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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

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

Acute kidney injury is a common complication of sepsis, and its mechanism is very complicated. The purpose of this study was to investigate the mechanism of key differentially expressed proteins and their related signaling pathways in the occurrence and development of acute kidney injury in sepsis through proteomics. Acute kidney injury was induced by intraperitoneal injection of lipopolysaccharide at 10 mg/kg. Renal tissues were analyzed by TMT quantitative proteomic analysis. Differentially expressed proteins (DEPs) were screened. Gene Ontology (GO) function analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and protein-protein interaction (PPI) network analysis were performed. We obtained 530 DEPs. GO analysis showed that the biological process of DEPs was mainly stress response. The molecular functions of DEPs mainly focus on catalytic activity. The cellular components of DEPs were mainly located in the intracellular and cytoplasm. KEGG analysis showed that DEPs were mainly involved in metabolic pathways. Ten key proteins with interaction degree, such as Isg15, Irf7, Oasl2, Ifit3, Apob, Oasl, Ube2l6, Ifit2, Ifih1 and Ifit1 were identified. Irf7 was significantly up-regulated in rat kidney tissues. The upregulation of Irf7 plays an important role in the mechanism of acute renal injury induced by sepsis. 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

To investigate the relation of glycemic and lipid metabolism with brain structure and cognitive function in people with diabetes, so as to improve cognitive function in these individuals. Based on the UK Biobank, 26,394 patients, who were diagnosed with diabetes by doctors between 2006 and 2010, were included in the study. The demographic information, clinical data of glycemic and lipid metabolism and cognitive function (brain MRI and cognitive function scores) were collected. Multiple linear regression and non-restricted cubic spline analyses were used to investigate the relations of glycemic and lipid metabolism with brain structure and cognitive function. In this study, the mean age of people with diabetes (containing 39 % females) was 59.58 ± 7.21 years. Higher random blood glucose (β = -0.116, p < 0.001) and glycosylated hemoglobin (HbA1c) (β = -0.062, p = 0.051) were associated with a smaller brain volume. Higher HbA1c (β = 0.036, p < 0.001; β = 0.023, p = 0.021) was related with worse cognitive function. Further analysis showed that HbA1c < 6.5 % had a protective effect on cognitive function, and HbA1c = 6.5 %∼8.5 % and >8.5 % was unrelated and negatively related with cognitive function, respectively. Different types of lipids had varying effects on cognitive function. Higher total cholesterol (TC) (β = 0.125, p = 0.008), low density lipoprotein-cholesterol (LDL-C) (β = 0.086, p = 0.025), and ApoB (β = 0.092, p = 0.026) were associated with more significant brain structural abnormalities. Conversely, triglyceride (TG) = 0.75∼8.0 mmol/L was positively correlated with cognitive function (β = -0.036, p < 0.001; β = -0.044, p < 0.001; β = 0.058, p = 0.001), and higher ApoA (β = -0.032, p < 0.001; β = -0.033, p < 0.001; β = 0.047, p = 0.004) was associated with better cognitive function. The age-stratified analysis revealed that the impact of lipids on cognitive function was age-dependent. TC and LDL-C were related to brain structural abnormalities in the 55-60 age group, while TG had a stronger protective effect on cognitive function in older adults, particularly those aged 65-70 years. In people with diabetes, higher HbA1c (>8.5 %), as well as elevated TC, LDL-C, and ApoB, are associated with worse brain structure and cognitive function. Conversely, HbA1c < 6.5 % and elevated TG within the range of 0.75∼8.0 mmol/L have a protective effect on cognitive function, and the later exhibited more evident impact in older adults. To prevent or delay the onset of dementia in people with diabetes, it may be necessary to intensify glycemic control, targeting an HbA1c level of <6.5 %. Additionally, the age-specific lipid-lowering strategies shall be considered, with more flexible triglyceride-lowering goals for elderly patients. 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

The concurrent rise of childhood obesity and hyperuricemia presents a serious public health concern. These conditions interact through complex metabolic mechanisms and significantly increase long-term risks of cardiometabolic diseases. Machine learning (ML) offers an effective framework for constructing efficient risk prediction models in pediatric populations. This study aimed to develop and evaluate two ML models-Random Forest (RF) and Support Vector Classification (SVC)-to predict the risk of childhood obesity and hyperuricemia by integrating clinical and biochemical variables. A total of 101 children were enrolled, including 60 with obesity and 41 with obesity plus hyperuricemia. Data preprocessing involved recursive feature elimination (RFE), ROSE-based oversampling, and feature standardization. Both RF and SVC models were trained and evaluated using area under the ROC curve (AUC), precision-recall curves, and calibration curves. SHAP (Shapley Additive Explanations) analysis was conducted to interpret feature contributions. Both models demonstrated strong predictive performance, with AUCs reaching 0.96. The SVC model achieved slightly higher average precision and recall, making it more suitable for community- or school-based screening of high-risk children. In contrast, the RF model exhibited superior calibration, suggesting its greater utility in clinical decision-making where probabilistic risk estimation guides personalized follow-up or intervention planning. SHAP analysis identified glomerular filtration rate (GFR), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) as key predictors, some exhibiting nonlinear associations with disease risk. RF and SVC models offer reliable tools for early risk prediction of obesity and hyperuricemia in children, each tailored to distinct clinical scenarios. These findings support early identification and targeted intervention. Future studies will explore the integration of metabolomic data and ensemble approaches to further enhance model performance and clinical applicability. 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

To investigate whether the systemic inflammatory response against inflammatory conditions in the periodontium is related to serum apolipoprotein B (ApoB) and A1 (ApoA1) concentrations. The study consisted of the Health 2000 Survey participants (n = 2709) aged 30-49 years. The inflammatory condition of the periodontium was assessed by means of the number of teeth with deepened (≥ 4 mm) and deep (≥ 6 mm) periodontal pockets. Systemic inflammation was measured by serum C-reactive protein (CRP) levels. The role of ApoB and ApoA1 was studied by performing regression analyses and stratified analyses (according to the median values). In logistic regression analyses, the number of teeth with deepened (≥ 4 mm) periodontal pockets was associated with serum CRP levels among those participants whose serum ApoB concentration was ≥ 1.12 g/L. When the participants' ApoB concentration was < 1.12 g/L, such an association between deepened periodontal pockets and CRP was not observed. The direction or strength of the association between periodontal pockets and CRP was not essentially different in the ApoA1 strata. Systemic response against poor periodontal condition varied between individuals. The variation appeared to be related more to the serum concentration of ApoB than ApoA1. 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

A fibre rich diet is linked to a healthier cardiometabolic profile and may promote fatty acid oxidation to lower acylcarnitine accumulation. This study aimed to determine whether total dietary fibre intake was related to cardiometabolic risk markers as well as acylcarnitine levels in apparently healthy adults, which concurrently may be related to blood pressure (BP). This study included 983 adults from the African-PREDICT study (aged 24 ± 3 years). Total fibre intake was determined using 24-hr dietary recalls, and 24-hr ambulatory BP was measured. Acylcarnitines were analysed in spot urine samples using liquid chromatography-tandem mass spectrometry-based metabolomics. Lower dietary fibre intake was related to a higher waist circumference (WC) and body mass index (BMI) as well as higher total cholesterol, low-density lipoprotein-cholesterol (LDL-C), triglycerides, Apo-lipoprotein-B, C-reactive protein (CRP), free carnitine, and short-chain acylcarnitine (C2-, C4- and C5-carnitine) levels (all p trend <0.05). Concurrently, all traditional cardiometabolic risk markers (WC, BMI, total cholesterol, LDL-C, triglycerides, Apo-B, and CRP) correlated positively with 24-hr BP. In multiple regression analyses, 24-hr SBP was associated with WC (β = 0.44; p < 0.001) and total energy intake (β = 0.096; p = 0.002), while 24-hr DBP was associated with WC (β = 0.283; p < 0.001), triglyceride levels (β = 0.085 p = 0.008), dietary fibre intake (β = -0.120; p < 0.001) and total energy intake (β = 0.128; p < 0.001). There was no relationship between acylcarnitine levels and 24-hr BP. We demonstrate that participants consuming a higher fibre diet had a more favourable metabolic profile than those consuming a low fibre diet, which was ultimately associated with lower BP. 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

Maternal circulating lipid concentrations impact the risk of pregnancy complications and infant health outcomes. The associations between physical activity and circulating lipids during pregnancy remain inadequately understood. A study was conducted from July 2024 to March 2025, involving the recruitment of 520 pregnant women in Wuhan, China. The Pregnancy Physical Activity Questionnaire (PPAQ) scores were evaluated in trimesters. Circulating lipid profiles, including total triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), apolipoprotein A1 (APOA1) and apolipoprotein B (APOB) concentrations, were assessed at each trimester. The daily energy expenditure of physical activity (EEPA) during the first, second, and third trimesters was recorded as 11.35, 9.07, and 9.48 metabolic equivalents-hour/day (METs-h/d). The EEPA in the first trimester was significantly greater than that in the second ( This study suggests that increased physical activity during pregnancy is associated with lower lipid levels. Moreover, maternal age appears to have a significant impact on physical activity and the metabolism of circulating lipids during pregnancy. 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

This study evaluated the efficacy and safety of tafolecimab in patients with type 2 diabetes (T2D) and hypercholesterolemia by a post-hoc analysis of pooled data from three phase 3 trials. Data from up to 12 weeks were analyzed to assess the effects of tafolecimab 450 mg every four weeks (Q4W) in patients with T2D and hypercholesterolemia. The primary endpoint was the percentage change in low-density lipoprotein cholesterol (LDL-C) levels from baseline to week 12. Secondary endpoints included the proportion of participants achieving LDL-C levels below 1.8 mmol/L at weeks 12, the proportion of patients achieving LDL-C ≥ 50% reduction and LDL-C < 1.4 mmol/L, as well as percentage changes from baseline to week 12 in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apo B), lipoprotein(a) [Lp(a)], and triglyceride (TG) levels. The reduction in LDL-C from baseline was significantly greater in patients receiving tafolecimab than in those receiving placebo (estimated treatment difference: - 64.02%, 95% confidence interval: [- 68.08%, - 59.96%], P < 0.0001). The proportion of patients achieving a reduction of over 50% and an absolute LDL-C value below 1.4 mmol/L was significantly higher in the tafolecimab group than that in the placebo group (P < 0.0001). Furthermore, a significantly greater proportion of patients in the tafolecimab group achieved LDL-C levels below 1.8 mmol/L at week 12 compared to the placebo group (P < 0.0001). The tafolecimab group also showed significant reductions in TG, non-HDL-C, apo B, and Lp(a) from baseline to week 12 compared to the placebo group (all P < 0.001). The incidence of adverse events was generally similar between the two groups. Tafolecimab 450 mg Q4W demonstrated a superior lipid-lowering efficacy and favorable safety profile compared to placebo. This suggests it could be a promising new treatment option for Chinese patients with T2D and hypercholesterolemia. 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

This study aimed to (1) evaluate small dense low-density lipoprotein cholesterol (sdLDL-C) dynamics from prediabetes to type 2 diabetes mellitus (T2DM) with complications, (2) validate existing sdLDL-C estimation formulas (Sampson’s, Srisawasdi’s, Han’s) in Chinese populations, and (3) develop a population-specific formula for enhanced accuracy. A multicenter study recruited 1,944 participants (216 controls, 70 with prediabetes, 212 with newly diagnosed T2DM, 164 with treated T2DM, and 1,286 in validation cohorts). Lipid profiles, including sdLDL-C (measured via enzymatic assays), were analyzed. Formula performance was assessed using spearman correlation, intraclass correlation coefficients (ICC), and multivariable linear regression. A novel formula was derived via multivariable regression. Atherogenic lipid triad manifestations emerged early: sdLDL-C was significantly elevated in participants with prediabetes (1.07 [0.73, 1.40] vs. 0.57 [0.44, 0.72] mmol/L in controls, P < 0.05) and further increased in those with T2DM, correlating strongly with triglycerides (TG; sdLDL-C elevation begins in prediabetes, highlighting its value for early atherosclerotic cardiovascular disease (ASCVD) risk assessment. Current formulas show population-specific limitations, whereas the new model provides improved accuracy for Chinese T2DM patients, enabling cost-effective sdLDL-C estimation and personalized lipid management. The online version contains supplementary material available at 10.1186/s12944-025-02636-0. Show less

This study aimed to elucidate the correlations among dyslipidemia, immune function, and clinical outcomes in patients with acute-on-chronic liver failure (ACLF), with particular emphasis on the clinical significance of lipid metabolism and cellular immune parameters in hepatitis B virus-associated ACLF (HBV-ACLF). A retrospective analysis was conducted on 803 patients with HBV-ACLF admitted to the Shanghai Public Health Clinical Center from January 2014 to January 2024. Patients were stratified into deceased (n = 414) and survival (n = 389) groups based on clinical outcomes. Clinical baseline data, lipid metabolic indices, and cellular immune parameters were collected. The Spearman correlation coefficient was utilized to assess the correlation between lipid metabolic indices and cellular immune parameters, and a multivariate Cox proportional hazards model was applied to analyze risk factors for mortality. Compared to the survival group, lipid metabolism indices in the deceased group were significantly reduced (P < 0.05). Lipid metabolism indices, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (APOA1), apolipoprotein B (APOB), total cholesterol (TC), and triglycerides (TG), demonstrated significant negative correlations with the severity of liver failure (P < 0.05). Correlation analysis with lymphocyte subset counts revealed positive correlations between low-density lipoprotein, TG, TC, APOB, and CD3 + T cells, CD4 + T cells, CD8 + T cells, and CD45 + T cells (P < 0.05). APOA1 and HDL-C were positively correlated with B cells and NK cells (P < 0.05). TG and APOB showed significant negative correlations with the CD4/CD8 ratio (P < 0.05). Multivariate Cox analysis identified age, creatinine, total bilirubin, international normalized ratio (INR), hepatic encephalopathy, and hepatorenal syndrome as independent risk factors affecting the short-term prognosis of HBV-ACLF, while sodium, APOA1, and APOB were identified as independent protective factors for ACLF (HR = 0.984, 95% CI: 0.974-0.995, P < 0.001, HR = 0.267,95% CI: 0.120-0.596, P = 0.001, HR = 0.486, 95% CI: 0.282-0.838, P = 0.010). Patients with HBV-ACLF exhibit decreased levels of TC, TG, LDL-C, HDL-C, APOA1, and APOB. These alterations in serum lipid profiles are associated with immune dysfunction and disease progression in HBV-ACLF. Notably, APOA1 and APOB serve as protective factors against 90-day mortality in hospitalized ACLF patients. Further investigation is warranted to elucidate the relationship between lipid metabolism disturbances and peripheral immunity in ACLF. Show less

Pentadecanoic acid (PEA), an odd-chain fatty acid derived from diet by the gut microbiome, has garnered increasing attention for its systemic health-promoting properties. Its potential role in bladder cancer (BC) occurrence and invasion, however, remains unclear. Large-scale cohorts' analyses were performed to assess the association between dietary PEA and BC occurrence and invasion. In vitro and in vivo experiments, including EJ and T24 BC cell assays and a BBN-induced mouse model, were conducted to experimentally assess the impact of PEA on BC. Serum proteomics, gut microbiome, and targeted fecal lipidomics analyses were employed to explore the underlying mechanisms. Dietary PEA was negatively associated with BC occurrence and invasion in cohort analyses. PEA suppressed EJ and T24 BC cell migration, invasion, and proliferation, while inhibiting BC development in a BBN-induced mouse model. In vivo serum proteomics identified differentially expressed lipid-related proteins (e.g., Apoe and Apob) following PEA treatment, implicating its modulation of lipid metabolism pathways. Considering the essential role of the gut-bladder axis, the gut microbiome analysis exhibited that PEA markedly altered bacteria (e.g., g_Alistipes) and fungi (e.g., o_Erysiphales, g_Teberdinia, and g_Gibberella), with concomitant lipid metabolism changes. Furthermore, targeted fecal lipidomics demonstrated the shifts in key lipids, such as phosphatidylethanolamines (PE) involved in essential lipid clusters, suggesting regulation by gut microbiome linked to BC development. Collectively, our findings demonstrate that PEA mitigates BC by reshaping the gut microbiome and modulating lipid metabolism, providing new insights into its molecular and therapeutic potential. Show less

Genome-wide association studies (GWAS) are rapidly advancing due to the improved resolution and completeness provided by Telomere-to-Telomere (T2T) and pangenome assemblies. While recent advancements in GWAS methods have primarily focused on identifying genetic variants associated with discrete phenotypes, approaches for quantitative traits (QTs) remain underdeveloped. This has often led to significant variants being overlooked due to biases from genotype multicollinearity and strict p-value thresholds. We propose an enhanced ensemble learning approach for QT analysis that integrates regularized variant selection with machine learning-based association methods, validated through comprehensive biological enrichment analysis. We benchmarked four widely recognized single nucleotide polymorphism (SNP) feature selection methods-least absolute shrinkage and selection operator, ridge regression, elastic-net, and mutual information-alongside four association methods: linear regression, random forest, support vector regression (SVR), and XGBoost. Our approach is evaluated on simulated datasets and validated using a subset of the PennCATH real dataset, including imputed versions, focusing on low-density lipoprotein (LDL)-cholesterol levels as a QT. The combination of elastic-net with SVR outperformed other methods across all datasets. Functional annotation of top 100 SNPs identified through this superior ensemble method revealed their expression in tissues involved in LDL cholesterol regulation. We also confirmed the involvement of six known genes (APOB, TRAPPC9, RAB2A, CCL24, FCHO2, and EEPD1) in cholesterol-related pathways and identified potential drug targets, including APOB, PTK2B, and PTPN12. In conclusion, our ensemble learning approach effectively identifies variants associated with QTs, and we expect its performance to improve further with the integration of T2T and pangenome references in future GWAS. Show less