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Lipoproteins are essential for lipid transport in all bilaterians. A single Apolipoprotein B (ApoB) molecule is the inseparable structural scaffold of each ApoB-containing lipoprotein (B-lps), which are responsible for transporting lipids to peripheral tissues. The cellular mechanisms that regulate ApoB and B-lp production, secretion, transport, and degradation remain to be fully defined. In humans, elevated levels of vascular B-lps play a causative role in cardiovascular disease. Previously, we have detailed that human B-lp biology is remarkably conserved in the zebrafish using an Show less

Primary hypobetalipoproteinemia (HBL) is mostly due to a polygenic origin or to monogenic disorders including loss of function (LOF) variants in APOB, much less frequently Angiopoietin-like 3 gene (ANGPTL3). A new heterozygous variant of uncertain significance (VUS), p.H343R missense variant in ANGPTL3 cosegregated with HBL in a family. The aim of the present study was to assess in vitro the functionality of this variant and to establish its causality in this family. Targeted next-generation sequencing was performed in the proband to assess monogenic and polygenic origins using an LDL-C-dedicated polygenic risk score (PRS All 8 HBL subjects had PRS This study shows that the novel ANGPTL3-p.H343R variant decreases ANGPTL3 secretion in vitro and can now be considered as a LOF variant. The lipid phenotype in this family results from a synergistic combination of the p.H343R ANGPTL3 variant and a polygenic HBL predisposition. Show less

Lipoprotein(a) [Lp(a)] is an LDL-like particle, which is synthesized and assembled in the liver, and whose plasma levels are strongly associated with, and considered to be causative of, atherosclerotic cardiovascular disease (ASCVD). Several promising pharmacological therapies that directly target Lp(a) are under development. We discuss the role of Lp(a) in ASCVD, describe the pharmacodynamics, pharmacokinetics, and metabolism of muvalaplin, an oral Lp(a) inhibitor, as well as reporting on the findings of the phase II KRAKEN trial in adults at high cardiovascular risk with elevated Lp(a). Muvalaplin is the first oral small molecule inhibitor of Lp(a) formation for the treatment of elevated Lp(a). In KRAKEN, muvalaplin significantly reduced Lp(a) levels in high-risk patients by up to 70% and 85.5% by traditional and novel isoform-insensitive intact assays, respectively. Safety and tolerability studies reported to date are promising, with minimal effect on plasminogen activity that was independent of dose. In terms of patient convenience and adherence, the oral dosing of muvalaplin may confer practical advantages over injectable Lp(a)-lowering therapies. The results of the MOVE-Lp(a) phase III trial, which is evaluating the effect of muvalaplin on cardiovascular outcomes in high-risk patients with elevated Lp(a), are eagerly awaited. Show less

Elevated lipoprotein(a) [Lp(a)] levels increase cardiovascular (CV) risk. Lp(a) contains oxidized phospholipids that may promote lipid oxidation more than other lipoproteins. The highly unsaturated omega-3 fatty acid eicosapentaenoic acid (EPA) has multiple double bonds that can trap free radicals in resonance structures. Purified ethyl-EPA reduced CV events in high-risk patients with elevated Lp(a) despite Lp(a)-associated risk elevation. Since Lp(a) is enriched in oxidized lipids, we hypothesized that Lp(a)-enriched plasma undergoes more rapid oxidation than other apolipoprotein B (ApoB)-containing particles and that EPA limits oxidation of Lp(a)-enriched plasma more effectively than less-unsaturated fatty acids or other lipid-lowering treatments. This property could limit the cellular stress responses in endothelial cells (ECs). Lp(a) was enriched to >50% total ApoB content to resemble an Lp(a)-associated 'high-risk' phenotype and compared with matching levels of small-dense LDL (sdLDL) and very-low-density lipoprotein by isopycnic centrifugation. Samples were then incubated with EPA (50 µM) or equivolume vehicle at 37°C for 30 min. Oxidation was initiated with copper sulfate and monitored by malondialdehyde formation. We also subjected EPA to oxidation before measuring its antioxidant activity when compared with other long chain, less saturated fatty acids and lipid-lowering agents. Human umbilical vein ECs (HUVECs) were incubated with Lp(a)-enriched plasma following oxidation in the absence and presence of EPA. Cell lysate samples were then analysed by global liquid chromatography-mass spectroscopy (LC/MS)-based proteomics for significant changes in protein expression (>1-fold). Lp(a)-enriched plasma contained the highest baseline oxidized lipid (P < 0.05) and underwent the most rapid oxidation. EPA, but neither the less-unsaturated fatty acids nor lipid agents attenuated oxidation of each fraction through 4 h (P < 0.01). Oxidized EPA had diminished antioxidant capacity corresponding to the extent of oxidation. Attenuation of Lp(a) oxidation with EPA also mitigated pro-inflammatory and cellular stress response changes in protein expression. Lp(a)-enriched plasma underwent more rapid oxidation than other ApoB-containing lipoproteins and promoted inflammatory changes in EC protein expression, a process attenuated by EPA. This action may contribute to reduced CV risk by EPA in those with elevated Lp(a) levels. Show less

End-stage renal disease (ESRD) is associated with high morbidity and mortality. Identifying patients with stage 4 chronic kidney disease (CKD) at risk of short-term progression to ESRD remains challenging. Accurate prediction can improve advanced care planning and patient outcomes. This study aimed to develop and validate a machine learning (ML) model for predicting progression within 25 weeks (approximately six months) of ESRD in patients with stage 4 CKD. Electronic health records (EHRs) of patients with stage 4 CKD were analyzed. Nine ML models including Ridge regression (Ridge), random forest (RF), and eXtreme Gradient Boosting (XGBoost) were used to predict short-term progression to ESRD within 25 weeks. The models were trained and externally validated using the data of 346 and 105 patients. Of the 451 patients with stage 4 CKD, 219 developed ESRD. Among the evaluated models, XGBoost demonstrated the best overall performance. In the internal validation, it achieved an area under the curve (AUC) of 0.93, an accuracy of 0.90, and an F1 score of 0.89. In the external validation, XGBoost maintained the highest AUC (0.85), accuracy (0.79), and F1 score (0.79), along with the highest average precision (0.89) and a low log-loss (0.48), indicating strong discriminative ability and good generalizability. The top predictive features included high-density lipoprotein cholesterol, Alb, Cys C, ApoB, FGB, Bun, Neutrophil, and Total cholesterol. This study demonstrated the feasibility of ML for assessing ESRD prognosis based on easily accessible clinical features. XGBoost demonstrated superior performance in both internal and external validation, suggesting its potential for future patient screening. Show less

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

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

Despite significant evidence of a genetic contribution to strabismus, precise genetic mechanisms have not been identified. There are distinct population differences in the prevalence of strabismus and its subtypes. This study aimed to explore the genetic contributions to strabismus in different ancestral groups. Case-control. The Genome-wide association study of common variants (minor allele frequency >1%) and rare variant association study at the gene level for strabismus. Individual single nucleotide polymorphisms (SNPs) significantly associated with strabismus and genes with significant burden of rare variants in strabismus. Genome-wide association study identified one locus with 3 significant SNPs (rs2247113, rs2667037, and rs2715926) in intron 1 of Genetic associations with strabismus differed between ancestry groups, although genes in similar pathways, such as synaptic signaling and structural muscle proteins, were found in multiple groups. This highlights the importance of including diverse populations in studies of genetic associations and suggests that multiple pathways may lead to strabismus in different population groups. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. Show less

Patients born with congenital porto-systemic shunts have been shown to have a high risk of benign and malignant liver tumors in otherwise healthy livers. This study aimed to evaluate the genetic landscape of liver tumors in patients with congenital porto-systemic shunts (CPSS) and correlate genotype with histological findings. Nodules from patients with CPSS and sporadic pediatric focal nodular hyperplasia (FNH) or FNH-like nodules were evaluated histologically and sequenced for a panel of 50 genes using next-generation sequencing. Thirty-eight nodules from 17 patients with CPSS were histologically classified as hepatoblastomas ( CPSS is strongly associated with nodules containing variants in 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

Type 2 diabetes mellitus (T2DM) is known to adversely impact brain health, leading to cognitive decline and brain tissue volume reduction. This study aimed to assess the damage to gray-white matter junction tissue volume (gwJTV) in T2DM patients with and without carotid artery plaques, and its association with various metabolic parameters. We conducted a cross-sectional study involving 69 T2DM patients, employing three-dimensional T1-weighted MRI scans to measure brain tissue volumes, particularly gwJTV, and analyzing blood samples for metabolic parameters. Voxel-based (VBA) and region-of-interest (ROI) analyses of gwJTV were performed to evaluate the group difference with and without carotid artery plaques and to determine correlations to metabolic biomarkers. Voxel-based and region-of-interest analyses revealed that participants with carotid plaques had lower gwJTV than those without at the specific brain area. ROI results study further demonstrated positive associations between gwJTV and metabolic parameters such as AST, ApoB, and LDL, and negative associations with C-peptide, creatinine, and hsCRP. Our findings suggest that gwJTV could be a valuable imaging biomarker for monitoring brain and vascular health in T2DM patients, particularly those affected by carotid atherosclerosis. 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

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

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

OxPL-apoB (oxidized phospholipids [OxPL] on apoB-100), which include OxPL present on Lp(a) (lipoprotein[a]), are associated with higher cardiovascular risk. Experimental studies suggest that OxPL may influence platelet function. This observational study assessed the association of OxPL-apoB with intrinsic and on‑clopidogrel platelet reactivity and long-term cardiovascular events in patients undergoing coronary angiography with or without percutaneous coronary intervention in 2040 patients in the EXCELSIOR trial (Impact of Extent of Clopidogrel-Induced Platelet Inhibition During Elective Stent Implantation on Clinical Event Rate). The association of OxPL-apoB to expression of CD62P, CD41, or PAC-1 levels and intrinsic and on-clopidogrel platelet reactivity to collagen and ADP was determined. The relationship of OxPL-apoB and Lp(a) to myocardial infarction-free survival and all-cause mortality at a median of 7 years was assessed using Cox regression models. Elevated levels of OxPL-apoB were associated with the severity of coronary obstruction, and higher prevalence of prior myocardial infarction, percutaneous coronary intervention, and coronary artery bypass graft surgery. No significant associations were present between OxPL-apoB and intrinsic or on-clopidogrel platelet reactivity or activation of platelet receptors. Analyzed individually in separate multivariable models, both OxPL-apoB (hazard ratio, 1.022 [95% CI, 1.005-1.040]; In patients undergoing coronary angiography with or without percutaneous coronary intervention, OxPL-apoB was not associated with intrinsic and on-clopidogrel platelet reactivity mediated by collagen or ADP. The association of OxPL-apoB and Lp(a) suggests that the accumulation of OxPL on Lp(a) may be a key determinant of long-term cardiovascular outcomes. URL: https://www.clinicaltrials.gov; Unique identifier: NCT00457236. 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

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

Calcific aortic valve stenosis (CAVS) is steadily rising worldwide with no effective pharmacological agents available. Observational studies implicated dyslipidaemia as a risk factor for CAVS. Whether dyslipidaemia is causative for CAVS and the therapeutic potential of different lipid-modifying drug targets for CAVS treatment remains unclear. We appraised the relationship of genetically-proxied lipid traits and 12 lipid-modifying drug targets with CAVS risk using Mendelian randomization (MR). Genetic variants associated with lipid traits and variants in genes encoding lipid-modifying drug targets were retrieved from GLGC. Summary-level data for CAVS were obtained from the TARGET consortium and FinnGen. Validation analyses were performed using genetic instruments retrieved from liver-derived gene expression and circulation plasma levels of targets. Colocalisation and mediation analyses were performed to evaluate the robustness of our findings and explore potential mediators (i.e., lipoprotein a (Lp(a)), body mass index, apolipoprotein B (ApoB)). The MR analyses supported that total cholesterol and LDL-cholesterol level were independent causal risk factors. The drug-target MR analysis suggested that genetic mimicry of PCSK9 inhibition should reduce CAVS risk (OR = 0.63, 95% CI = 0.56-0.70), which was corroborated by colocalisation analysis. Secondary analyses supported a genetically proxied effect of liver-specific PCSK9 expression (OR = 0.94 per SD reduction in PCSK9 expression, 95% CI = 0.88-1.00) and circulating plasma levels of PCSK9 (OR = 0.86 per SD reduction in PCSK9 protein, 95% CI = 0.83-0.88) on CAVS risk. ApoB and Lp(a) mediated 55.9% and 4.5%, respectively, of the total effect of PCSK9 on CAVS risk. Multiple sensitivity analyses supported this observation. Our study supports total cholesterol, LDL-cholesterol as a causal factor for CAVS, and genetically proxied inhibition of PCSK9 may reduced its risk. 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

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

Obesity and dysregulated cytokine levels are prevalent in schizophrenia patients undergoing antipsychotic treatment. While cytokines are implicated in obesity, their relationship with psychopathology in schizophrenia remains underexplored. This study investigated associations between body mass index (BMI), cytokine levels, and clinical symptoms in chronic schizophrenia patients. In this cross-sectional study,201chronic schizophrenia patients (Chinese Han population) were stratified into high BMI (BMI≥25kg/m A significant negative correlation was observed between BMI and IL-2( Higher BMI in chronic schizophrenia is associated with reduced IL-2 levels, attenuated negative symptoms, and adverse lipid profiles. TNF-α may modulate psychopathology severity. These findings highlight complex interactions between metabolic dysregulation, immune markers, and clinical manifestations in schizophrenia. 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