects of rapamycin (RaPa) and chloroquine (CQ) on this model to explore their therapeutic potential and side effects. An early MASLD mouse model was constructed via short-term HFHC diet feeding. Model mice were intraperitoneally injected with RaPa or CQ. Drug effects were analyzed on body weight, liver weight, lipid metabolism-related genes (APOB, FASN, PLIN2), inflammatory factors (IL-6, IL-10), and fibrosis markers (LOX, Col-1α-1, CCL2, TGFβ1, PDGFRβ, α-SMA) at mRNA and protein levels. RaPa ameliorated body weight and liver weight in early MASLD mice, downregulated FASN and PLIN2 expression, upregulated IL-10 mRNA levels, and alleviated hepatic steatosis, but induced metabolic disorders such as Insulin resistance and hyperlipidemia. In contrast, CQ promoted FASN and PLIN2 expression, exacerbated hepatic steatosis, reduced IL-10 mRNA levels, and upregulated fibrosis-related markers (LOX, TGFβ1, PDGFRβ, α-SMA) at both mRNA and protein levels, thereby driving MASLD progression to liver fibrosis. Notably, CQ improved metabolic abnormalities in model mice, including obesity, hyperlipidemia, and Insulin resistance. RaPa and CQ exhibit dual effects on early MASLD: RaPa alleviates hepatic steatosis but exacerbates metabolic disorders, whereas CQ improves metabolic abnormalities but accelerates liver fibrosis. This paradox highlights the need to balance metabolic regulation and liver injury prevention in MASLD treatment, providing critical experimental insights for targeted drug development. Show less

Increasing evidence underscores the driving role of coding and non-coding variants in cancer development. Analyzing gene sets in biological processes offers deeper insights into the molecular mechanisms of carcinogenesis. Here, we developed geMER to identify candidate driver genes genome-wide by detecting mutation enrichment regions within coding and non-coding elements. We subsequently designed a pipeline to identify a core driver gene set (CDGS) that broadly promotes carcinogenesis across multiple cancers. CDGS comprising 25 genes for 25 cancers displayed instability in DNA aberrations. Variants within the TTN enrichment region may influence the folding of the I-set domain by altering local polarity or side-chain chemistry properties of amino acids, potentially disrupting its antigen-binding capacity in LUAD. Multi-omics analysis revealed that APOB emerged as a candidate oncogene in LIHC, whose genetic alterations within the enrichment region may activate key TFs, upregulate DNA methylation levels, modulate critical histone modifications, and enhance transcriptional activity in the HepG2 and A549 cell lines compared to Panc1. Additionally, CDGS mutation status was an independent prognostic factor for the pan-cancer cohort. High-risk patients tended to develop an immunosuppressive microenvironment and demonstrated a higher likelihood of responding to ICI therapy. Finally, we provided a user-friendly web interface to explore candidate driver genes using geMER ( http://bio-bigdata.hrbmu.edu.cn/geMER/ ). Show less

Atherosclerosis is a chronic inflammatory condition that remains a major global cause of cardiovascular morbidity and death. Circular RNAs (circRNAs), emerging as key regulators of biological processes, have been linked to atherosclerosis because of their functions in inflammation, lipid metabolism, and plaque stability. This review explores the biogenesis and cellular functions of circRNAs, highlighting specific circRNAs, such as circANRIL, circHIPK, and circRSF1, which influence atherosclerosis progressions and development. CRISPR-Cas technology, specifically Cas9 and Cas13, has transformed the way atherosclerosis is studied and potentially treated. Targeting PCSK9, LDLR, and APOB to modify lipid metabolism, including lowering LDL cholesterol and repairing mutations in familial hypercholesterolemia, has been made possible using CRISPR-Cas9 in atherosclerosis models. In parallel, CRISPR-Cas13 offers a novel approach for RNA-level intervention by selectively editing circRNAs, providing a dynamic approach to regulate atherosclerosis-related pathways. In order to convert these findings into therapeutic treatments, future research should focus on elucidating the mechanics of circRNA, which in turn determines CRISPR-Cas13, and designing specific delivery systems. This review paper demonstrates the revolutionary promise of circRNA research and CRISPR innovation in the treatment of atherosclerosis and underscores the need for extensive preclinical validation to bridge the gap towards clinical use. Show less

Mania, a core feature of bipolar disorder, is characterized by impulsivity, hyperactivity, and mood disturbances. Impulsivity has been linked to lipid metabolism, particularly cholesterol and apolipoproteins. This study investigates the relationship between lipid profile, apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB), and impulsivity in first-episode mania patients. A case-control study was conducted at Sriram Chandra Bhanja (SCB) Medical College, Cuttack, involving 60 patients with first-episode mania and 60 age-matched healthy controls. Lipid parameters, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), ApoA1, and ApoB, were measured. Impulsivity was assessed using the Barratt Impulsiveness Scale (BIS-11). Independent samples t-tests and Pearson's correlation were used for statistical analysis. Mania patients had significantly lower TC (156.58 ± 14.00 mg/dL vs. 175.93 ± 23.59 mg/dL, p < 0.001), LDL (75.00 ± 9.24 mg/dL vs. 83.58 ± 16.86 mg/dL, p = 0.001), and TG (74.03 ± 11.94 mg/dL vs. 96.43 ± 29.48 mg/dL, p < 0.001) compared to controls. ApoB levels were higher in mania patients (795.95 ± 725.44 mg/dL vs. 549.53 ± 796.67 mg/dL, p = 0.079), though not statistically significant. BIS-11 scores negatively correlated with cholesterol levels, particularly TC and LDL, suggesting an association between hypercholesterolemia and increased impulsivity. Lower cholesterol levels, particularly LDL, are significantly associated with impulsivity in first-episode mania patients. These findings highlight the potential role of lipid metabolism in psychiatric disorders and suggest lipid monitoring in high-risk individuals. Show less

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that increases risk for premature coronary artery disease and has accessible and effective interventions. The Dutch lipid clinic network is currently the most used diagnostic criterion; however, genetic sequencing provides a definitive diagnosis of FH. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify individuals who were genotype positive for FH. Participants were recruited from 3 geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; and Jacksonville, FL). Participants underwent Exome+ sequencing (dba Helix, San Mateo, CA) and return of results for specific genetic findings in At the time of the study, 84 413 participants were enrolled in the Tapestry study. Annotation and interpretation of all variants in genes for FH resulted in the identification of 419 likely pathogenic and pathogenic variants (prevalence, 0.50%), which included 116 Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have familial hypercholesterolemia. URL: https://www.clinicaltrials.gov; Unique identifier: NCT05212428. Show less

Coronary heart disease (CHD) arises from a complex interplay of genetic and environmental factors. This study examines the influence of This retrospective case-control study enrolled 900 CHD patients and 900 control subjects. We evaluated associations between conventional cardiovascular risk factors and polymorphisms at the No significant differences were observed in the distribution of The Show less

Apolipoprotein B48 (ApoB48) may be an indicator of residual cardiovascular risk beyond conventional lipid measures. However, its performance for detecting coronary artery disease (CAD), alone and in combination with the ankle-brachial index (ABI), remains to be investigated. This cross-sectional study (358 patients; 299 and 59 with and without CAD, respectively) assessed the value of ApoB48 (cutoff: ≥4.5 μg/mL) and ABI (cutoff: <0.9) in detecting CAD. Subgroup analyses were performed for patients with diabetes mellitus, hypertension, dyslipidemia, and low levels of low-density lipoprotein-cholesterol (LDL-C) (<100 mg/dL). Baseline characteristics, including lipid profiles and biomarker levels, were compared between patients with and without CAD. Patients with CAD exhibited significantly higher ApoB48 levels compared to those without (5.1 ± 3.2 vs. 4.0 ± 2.2 μg/mL, respectively, p = 0.001); there were no significant differences in ABI values. The sensitivity and specificity of ABI alone for CAD were 16.7% and 81.4%, respectively, while those for ApoB48 alone were 48.2% and 61.0%, respectively. Combining both markers improved sensitivity to 55.5%, though specificity declined to 47.5%. Subgroup analyses revealed that ApoB48 maintained superior sensitivity across groups with diabetes, hypertension, dyslipidemia, and low levels of LDL-C. Lipid parameters (LDL-C, non-high density lipoprotein-cholesterol, and triglycerides) showed minimal discriminatory power between patients with and without CAD. ApoB48 demonstrates superior sensitivity for CAD detection compared to ABI, particularly in high-risk patients. While combining ApoB48 and ABI enhances sensitivity, it compromises specificity, suggesting the need for balanced diagnostic strategies. ApoB48 may be a valuable marker of residual cardiovascular risk, particularly in patients with well-controlled LDL-C or comorbid metabolic conditions. Show less

Emerging lipid-lowering therapies, such as Plozasiran, target apolipoprotein C-III (APOC-III) by inhibiting its hepatic production at the mRNA level, presenting a novel approach to lipid regulation. However, the safety and efficacy of plozasiran have yet to be fully established. We searched PubMed, Scopus, Web of Science, and Cochrane CENTRAL register of trials for studies comparing plozasiran to placebo in patients with dyslipidemic disorders. The primary outcomes were percentage changes from baseline in triglyceride (TG) and APOC-III levels at 24 weeks and the end of the study. Secondary outcomes included changes in other lipid parameters and safety outcomes at 24 weeks and the end of the study. A protocol was registered to PROSPERO under registration number [CRD420251026605]. Four studies encompassing 1,514 participants were included in our meta-analysis. Plozasiran significantly improved TGs, APOC-III, non-high-density lipoprotein cholesterol (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) levels at both 24 weeks and study completion. Subgroup analyses based on dose and regimen revealed consistent findings. Quarterly administration of plozasiran at 10 mg, 25 mg, and 50 mg resulted in significant reductions in TGs, APOC-III, non-HDL-C, and HDL-C at both 24 weeks and study completion. For ApoB, all three doses produced significant reductions at 24 weeks; however, only the 25 mg and 50 mg quarterly regimens sustained these reductions through the end of the study. Regarding safety, patients receiving plozasiran experienced a higher incidence of any adverse events, headache, and mild rises in HbA1C levels. Subgroup analysis revealed a dose-dependent pattern for certain safety outcomes. While Plozasiran shows strong potential as a therapeutic option for severe dyslipidemic conditions, further studies are needed to compare its efficacy and safety with currently available treatments and, more importantly, evaluate its impact on clinical outcomes for implementation in clinical practice. Show less

Primary bone marrow large B-cell lymphoma (PBM-LBCL) is a rare entity with poorly defined genetic features. We performed whole-exome sequencing on bone marrow specimens from 19 PBM-LBCL cases and compared them with 11 cases of conventional diffuse large B-cell lymphoma (DLBCL) with secondary bone marrow involvement. Clinicopathological characteristics, including hemophagocytic lymphohistiocytosis (HLH), hepatosplenomegaly, International Prognostic Index (IPI) score, treatment with chemotherapy plus rituximab, CD5 expression, histopathological patterns, germinal center B-cell-like subtype and follow-up duration, did not differ significantly between the two groups. Both IPI score and treatment regimen emerged as independent predictors of survival. Sequencing analysis revealed 7974 moderate- to high-impact variants. The MCD molecular subtype predominated in both cohorts, while the EZB subtype was observed exclusively in PBM-LBCL. A distinct 16-gene mutational signature differentiated PBM-LBCL from DLBCL. Among these, 10 genes (KMT2D, APOB, BBS9, CFAP46, EIF4G3, FAT1, MED12L, TG, TNR, ZFHX4) were uniquely mutated in PBM-LBCL, and three genes (CNTNAP3B, IL16, ZNF814) were exclusive to DLBCL. Mutations in COL5A3, PCNT, HMCN2, and OSBPL10 were associated with HLH. Notably, BTG1 mutation was significantly associated with poor prognosis in both univariate and elastic net-regularized multivariate analyses. In summary, PBM-LBCL harbors a distinct genetic profile, characterized by a unique 16-gene signature that distinguishes it from DLBCL with secondary bone marrow involvement. BTG1 mutation is associated with adverse outcomes, highlighting their potential as prognostic biomarkers or therapeutic targets. These findings advance our understanding of the molecular landscape and prognostic stratification of PBM-LBCL. Show less

Cholecystectomy alters lipid profiles and is associated with the risk of major adverse cardiac and cerebrovascular events (MACCE), yet the results are ambiguous. To assess the causal effects of cholecystectomy on blood lipid levels and risks of MACCE, we performed Mendelian randomization (MR) aiming to reduce confounding. We used genetic data on gallbladder removal, lipid levels, and MACCE from public databases. MR analysis estimated causal effects using genetic variants as instruments. Enrichment analysis identified relevant metabolic pathways, while multivariable MR evaluated specific lipid subtypes. Expression Quantitative Trait Loci MR pinpointed key genes, with cellular distribution insights from single-cell sequencing. Cholecystectomy was associated with delayed onset of angina, coronary heart disease, heart failure, myocardial infarction, and stroke. The ApoB/ApoA1 ratio was a key mediator, and the LPL gene influenced lipid-related cardiovascular risk. Cholecystectomy may reduce cardiovascular risks by lowering the ApoB/ApoA1 ratio, which highlights the role of lipid regulation in mitigating cardiovascular risk post-cholecystectomy. Show less

To investigate the relationship between serum lipid levels and the risk of Chronic obstructive pulmonary disease (COPD) in the UK Biobank. We performed this prospective study in 381,938 adults without COPD from UK Biobank. Serum high-density cholesterol (HDL-C), low-density cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), apolipoprotein A (ApoA) and apolipoprotein B (ApoB) were measured and classified into quintiles. Restricted cubic spline (RCS) analysis was applied to visualize the dose-response relationship between lipids and COPD risk and Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). We documented 10,443 incident COPD cases. Nonlinear relationships were found between HDL-C, LDL-C, TC, ApoA, ApoB and COPD risk with RCS analysis (P values for non-linearity < 0.05). Accordingly, multivariable-adjusted regression analysis indicated abnormal HDL-C and ApoA, and low LDL-C, TC and ApoB were associated with increased risk of COPD. Compared to intermediate quintile (Q3) group, both high or low HDL-C and ApoA were associated with risk of COPD. Corresponding HRs (95% CIs) were 1.15 (1.08-1.22), 1.16 (1.09-1.23) in Q1 group and 1.08 (1.01-1.16), 1.07 (1.00-1.14) in Q5 group. For LDL-C, TC and ApoB, there were more than 29% higher risk was observed in Q1 group with HRs (95% CIs) of 1.34 (1.27-1.42), 1.38 (1.30-1.46) and 1.29 (1.21-1.37), while HRs (95% CIs) were 0.88 (0.83-0.94), 0.92 (0.86-0.98) and 0.90 (0.84-0.95) in Q5 groups. We also observed the interactions between specific lipids and age at recruitment, sex and smoking status with stratified analysis. Our study provides the first evidence demonstrating the associations between six major serum lipids and COPD risk, revealing multiple nonlinear relationships. There were U-shaped associations between serum HDL-C, ApoA and COPD risk, and L-shaped associations between LDL-C, TC, ApoB and COPD risk. Show less

Biochemical items play a significant role in clinical decision-making, so this study aims to evaluate the performance of different biochemical platforms. We collected 1,524 serum samples that were centrifuged, and plasma was analyzed for HDL-C, LDL-C, Apo A1, Apo B, PA, and Fs-CRP with the Mindray BS2000M and Roche Cobas 8000 platforms. The results were evaluated by a non-parametric two-related sample test, Passing-Bablok regression analysis, Weighted Least Square analysis (WLS), and Bland-Altman analysis according to CLSI EP09-A3, EP5-A2, and EP15-A3. Between the two systems, there were statistically significant differences in the average bias of LDL-C, Apo A1, Apo B, PA, and Fs-CRP ( These findings suggest that the two platforms have good correlation and consistency in high-concentration medical decision levels in HDL-C, LDL-C, Apo A1, Apo B, and Fs-CRP, and all levels of PA in the two platforms are interchangeable and can replace each other. Show less

Women diagnosed with PCOS exhibit a high prevalence of obstructive sleep apnea (OSA). This study aims to assess risk factors of OSA among patients with PCOS. This retrospective study included 126 patients with PCOS who were categorized into an OSA group (n = 30) and a non-OSA group (n = 96) according to the apnea-hypopnea index (AHI). A control group comprised 72 patients without PCOS who presented during the same period for infertility due to fallopian tube, pelvic, or male factors. Patients with PCOS A multivariate logistic regression model was used to analyze independent risk factors for OSA in the PCOS group. Patients with PCOS had significantly higher AHI values and elevated values for various physical indicators, including body mass index (BMI) and neck, waist, and hip circumferences; prolactin (PRL); fasting plasma glucose (FPG); insulin (FINS); triglycerides (TG); homeostasis model assessment of insulin resistance (HOMA-IR); 2-hour postprandial glucose (2-hPG) and insulin (2-hINS); AHI; and oxygen desaturation index (ODI). Conversely, levels of high-density lipoprotein cholesterol (HDL-C) and lowest oxygen saturation (LSaO OSA in PCOS patients is linked to metabolic indicators. High neck circumference and BMI levels were independent risk factors, highlighting the need for OSA in routine PCOS screening, particularly in the context of metabolic dysregulation. Show less

Dipeptidyl peptidase-4 inhibitors (DPP-4i) serve as an incretin-based hypoglycemic class for the treatment of type 2 diabetes (T2D). DPP-4i have been reported to produce a pleiotropic effect on lipid profiles in addition to regulation of glucose homeostasis. The aim of this systematic review and meta-analysis was to quantitatively evaluate the impact of DPP-4i on lipid parameters in patients with T2D. PubMed, Embase, and The Cochrane Library were systematically searched for randomized controlled trials. Trials were identified if changes in lipid parameters, including low-density-lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), high-density-lipoprotein cholesterol (HDL-C), non-HDL-C, and apolipoprotein B (ApoB) were reported. A total of 95 publications were identified. DPP-4i significantly reduced levels of LDL-C (-3.48 mg/dL; 95% CI, -4.77 to -2.20; I2 = 70%, P < .00001), TC (-2.59 mg/dL; 95% CI, -3.88 to -1.29; I2 = 73%, P < .0001), TG (-5.39 mg/dL; 95% CI, -8.04 to -2.75; I2 = 77%, P < .0001), and non-HDL-C (-6.27 mg/dL; 95% CI, -10.94 to -1.60; I2 = 53%, P = .008). No significant effect was found on HDL-C (-0.32 mg/dL; 95% CI, -1.19 to 0.55; I2 = 97%, P = .47) and ApoB (-0.88 mg/dL; 95% CI, -3.36 to 1.60; I2 = 36%, P = .49) during DPP-4i treatment. DDP-4i significantly improved lipid parameters including LDL-C, TC, TG, and non-HDL-C in patients with T2D. This underscores the potential cardiovascular benefits of DPP-4i and their role in improving diabetes-related outcomes. PROSPERO registration no. CRD42020175999. Show less

To determine whether low-density lipoprotein cholesterol (LDL-C) levels, set by the balance of clearance and production, causally contribute to septic shock 28-day mortality. We measured LDL-C levels and genotypes in patients with septic shock. Using Genotyping and Genome-Wide Association Study summary statistics from over 150,000 Japanese participants, we genetically predicted pre-infection LDL-C levels. Two-sample Mendelian randomization was used to assess the causal relationship between predicted pre-infection LDL-C levels and 28-day mortality. We analyzed PCSK9 and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) genotypes to determine if LDL-C clearance or production was the underlying mechanism. Multicenter ICUs in Japan. Genotyped septic shock patients ( n = 614). None. Predicted pre-infection LDL-C levels were much higher than directly measured LDL-C levels at the onset of septic shock (141 mg/dL vs. 40 mg/dL, p < 0.001). Two-sample Mendelian randomization revealed that high predicted pre-infection LDL-C levels were causally associated with increased septic shock 28-day mortality (hazard ratio, 2.78; p = 0.039). PCSK9 genetic variants that increase LDL-C clearance via the LDL receptor (genetically proxied PCSK9 inhibitor treatment) were associated with decreased mortality ( p = 0.003) while HMGCR genetic variants that decrease LDL-C production (genetically proxied statin treatment) were not associated with decreased septic shock mortality (indeed the opposite effect was observed, p = 0.039). The two main genetic variants driving the association between high predicted pre-infection LDL-C levels and increased mortality were in apolipoprotein genes ( ApoB100 -rs13306206 and ApoE -rs7412), apolipoproteins involved in LDL-C binding to the LDL receptor. Low LDL-C clearance explains the causal association between high genetically predicted pre-infection LDL-C levels and increased septic shock mortality. PCSK9 , ApoB , and ApoE variants were identified as causal, all related to the LDL receptor or its interaction with LDL-C. Enhancing LDL receptor-mediated clearance of pathogen lipid toxins may improve septic shock outcomes. Show less

Atherosclerosis is partially driven by the accumulation of oxidised low-density lipoprotein (oxLDL), which facilitates foam cell formation and vascular inflammation. This research examines the efficacy of bamboo charcoal (BC) as a bioactive agent for neutralising oxLDL using both in silico and in vitro methodologies. Molecular docking demonstrated significant binding affinities between BC and essential constituents of oxLDL, such as oxidised cholesterol and apolipoprotein B-100, facilitated by π-π stacking and electrostatic interactions. Molecular dynamics simulations demonstrated the stability of these complexes over 300 ns, indicating sustained molecular interactions. Quantum chemical calculations employing density functional theory showed a narrow HOMO-LUMO gap of 0.45 eV and a significant dipole moment of approximately 45 D, underscoring the reactive and polar characteristics of BC. Electrostatic potential mapping and thermodynamic analyses provided additional evidence for BC's spontaneous and stable binding to oxLDL components. The Oil Red O staining and total cholesterol estimation assays were conducted on oxLDL-treated RAW 264.7 macrophages in vitro indicated that BC significantly decreased macrophage-derived foam cell formation, thereby confirming its ability to reduce oxLDL-induced lipid accumulation. The findings suggest that BC functions as a physical adsorbent and a participant in direct chemical interactions with oxLDL, providing a dual-action therapeutic approach to atherosclerosis. Show less

Cardiovascular diseases (CVDs) are the leading global cause of mortality and disability, with prevalence increasing due to aging and risk factors like obesity and hypertension. The retina, rich in microvasculature, provides a unique opportunity to investigate microvascular dysfunction linked to CVDs and other systemic vascular diseases. This study used a multifaceted approach to assess the genetic correlation and causal relationship between retinal characteristics and CVDs. Linkage disequilibrium score regression (LDSC) and Mendelian randomization (MR) analyses were conducted using genome-wide association study (GWAS) data from the UK Biobank and FinnGen datasets. A cross-sectional study was also conducted to validate the findings, collecting optical coherence tomography (OCT) images from 124 eyes (89 with CVDs and 35 healthy controls). A prediction model is based on least absolute shrinkage and selection operator (LASSO) regression to assess the risk of CVD. Using LDSC and two-sample MR, we found genetic evidence consistent with a causal effect whereby genetically proxied thinner retinal nerve fiber layer (RNFL) was associated with higher risks of hypertension and myocardial infarction (MI), while genetically proxied thicker photoreceptor inner segment/outer segment (PR-IS/OS) was associated with coronary heart disease and MI (false discovery rate [FDR] thresholds as reported). Genetically proxied thinner retinal pigment epithelium (RPE) showed an inverse association with stroke risk. Several circulating biomarkers-including lipoprotein(a) [Lp(a)], low-density lipoprotein cholesterol (LDL-C), and ApoB-exhibited MR evidence of association with multiple CVDs. In a cross-sectional cohort, retinal layer differences and their relationships with lipids were directionally consistent with the genetic findings. Retinal structural traits measured by OCT-particularly RNFL, PR-IS/OS, and RPE thickness-are best interpreted as non-invasive markers that reflect systemic vascular biology. Our MR analyses support shared etiologic pathways between retinal microstructure and CVDs rather than implying that retinal damage clinically causes cardiovascular events. Findings warrant validation in larger and more diverse populations and should not be considered definitive proof of causality. Show less

Emerging evidence suggests that ApoB outperforms LDL-C in predicting cardiovascular risk, especially in cases of discordance with the two. However, the specific type and composition of lipoprotein particles in this situation remain unclear. 375,544 individuals were enrolled from the UK Biobank without baseline cardiovascular disease, not on lipid-lowering therapy, and with available lipid nuclear magnetic resonance (NMR) data. Based on whether the absolute difference in baseline percentile of LDL-C and ApoB level was over 10 units, participants were categorized into concordant, discordantly high ApoB, and discordantly low ApoB group. The primary endpoint was major adverse cardiovascular events (MACE). Cox regression analysis showed the risk of MACE was increased in the discordantly high ApoB group (HR, 1.11; 95% CI, 1.06-1.15) and reduced in the discordantly low ApoB group (HR, 0.87; 95% CI, 0.83-0.93). Similar trends were observed in the NMR data. Compared to the other two groups, the discordantly high ApoB group exhibited the highest concentrations of VLDL-C, VLDL-CE, and VLDL particles. However, the CE content per LDL, IDL, and VLDL particle was lower in this group. Mediation analysis showed that VLDL particles and triglycerides mediated 25.5% and 26.6% of the MACE risk, respectively, in the discordantly high ApoB group (both P < 0.001). ApoB is a more comprehensive marker of cardiovascular risk than LDL-C. The higher cardiovascular risk in discordantly high ApoB individuals was partly mediated by VLDL; however, no conclusive evidence indicated that VLDL provides additional prognostic value beyond triglyceride measurements alone. Show less

Individuals with familial hypercholesterolemia (FH) are at high risk of premature cardiovascular disease. A healthy lifestyle and lipid-lowering medication are essential to reduce this risk. We examined if adherence to a heart healthy diet provides additional risk reduction independent of lipid-lowering medication. The Dutch Lipid Clinic Network (DLCN) criteria was used to diagnose FH (n=559 individuals with probable or definite FH) in the Copenhagen General Population Study(n=106,899) and the Copenhagen City Heart Study(n=7,451). Individuals were categorised by their level of heart healthy dietary adherence to Danish dietary guidelines, corresponding to international guidelines. Concentrations of low-density lipoprotein (LDL) cholesterol, apolipoprotein B (apoB), non-high-density lipoprotein (HDL) cholesterol, remnant cholesterol, triglycerides, and lipoprotein(a) (Lp(a)), and risk of ischaemic heart disease (IHD) were assessed by clinical FH category and level of dietary adherence. Women had a higher heart healthy dietary adherence compared to men. Mean concentrations of LDL cholesterol, apoB, non-HDL cholesterol, remnant cholesterol, and triglycerides increased stepwise by lower dietary adherence category, regardless of clinical FH category. Lp(a) concentration did not change by adherence to dietary guidelines. Results were similar in individuals taking lipid-lowering medication. Risk of ischemic heart disease (IHD) was lower in individuals with a higher dietary adherence (ranging from 8 to 57 % lower risk) compared to individuals with a very low dietary adherence regardless of clinical FH category. Adherence to a heart healthy diet is associated with lower concentrations of atherogenic lipids and lipoproteins, and lower risk of IHD in individuals with clinical FH, independent of treatment with lipid-lowering medication. Dietary adherence should be emphasised as an important tool in addition to treatment with lipid-lowering medication in individuals with FH. Show less

Familial hypercholesterolemia (FH) is a genetic disorder driven in part by mutations in three genes that encode components of the cholesterol pathway: LDLR, APOB, and PCSK9. However, the majority of FH genetics has been performed in individuals of European descent. Here, we leveraged a cohort of 300 patients from the Mexican FH registry to understand how rare, high liability alleles and common variants might contribute to shaping individual risk. Using a combination of whole exome and of short- and long-read whole genome sequencing, we report three key findings. First, we observed that rare pathogenic point mutations and structural variants in all known FH genes, together with variants in APOE, CREB3L3, and PLIN1, contribute to a molecular FH diagnosis in 67% of families, including novel gene-disruptive copy number variants (CNVs) which arose in a native American background. Second, ancestry-adjusted polygenic risk score analysis identified a significant liability for coronary artery disease, hypertension, LDL, HDL, and Type 2 Diabetes. The polygenic signal for LDL was present in patients with rare, pathogenic FH mutations and was more prominent in individuals bereft of a molecular FH diagnosis. Finally, we report both a whole-gene duplication and common, non-coding variants in a novel locus, PDZK1, which contribute to the genetic burden of FH, a finding we replicated in the UK Biobank (UKB). Together, our analyses illustrate the value of genetic studies in non-European populations and reinforce the notion that individual risk to disease can arise from both rare, large effect alleles (alone or in combination across genes) and common variants that increase the mutational burden of a biological system. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver condition globally, driven by strong genetic and environmental components. This review summarizes recent advances in understanding the genetic architecture of MASLD. Genome-wide association studies (GWAS) have identified several key risk variants, primarily in genes such as Show less

High-density lipoprotein (HDL) and small dense low-density lipoprotein (sdLDL) represent two critical yet contrasting components in lipid metabolism and cardiovascular risk modulation. While HDL has traditionally been viewed as cardioprotective due to its role in reverse cholesterol transport and anti-inflammatory effects, emerging evidence emphasizes that HDL functionality-rather than concentration alone-is pivotal in atheroprotection. Conversely, sdLDL particles are increasingly recognized as highly atherogenic due to their enhanced arterial penetration, oxidative susceptibility, and prolonged plasma residence time. This review critically examined the physiological roles, pathological implications, and therapeutic interventions targeting HDL function and sdLDL burden. Lifestyle modifications, pharmacologic agents including statins, fibrates, PCSK9 inhibitors, and novel therapies such as icosapent ethyl were discussed in the context of their effects on HDL quality and sdLDL reduction. Additionally, current clinical guidelines were analyzed, highlighting a paradigm shift away from targeting HDL-C levels toward apoB-driven risk reduction. Although HDL-targeted therapies remain under investigation, the consensus supports focusing on lowering apoB-containing lipoproteins while leveraging lifestyle strategies to improve HDL functionality. In the setting of heart failure, particularly with preserved ejection fraction (HFpEF), alterations in HDL composition and elevated sdLDL levels have been linked to endothelial dysfunction and systemic inflammation, further underscoring their relevance beyond atherosclerosis. A comprehensive understanding of HDL and sdLDL dynamics is essential for optimizing cardiovascular prevention strategies. Show less

Recent progress in laboratory medicine provides powerful tools for the detailed evaluation of cardiovascular risk in military populations. This study aimed to characterize cardiometabolic biomarker profiles across four Polish military groups through chemometric analysis. The study included 392 participants (336 men, 56 women, aged 19-56 years). In total, 23 serum biomarkers from lipid, metabolic, hepatic, hormonal, and bone axes, and lactate dehydrogenase (LDH) were analyzed. Random forest (RF) modeling and effect-size profiling identified group-specific signatures. Group 4 (exposed to extreme acceleration forces and ionizing radiation) exhibited a systemic stress and metabolic-load profile with higher N-terminal pro-B-type natriuretic peptide (NT-proBNP, 36.7 ± 48.2 pg/mL) and calcium (Ca, 10.4 ± 0.88 mg/dL), and lower parathyroid hormone (PTH, 15.4 ± 10.1 pg/mL) and C-terminal telopeptide of type I collagen (β-CTX, 0.22 ± 0.19 ng/mL). Group 2 (exposed to fuels and exhaust gases) and group 3 (exposed to vibration, noise, ionizing radiation) showed an atherogenic-hepatometabolic axis with elevated apolipoprotein B (apoB, 1.04 ± 0.31; 0.97 ± 0.29 g/L), non-high-density lipoprotein cholesterol (N-HDL, 151.0 ± 46.7; 147.0 ± 41.4 mg/dL), and alanine aminotransferase (ALT). Group 1 (exposed to a biological hazard) displayed higher glucose (Glu, 96.0 ± 25.6 mg/dL) and triglycerides (TG, 151.0 ± 113.0 mg/dL) with lower magnesium (Mg, 2.03 ± 0.27 mg/dL). RF modeling confirmed these constellations. This study was exploratory in nature, providing a foundation for future longitudinal research. These findings provide a rationale for tailored cardiovascular surveillance, although causal inference is limited by the cross-sectional design. Show less

The purpose of this study was to identify the functional characteristics of blood proteins which are important in assessing reproductive health due to their immunoregulatory effects in women residing in the European North and Arctic regions of the Russian Federation. A total of 557 women aged 21-55 (36.89 ± 0.54), engaged in intellectual professions, born and long-term residents of the European North (Arkhangelsk Oblast) and Arctic (Murmansk Oblast, Svalbard archipelago) participated. The hemogram, phagocytic activity of neutrophils, erythrocyte aggregation, lymphocyte content with CD3, CD4, CD8, CD10, CD19, CD16, CD71, CD95 phenotypes, cytokines: TNF-α, IFN-γ, IL-6, IL-10, extracellular receptors: sCD71, sCD62L, sApo-1/Fas, sFasL, circulating immune complexes, sex hormones, and as well as immunoregulatory blood proteins: haptoglobin, transferrin, immunoglobulins, lipoproteins, apoproteins, were evaluated. In women from Arkhangelsk Oblast, transferrin levels showed a substantial increase, while IgA levels decreased relative to the reference range. In women from Murmansk Oblast, haptoglobin, IgM, and IgA levels increased, and a reduction in IgG levels was observed. In women from the Svalbard Archipelago, transferrin and IgM concentrations increased, whereas IgG and IgA levels decreased. Additionally, in women from the European North and Arctic, a decrease in ApoB and ApoA-I content was observed. Elevated levels of transferrin and a decrease in lymphocytes with a transferrin receptor CD71+ and an increase in soluble transferrin receptor sCD71 levels were noted. Elevated haptoglobin levels are related to lymphocyte activation. The frequent occurrence of reduced IgA and IgG levels suggests impaired immunoglobulin class switching. Reduced levels of ApoB and ApoA-I indicate the early stages of lipid metabolism disorders. The immunoregulatory role of blood proteins determines their functional characteristics in women living in the European North and the Arctic. Reduced antioxidant protection, metabolic disorders, and dysregulation of the immune response in women living in Northern and Arctic regions can lead to reproductive health risks. Show less

Lipoprotein(a) [Lp(a)] is an independent, inherited risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. Lp(a) is an LDL-like particle containing apoB-100 and apo(a). Lifestyle changes and statin therapy lower LDL-cholesterol and apoB, but do not reduce Lp(a), whereas PCSK9 inhibitors exert a modest effect. There are currently no approved Lp(a)-lowering drugs, although several are at various phases of clinical development. We discuss the role of Lp(a) as a therapeutic target, describe the development, pharmacodynamics, pharmacokinetics, and metabolism of zerlasiran, a small interfering RNA (siRNA) targeting Lp(a), and report the findings of recent clinical trials. The GalNAc-conjugated siRNA zerlasiran reduces Lp(a) by targeting hepatic apo(a) synthesis and subsequent assembly of Lp(a), with comparable efficacy to other Lp(a)-lowering therapies in phase II development. Its long half-life, infrequent dosing, and potentially lower cost, together with its favorable safety and tolerability profile, make zerlasiran a promising candidate. However, long-term studies are needed to assess its impact on major adverse cardiovascular events and safety in diverse patient populations, and across different clinical settings. The phase III cardiovascular outcome study has not commenced. Show less

Oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) reflect pro-inflammatory properties of Lp(a) (lipoprotein(a)). The effect of OxPL-apoB on major adverse cardiovascular events (MACE) in patients with acute coronary syndrome in recent the era is not known. OxPL-apoB levels and Lp(a) were measured in 11 630 participants before and 5185 participants 4 months after randomization to alirocumab or placebo in the ODYSSEY OUTCOMES trial. Proportional hazards models adjusted for baseline covariates evaluated associations between log Participants were followed for a median 2.9 years; the median age was 58 years, and 23.9% were female. Alirocumab reduced median placebo-adjusted OxPL-apoB by 13.0% and Lp(a) by 26.2% (both In patients with recent acute coronary syndrome receiving optimized statin treatment, elevated OxPL-apoB levels predicted MACEs, a relationship abrogated by alirocumab. The interaction of OxPL-apoB and Lp(a) in the placebo group indicates that OxPL-apoB independently predicts MACEs when Lp(a) levels are relatively low. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT001747 and NCT01663402. Show less

Due to the growth in the global consumption of assisted reproductive technology (ART), it is possible that long-term health impacts on offspring have come into focus. ART has offered a welcome solution to infertility, but the fear has been on its effect on the metabolic health of children born on their behalf. Past studies indicate that ART-conceived individuals can have characteristic metabolic profiles relative to their naturally conceived (NC) peers and are therefore potentially predisposed to changes in lipid and glucose handling. Physiopathological glycolipid metabolism, a hallmark of cardiometabolic health, is believed to be modulated not only by environmental and other external factors but also by intracellular regulation proteins, including sterol regulatory element-binding protein (SREBP) and miR-33, although there is little evidence on the effects of ART on these regulatory pathways in early childhood. This paper sought to compare the glycolipid metabolic profile of the kids who are in preschool age and who were conceived through ART and kids who were NC. The second aim was to study the expression of SREBP-1/2 and miR-33 in peripheral blood and the possible nature of the role of these players in regulating early-life metabolism. A total of 220 children aged between 3 and 6 years were recruited of which complete data has been obtained from 206 children out of 98 that were conceived via in vitro fertilization/intracytoplasmic sperm injection (ICSI) (ART group) and 108 that were conceived naturally (NC group). Anthropometric measures-such as body weight, height, and waist circumference-to determine physical growth and obesity status were taken. Biochemical variables, triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), fasting serum insulin (FINS), and homeostatic model assessment of insulin resistance (HOMA-IR) were determined. A centrifugal column was used to obtain peripheral blood RNA, and relative gene expression levels of SREBP-1, SREBP-2, miR-33a, and miR-33b were measured by qPCR. Compared with the IVF group, children in the ICSI group had significantly lower weight, height, and waist circumference ( Our data suggest that although children born by means of ART are otherwise normal in their glycolipid metabolism, they are more prone to overweight and obesity and have different biochemical and molecular characteristics than NC children. The upregulation of miR-33b, SREBP-1, and SREBP-2 observed indicates that ART can play a role in regulating the process of glycolipid metabolism during early childhood at a molecular level. Such alterations might not present the form of a blatant metabolic condition at this age but may consist of initial symptoms of future troublesome metabolic health. Prolonged follow-up of the ART offspring and additional mechanistic work are desirable to be able to determine whether these early changes are the underlying reasons behind higher metabolic risk as adults. Show less

There were some evidences to suggest the correlation between circulating lipid levels and cholecystitis, but no evidence had been indicated the causal relationship between lipid-lowering drugs and cholecystitis. To investigate this, we employed drug target Mendelian randomization (MR), summary-data-based MR (SMR), and genetic colocalization analyses to assess the association between lipid-lowering drugs and cholecystitis. In this study, we used 2 sets of genetic tools to proxy lipid-lowering drugs: elevated high-density lipoprotein cholesterol (CETP), decreased low-density lipoprotein cholesterol (LDLR, HMGCR, NPC1L1, PCSK9, APOB, and ABCG5/ABCG8), and decreased triglycerides (LPL, PPARA, ANGPTL3, and APOC3); the expression quantitative trait locus of target genes from the eQTLGen consortium and Genotype-Tissue Expression project V8. Then, the causal effects of these lipid-lowering drugs genetic proxies on cholecystitis were estimated using a variety of MR, SMR, and colocalization as sensitivity analyses. Collectively, in the MR results, we found that the significant causal effects between genetically proxied ABCG5/ABCG8 enhancement and HMGCR inhibitors were associated with a reduced risk of cholecystitis. The results of SMR and heterogeneity in dependent instruments tests indicated that the expression of ABCG5/ABCG8 and HMGCR in multiple tissues were associated with cholecystitis. In conclusion, our study provides genetic evidence demonstrating a causal relationship between the enhancement of ABCG5/ABCG8 gene proxies and the use of HMGCR inhibitors with a reduced risk of cholecystitis. These findings support the potential reuse of lipid-lowering drugs in patients with cholecystitis and could inform the development of effective treatment strategies for this population in clinical practice. Show less