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Apolipoproteins as an integral part of lipoproteins are crucial for the transport and metabolism of lipids. However, there is a lack of longitudinal studies to quantify the concentrations of maternal apolipoproteins from preconception to postpartum and their associations with maternal metabolic health and offspring birth outcomes. Quantification of apolipoproteins was performed on maternal plasma samples (N = 243 trios) collected at preconception, 26-28 weeks' pregnancy, and three months postpartum in the Singapore PREconception Study of long-Term maternal and child Outcomes (S-PRESTO) cohort study. Linear regression models and network analysis were implemented to investigate the association of apolipoproteins with maternal genetic variants, biochemical measures, metabolic risk factors, and offspring birth outcomes. The concentrations of ApoC-III, ApoB and ApoL1 substantially increased in pregnancy compared to preconception and postpartum. Genome-wide association studies (GWAS) identified multiple single-nucleotide polymorphisms (SNPs) associated with plasma apolipoproteins (P < 5.00E-08), including APOE-rs7412 for ApoE, LPA-rs56393506 for Apo(a), APOM-rs707921 for ApoM, ABCC4-rs117797426 for ApoJ, THSD7B-rs575613 for ApoA-II, and LOC102724443-rs140433245 for ApoA-IV. Plasma apolipoproteins were strongly associated with biochemical measures including lipidomic profiles, lipoprotein features and fat-soluble vitamins, as well as metabolic risk factors including glycaemic traits, liver enzymes, inflammatory markers, albumin, and blood pressure. Integrative network analysis of apolipoproteins and their correlates/determinants revealed both shared and specific associations, with the strongest relationships observed among apolipoproteins, cholesterol, triglycerides, alpha tocopherol, and GlycA (P We describe the longitudinal landscape of maternal circulating apolipoproteins from preconception to postpartum and their associations with maternal metabolic risk factors and offspring birth outcomes. This multi-omics characterisation of biochemical correlates and genetic determinants of maternal apolipoproteins will deepen our understanding of the molecular basis of metabolic flexibility in expectant mothers, leading to better assessment of pregnancy-related outcomes. This research was supported by the Singapore National Research Foundation under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health's National Medical Research Council (NMRC), Singapore- NMRC/TCR/004-NUS/2008; NMRC/TCR/012-NUHS/2014. The Singapore Lipidomics Incubator (SLING) is supported by grants from the National University of Singapore via the Life Sciences Institute, the National Research Foundation (NRF, NRFI2015-05 and NRFSBP-P4) and A∗STAR IAF-ICP I1901E0040. Additional funding is provided by Institute for Human Development and Potential (IHDP)-Agency for Science, Technology and Research (A∗STAR), Singapore. Show less

This study aims to evaluate the relationship between apolipoproteins (ApoA1, ApoB, and the ApoB/A1 ratio) and the incidence of major adverse cardiovascular events (MACE) in patients with coronary artery disease (CAD) and impaired kidney function, assessing their potential role in secondary prevention. A prospective cohort of 1,640 patients with impaired kidney function who underwent percutaneous coronary intervention in China was analyzed. Patients were categorized based on the measurements of ApoA1, ApoB, and ApoB/A1 ratio. MACE, defined as a composite of all-cause mortality, cardiovascular death, nonfatal myocardial infarctions, strokes, and unplanned revascularizations, was tracked post-procedure, with statistical analyses including Kaplan-Meier survival curves and Cox regression models to identify associations with apolipoproteins. Subgroup analyses according to kidney function were conducted. During a median follow-up of 3.1 years, 324 MACE events were observed. Multivariable Cox regression analyses illustrated higher levels of ApoB and the ApoB/A1 ratio were significantly associated with increased MACE incidence (adjusted HR [95%CI] 1.668[1.044-2.666]; adjusted HR [95%CI] 2.231[1.409-3.533], respectively), while lower ApoA1 levels correlated with a higher risk (adjusted HR [95%CI] 0.505[0.326-0.782]). ROC curve analyses indicated comparable predictive performances to traditional risk factors like LDL cholesterol. Subgroup analysis revealed that the above association was not statistically significant in the moderate-to-severe renal impairment CAD patients (eGFR < 45 mL/min/1.73 m Our findings illustrate that apolipoproteins, specifically ApoA1 and ApoB, along with their ratio, are significant predictors of major adverse cardiovascular events in CAD patients with impaired kidney function. These results emphasize the need for incorporating apolipoprotein measurements in secondary prevention strategies for this high-risk population. Show less

Treatment to lower high levels of low-density lipoprotein cholesterol (LDL-C) reduces incident coronary artery disease (CAD) risk but modestly increases the risk for incident type 2 diabetes (T2D). The extent to which genetic factors across the cholesterol spectrum are associated with incident T2D is not well understood. To investigate the association of genetic predisposition to increased LDL-C levels with incident T2D risk. In this large prospective, population-based cohort study, UK Biobank participants who underwent whole-exome sequencing and genome-wide genotyping were included. Participants were separated into 7 groups with familial hypercholesterolemia (FH), predicted loss of function (pLOF) in APOB or PCSK9 variants, and LDL-C polygenic risk score (PRS) quintiles. Data were collected between 2006 and 2010, with a median follow-up of 13.7 (IQR, 12.9-14.5) years. Data were analyzed from March 1 to November 1, 2024. LDL-C level, LDL-C PRS, FH, or pLOF variant status. Cox proportional hazards regression models adjusted for age, sex, genotyping array, lipid-lowering medication use, and the first 10 genetic principal components were fitted to assess the association between LDL-C genetic factors and incident T2D and CAD risks. Among the 361 082 participants, mean (SD) age was 56.8 (8.0) years, 194 751 (53.9%) were female, and mean (SD) baseline LDL-C level was 138.0 (33.6) mg/dL. During the follow-up period, 22 619 (6.3%) participants developed incident T2D and 17 966 (5.0%) developed incident CAD. The hazard ratio for incident T2D was lowest in the FH group (0.65; 95% CI, 0.54-0.77), while the highest risk was in the pLOF group (1.48; 95% CI, 1.18-1.86). The association between LDL-C PRS and incident T2D was 0.72 (95% CI, 0.66-0.79) for very high LDL-C PRS, 0.87 (95% CI, 0.84-0.90) for high LDL-C PRS, 1.13 (95% CI, 1.09-1.17) for low LDL-C PRS, and 1.26 (95% CI, 1.15-1.38) for very low LDL-C PRS. CAD risk increased directly with the LDL-C PRS. In this cohort study, LDL-C and T2D risks were inversely associated across genetic mechanisms for LDL-C variation. Further elucidation of the mechanisms associating low LDL-C risk with increased risk of T2D is warranted. Show less

This study investigates the relationship between serum homocysteine, blood lipids, and perinatal outcomes in patients with diet-controlled gestational diabetes mellitus (GDM) and those with normal glucose tolerance (NGT). A prospective cohort of 150 diet-controlled GDM patients and 150 pregnant women with NGT, all delivering at our hospital, were selected based on predefined criteria. Data on demographics, physical parameters, and perinatal outcomes were compiled. Blood samples for fasting plasma glucose (FPG), homocysteine (Hcy), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apoB), and apolipoprotein A1 (apoA1) were collected before delivery. GDM patients exhibited higher levels of FPG, Hcy, and the apoB/apoA1 ratio, but lower HDL-C and apoA1 levels compared to the NGT group. Adverse outcomes such as macrosomia, premature rupture of membranes, and postpartum hemorrhage were more prevalent in the GDM group. In GDM patients, neonatal birth weight positively correlated with FPG and TG levels. Stratified Hcy analysis in GDM showed no significant differences in perinatal outcomes. However, the third quartile of the apoB/apoA1 ratio had a lower incidence of macrosomia compared to the first quartile, and the second quartile showed a higher incidence of birth asphyxia. GDM patients demonstrated increased levels of Hcy, FPG, and the apoB/apoA1 ratio, correlating with more adverse perinatal outcomes than healthy pregnant individuals. The relationships between Hcy, lipids, and these outcomes remain inconclusive, highlighting the need for further research. Show less

Familial hyperlipidemia (familial hypercholesterolemia, FH) is an autosomal genetic disorder. It includes type heterozygous familial hyperlipidemia (heterozygous familial hypercholesterolemia). HeFH is mainly caused by mutations in the LDLR, APOB, and PCSK9 genes and is characterized by elevated plasma low-density lipoprotein cholesterol levels. We present a case of HeFH attributed to an APOB gene mutation. The whole-genome DNA of peripheral blood was extracted from the blood of the proband and their parents, and the exons of peripheral blood were sequenced through high-throughput sequencing. The selected mutation sites were verified by sequencing using the Sanger method. A heterozygous mutation, c.6551A>G (p.Y2184C), in exon 26 of the APOB gene (Chr2-21233189) was identified in both the proband and the mother. Combined with the clinical features, HeFH caused by this mutation was initially considered. For patients with a high degree of clinical suspicion of FH, a definitive diagnosis should be established through genetic testing, enabling patients to receive early treatment and effectively prevent the occurrence of cardiovascular events. Show less

Familial hypercholesterolemia (FH) and other disorders with similar features are common genetic disorders that remain underdiagnosed and undertreated, due in part to the cost of screening. The aim of this study was to design and implement a whole gene targeted NGS panel for the molecular diagnosis of FH and statin intolerance with an emphasis on high quality variant calling, including copy number analysis. A whole gene panel for hybridisation-based short read NGS was designed for the dominant FH-genes low density lipoprotein receptor ( The panel sequencing resulted in high coverage and confident variant calling of included genes. Known causal variants were found in common dominant FH-genes in 43 % of the cohort. Copy number variants were found in This new tool can be used for a comprehensive high-quality molecular genetic analysis according to guidelines for the diagnosis and treatment of FH. Show less

In preliminary research and literature review, we identified a potential link between chronic obstructive pulmonary disease (COPD) and lipid metabolism. Therefore, this study employed Mendelian randomization (MR) analysis to investigate the potential causal connection between blood lipids and COPD. A genome-wide association study (GWAS) on COPD was conducted, encompassing a total of 112,583 European participants from the MRC-IEU. Additionally, extensive UK Biobank data pertaining to blood lipid profiles within European cohorts included measurements for low-density lipoprotein cholesterol (LDL-C) with 440,546 individuals, high-density lipoprotein cholesterol (HDL-C) with 403,943 individuals, triglycerides (TG) with 441,016 individuals, total cholesterol (TC) with 187,365 individuals, apolipoprotein A-I (apoA-I) with 393,193 individuals, and apolipoprotein B (apoB) with 439,214 individuals. Then, MR analyses were performed for lipids and COPD, respectively. The primary analytical technique employed was the inverse-variance weighted (IVW) approach, which included a 95% confidence interval (CI) to calculate the odds ratio (OR). Additionally, a sensitivity analysis was conducted to assess the dependability of the MR analysis outcomes. MR analysis was primarily based on IVW, unveiled a causal link between COPD and LDL-C (OR=0.994, 95% CI (0.989, 0.999), P=0.019), TG (OR=1.005, 95% CI (1.002, 1.009), P=0.006), and apoA-I (OR=0.995, 95% CI (0.992, 0.999), P=0.008), in addition, no causal link was found with HDL-C, TC, apoB. Sensitivity analysis demonstrated the robustness of these causal relationships. However, through multivariate MR(MVMR) and multiple testing correction, LDL-C and TG had no causal effect on the outcome. ApoA-I remained a protective factor for the risk of COPD (OR=0.994, 95% CI (0.990-0.999), P=0.008). Through MR analysis, this study offers evidence of a causal link between apoA-I with COPD. This further substantiates the potential role of lipid metabolism in COPD, and has significant clinical implications for the prevention and management of COPD. Show less

High apolipoprotein B-containing (apoB-containing) low-density lipoproteins (LDLs) and low apoA1-containing high-density lipoproteins (HDLs) are associated with atherosclerotic cardiovascular diseases. In search of a molecular regulator that could simultaneously and reciprocally control both LDL and HDL levels, we screened a microRNA (miR) library using human hepatoma Huh-7 cells. We identified miR-541-3p that both significantly decreases apoB and increases apoA1 expression by inducing mRNA degradation of 2 different transcription factors, Znf101 and Casz1. We found that Znf101 enhances apoB expression, while Casz1 represses apoA1 expression. The hepatic knockdown of Casz1 in mice increased plasma apoA1, HDL, and cholesterol efflux capacity. The hepatic knockdown of Zfp961, an ortholog of Znf101, reduced lipogenesis and production of triglyceride-rich lipoproteins and atherosclerosis, without causing hepatic lipid accumulation. This study identifies hepatic Znf101/Zfp961 and Casz1 as potential therapeutic targets to alter plasma lipoproteins and reduce atherosclerosis without causing liver steatosis. Show less

Evidence have indicated relation between apolipoproteins and neurodegenerative disorders (NDDs). However, previous studies have produced inconsistent results, and a comprehensive analysis of apolipoproteins in NDDs is currently lacking. Using Cox proportional hazards regression analysis based on data from UK Biobank, we examined the association between baseline serum levels of apolipoprotein A (ApoA) and apolipoprotein B (ApoB) and risk of Parkinson's disease (PD), Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and multiple sclerosis. Elevated baseline levels of serum ApoA (HR = 0.84, 95 % CI: 0.71-0.99, P = 0.047) and ApoB (HR = 0.67, 95 % CI: 0.57-0.78, P = 3.18E-07) were associated with a reduced risk of incident PD. Subgroup analyses suggested the protective effect of serum ApoA was more significant for older participants and those with lower alcohol consumption, while higher serum ApoB was a more significant protective factor in males and those without stroke. No significant associations were found between apolipoproteins and other NDDs. Increased baseline levels of serum ApoA and ApoB are linked to a lower risk of PD. These findings enhance understanding of the role of apolipoproteins in PD, and have implications for the development of therapeutic strategies in clinical trials. Show less

Major depressive disorder (MDD) and bipolar disorder (BD) often coexist with metabolic syndrome. Both are linked to increased atherogenicity and a higher risk of cardiovascular diseases. Nevertheless, a comprehensive analysis of key atherogenic biomarkers in MDD/BD is still lacking. This meta-analysis evaluates the relationship between atherogenic indices and MDD/BD, while identifying the most effective atherogenic biomarker. This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched electronic databases, including PubMed, Google Scholar, and Web of Science, for articles published up to August 1, 2024. We included 85 eligible studies (14 on BD and 71 on MDD), covering 70,856 participants: 18,738 patients and 52,118 healthy controls. MDD/BD patients showed significant increases (p < 0.001) in the Castelli Risk Index 2 (CRI2), Atherogenic Index of Plasma (AIP), and (triglyceride or TG + low-density lipoprotein + very low-density lipoprotein)/(high-density lipoprotein cholesterol or HDL + Apolipoprotein A or ApoA) ratio, but not CRI1 and ApoB/ApoA ratio. Significant lower HDL and lecithin: cholesterol acyltransferase activity, and higher TG levels were observed in MDD/BD patients compared with controls. There were no significant differences between MDD and BD patients. Most included studies lacked the most essential information on the inclusion and exclusion of important confounders. AIP is the most effective atherogenicity index for mood disorders. Regular lipid profiling and metabolic syndrome screening are crucial in MDD/BD. Early intervention with lipid-lowering therapies is recommended to prevent the worsening of atherogenicity and disease progression. Show less

At present, there is no consensus on the relationship between selenium (Se) exposure and human serum lipid metabolism. The etiological role of high-Se exposure in lipid markers, dyslipidemia, and nonalcoholic fatty liver (NAFLD) remains unclear. We used serum untargeted metabolomics analysis to evaluate whether high-Se exposure is cross-sectionally associated with lipid metabolism in adults from high-Se exposure area (n = 112) and control area (n = 101) in Hubei Province, China. An untargeted liquid chromatography/mass spectrometry (LC/MS)-based metabolomic analysis identified 144 differential pathways and yielded 204 differentially abundant metabolites, including 32 lipid metabolites associated with lipids profiles. To further explore the correlation between Se exposure and serum lipid metabolism, we measured serum levels of lipid profiles among all the people, including serum cholesterol (CHOL), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (APOB). The average serum Se level of the high-Se exposure group was 537.18 μg/L, significantly higher than 72.98 μg/L in the control group (p < 0.0001). The measurement levels of serum TG, LDL-C, HDL-C, and APOB in the high-Se exposure group were 1.03 (0.76, 1.34) mmol/L, 2.25 ± 0.48 mmol/L, 1.12 ± 0.24 mmol/L, and 0.77 ± 0.15 g/L, respectively, while the control group were 1.13 (0.84, 1.80) mmol/L, 2.56 ± 0.61 mmol/L, 1.02 ± 0.22 mmol/L, and 0.83 ± 0.16 g/L, respectively (all p values <0.05). Correlation analysis showed a significant negative correlation between serum Se and CHOL (r = -0.201, p < 0.01), serum Se is also associated with metabolomics markers, the negative correlation includes glyceric acid and ect., the positive correlation includes phosphorylcholine and ect. Our study suggests that high-Se exposure is negatively associated with serum lipid profiles and decreases the risk of high-TC and HDL-C dyslipidemia. Show less

To investigate serum lipid profile in early, treatment-naïve psoriatic arthritis (PsA) and to determine whether changes in classical lipids or apolipoproteins are specific to PsA. Total cholesterol, non-high-density lipoprotein cholesterol (non-HDL-c), low-density lipoprotein cholesterol (LDL-c), HDL-c, triglycerides, apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1) were compared in newly diagnosed untreated PsA patients (n=75) to sex- and age-matched controls (healthy control (HC)) (n=61) and early untreated rheumatoid arthritis (RA) patients (n=50). Among classical lipid measurements, HDL-c levels were lower in PsA than in HC and RA (df 2, χ Early, treatment-naïve PsA patients exhibit a distinct pro-atherogenic lipid profile, characterised by decreased ApoA1 and increased ApoB levels, distinguishing them from early RA patients and healthy controls. These findings highlight the potential of apolipoprotein measurements to serve as more accurate indicators of lipid disturbances in PsA than traditional serum lipids and as aid to diagnosis of patients presenting with early arthritis. Show less

The existing evidence regarding the impact of tamoxifen on lipoprotein(a) and apolipoproteins remains inconsistent. Therefore, this updated meta-analysis of randomized controlled trials (RCTs) aims to enhance the quality of evidence concerning the effects of tamoxifen on these lipid parameters. Eligible RCTs published up to October 2024 were meticulously selected through a comprehensive search. A meta-analysis was then performed using a random-effects model, and results were presented as the weighted mean difference (WMD) with a 95% confidence interval (CI). Findings from the random-effects model revealed an increase in ApoA-I (WMD: 15.22 mg/dL, 95% CI: 6.43-24.01, P = 0.001), alongside decreases in ApoB (WMD: -9.33 mg/dL, 95% CI: -15.46 to -3.19, P = 0.003) and lipoprotein(a) (WMD: -3.35 mg/dL, 95% CI: -5.78 to -0.91, P = 0.007) levels following tamoxifen treatment in women. Subgroup analyses indicated a more significant reduction in lipoprotein(a) levels in RCTs with a duration of ≤24 weeks (WMD: -3.65 mg/dL) and in studies using tamoxifen doses of ≥20 mg/day (WMD: -4.53 mg/dL). This meta-analysis provides evidence that tamoxifen leads to a decrease in lipoprotein(a) levels, along with reductions in ApoB and increases in ApoA-I among women. Show less

Percutaneous coronary intervention (PCI) is a practical and effective method for treating coronary heart disease (CHD). This study aims to explore the influencing factors of major cardiovascular events (MACEs) and hospital readmission risk within one year following PCI treatment. Additionally, it seeks to assess the clinical value of Apolipoprotein B/Apolipoprotein A-I (ApoB/ApoA-I) in predicting the risk of one-year MACEs and readmission post-PCI. A retrospective study included 1938 patients who underwent PCI treatment from January 2010 to December 2018 at Shandong Provincial Hospital affiliated with Shandong First Medical University. Patient demographics, medications, and biochemical indicators were recorded upon admission, with one-year follow-up post-operation. Univariate and multivariate Cox proportional hazards regression models were utilized to establish the relationship between ApoB/ApoA-I levels and MACEs/readmission. Predictive nomograms were constructed to forecast MACEs and readmission, with the accuracy of the nomograms assessed using the concordance index. Subgroup analyses were conducted to explore the occurrence of MACEs and readmission. We observed a correlation between ApoB/ApoA-I and other lipid indices, including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) (P < 0.001). Univariate and multivariate Cox regression analyses demonstrated that ApoB/ApoA-I is an independent risk factor for MACEs in post-PCI patients (P = 0.038). Within one year, the incidence of MACEs significantly increased in the high-level ApoB/ApoA-I group (ApoB/ApoA-I ratio ≥ 0.824) (P = 0.038), while the increase in readmission incidence within one year was not statistically significant. Furthermore, a nomogram predicting one-year MACEs was established (Concordance Index: 0.668). Subgroup analysis revealed that ApoB/ApoA-I was associated with the occurrence of both MACEs and readmission in male patients, those using CCB/ARB/ACEI, those without multivessel diseases, or those with LDL-C < 2.6 mmol/L. The ApoB/ApoA-I ratio serves as an independent risk factor for one-year MACEs in post-PCI patients and correlates closely with other blood lipid indicators. ApoB/ApoA-I demonstrates significant predictive value for the occurrence of MACEs within one year.Trial registration Chinese clinical trial registry: No.ChiCTR22000597-23. Show less

Atherosclerotic cardiovascular disease (ASCVD) is a major threat to human life and health, and dyslipidemia with elevated low-density lipoprotein cholesterol (LDL-C) is an important risk factor, and in the optimal LDL-C scenario, apolipoprotein B (ApoB) has a more predictive value of ASCVD risk. The study is a genome-wide association study (GWAS) based on a European population. A large GWAS dataset for atherosclerotic cardiovascular diseases was targeted, including coronary heart disease (CHD), ischemic stroke (IS), large-artery atherosclerotic stroke (ISL), small-vessel stroke (ISS), and myocardial infarction (MI). Univariate two-sample mendelian randomization (MR) analyses of ApoB and the above cardiovascular diseases were performed separately, and the association was assessed mainly using the inverse variance weighted (IVW) method, with confidence intervals for the superiority ratios set at 95%. In addition, the experiment was supplemented using MR-Egger, weighted model and weighted median (WM). Based on the results of univariate two-sample mendelian randomisation analysis, it was shown that there was a causal relationship between ApoB and CHD (OR = 1.710, 95% CI 1.529-1.912, P = 0.010), ISL (OR = 1.430, 95% CI 1.231-1.661, P = 2.714E-06), ISS (OR = 1.221, 95% CI 1.062-1.405, P = 0.005) were causally related to each other and the disease prevalence ratio was positively correlated with ApoB concentration. This MR analysis demonstrated a causal relationship between ApoB and CHD, ISL, ISS, but not with the risk of developing IS and MI, which further validated the relationship between ApoB and the risk of ASCVD, and contributed to a better understanding of the genetic impact of ApoB on ASCVD, and to a certain extent, could improve the management of ApoB and reduce the prevalence of ASCVD. Show less

Apolipoprotein B (apoB) distribution and its implications as an atherosclerotic cardiovascular disease (ASCVD) risk-enhancing factor among individuals of diverse Hispanic or Latino backgrounds have not been described. To describe the distribution of apoB in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort and to characterize associations of baseline sociodemographic and clinical variables with apoB and self-identified Hispanic or Latino background. The HCHS/SOL was a prospective, population-based cohort study of diverse Hispanic or Latino adults living in the US who were recruited and screened between March 2008 and June 2011. Sampling weights were used to generate a population-based sample of Hispanic or Latino participants aged 18 to 74 years who resided in 4 US metropolitan areas (Bronx, New York; Chicago, Illinois; Miami, Florida; and San Diego, California). ApoB concentration was measured in participants from the HCHS/SOL, and apoB tertiles were compared across demographic groups, including self-identified Hispanic or Latino background. Median percentage continental genetic ancestry (West African, Amerindian, and European) was compared across apoB tertiles. ApoB measured in mg/dL from serum or plasma using an immunoturbidimetric assay. ApoB tertiles were determined, and traditional lipids were evaluated across apoB tertiles. ApoB and traditional lipid measurements were assessed across ASCVD risk categories. Additionally, scatterplots were created to observe correlations between apoB and low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol. Overall mean (SD) apoB concentration was 99.8 (0.4) mg/dL, with male participants displaying significantly higher mean levels than female participants (102.4 vs 97.4 mg/dL, respectively). Mean (SD) participant age was 41.1 (0.8) years, and 8376 participants (51.9%) were female. ApoB levels were higher among older age groups. There was significant heterogeneity in mean apoB concentrations across self-identified Hispanic or Latino background groups, ranging from 95.1 mg/dL in Dominican individuals to 104.8 mg/dL in Cuban individuals. The prevalence of elevated apoB (≥130 mg/dL) was greater across higher predicted ASCVD risk categories. Among participants with a 10-year predicted ASCVD risk of 7.5% or higher, 26.5% had an elevated apoB. Median West African ancestry was lower across higher tertiles of apoB. In this cohort study among participants from the HCHS/SOL, elevated apoB was present in one-quarter of a diverse cohort study of Hispanic or Latino individuals who were at intermediate or high predicted ASCVD risk. Differences in apoB distribution among Hispanic or Latino individuals may have important implications for apoB's use in ASCVD risk assessment. Show less

Cholesterol efflux capacity (CEC) of HDL (high-density lipoprotein) is inversely associated with incident cardiovascular events, independent of HDL cholesterol. Obesity is characterized by low HDL cholesterol and impaired HDL function, such as CEC. Bariatric surgery, including Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), broadly leads to improved cardiovascular outcomes, but impacts on risk factors differ by procedure, with greater improvements in weight loss, blood pressure, and glycemic control after RYGB, but greater improvements in HDL cholesterol and CEC levels after SG. This study sought to determine effects of RYGB and SG on HDL protein and lipid cargo and investigate associations with CEC changes. We prospectively studied nondiabetic, premenopausal Hispanic women with severe obesity not using lipid medications undergoing RYGB (n=31) or SG (n=36). Anthropometric measurements and blood sampling were obtained before and at 6 and 12 months after surgery. HDL was isolated from plasma, and quantitative proteomic and lipidomic assessments were performed with LC-MS/MS (liquid chromatography with tandem mass spectrometry). CEC was assessed ex vivo using apoB-depleted serum. Participants experienced similar, significant weight loss over 12 months following bariatric surgery (38.0±10.4 kg) regardless of the procedure. Relative quantities of 47 proteins (34 increased, 13 decreased) and 150 lipids (71 increased, 79 decreased) carried on HDL were significantly altered following either surgical procedure. Proteins with similar aggregate response patterns were clustered into 15 groups (5 increased, 5 decreased, 5 minimal change) and lipids with similar aggregate responses into 25 groups (7 increased, 11 decreased, 7 minimal change). Network mediation analyses suggested that changes in 4 protein and 2 lipid clusters mediated changes in ABCA1 (ATP-binding cassette transporter A1) CEC and that 1 lipid cluster mediated changes in non-ABCA1 CEC. The protein and lipid clusters that mediated changes in CEC were distinct between SG and RYGB. Bariatric surgery produces substantial changes in HDL lipid and protein cargo, and specific changes may mediate changes in HDL function in CEC. Further study of these mechanisms may lead to improved interventions to reduce cardiovascular risk in patients with obesity. Show less

Apolipoprotein B (apoB) is the main structural protein of LDLs, triglyceride-rich lipoproteins and lipoprotein(a), and is crucial for their formation, metabolism and atherogenic properties. In this Review, we present insights into the role of apoB-containing lipoproteins in atherogenesis, with an emphasis on the mechanisms leading to plaque initiation and growth. LDL, the most abundant cholesterol-rich lipoprotein in plasma, is causally linked to atherosclerosis. LDL enters the artery wall by transcytosis and, in vulnerable regions, is retained in the subendothelial space by binding to proteoglycans via specific sites on apoB. A maladaptive response ensues. This response involves modification of LDL particles, which promotes LDL retention and the release of bioactive lipid products that trigger inflammatory responses in vascular cells, as well as adaptive immune responses. Resident and recruited macrophages take up modified LDL, leading to foam cell formation and ultimately cell death due to inadequate cellular lipid handling. Accumulation of dead cells and cholesterol crystallization are hallmarks of the necrotic core of atherosclerotic plaques. Other apoB-containing lipoproteins, although less abundant, have substantially greater atherogenicity per particle than LDL. These lipoproteins probably contribute to atherogenesis in a similar way to LDL but might also induce additional pathogenic mechanisms. Several targets for intervention to reduce the rate of atherosclerotic lesion initiation and progression have now been identified, including lowering plasma lipoprotein levels and modulating the maladaptive responses in the artery wall. Show less

Familial hypercholesterolemia (FH) is less rare than one might think and, despite highly effective lipid-lowering therapies (LLT), more than half of the patients treated do not reach the lipid target indicated by the guidelines. In these patients, lipoprotein apheresis (LA) is the most effective tool to lowering apo-B containing atherogenic lipoproteins. In own center, since 1994, thanks to routinely cascade testing performed in patients who start LA, we have identified a pediatric population (30 subjects) that we analyzed retrospectively. Cascade screening, performed in subject with premature cardiovascular events or inherited dyslipidemias, is an effective approach to identified pediatric FH, a condition that pediatricians should also be aware. A dedicate network is required to investigate the involved genetic mutations and to set up a management program, including lipoprotein (a) measurement and subclinical atherosclerosis evaluation. Moreover, it is important that medical staff use a therapeutic pathway to help patients overcome discomfort associated with disease and chronic LLT, as well as improve adherence to lipid-lowering drugs. Show less

Hypertension is recognized as a modifiable risk factor for cardiovascular diseases, alongside dyslipidemia. Studies have revealed that between 15 and 31% of individuals have both hypertension and dyslipidemia. However, emerging evidence suggests that natural therapies and yoga can help manage mild increases in blood pressure. This study aimed to evaluate the impact of yogic and naturopathy treatments on lipid profiles in hypertensive patients, thereby contributing to the existing literature. A randomized controlled experiment was conducted, involving 262 hypertensive patients randomly assigned to either the study group (SG) or control group (CG). The SG, consisting of 131 individuals, received yoga and naturopathic treatments for 10 days, while the CG (n = 131) did not. The lipid profile was measured at the beginning and end of the 10 days, and they were followed up and reassessed after 9 months. The study involved a total of 262 individuals, with 111 in the SG and 125 in the CG. After the 10-day intervention period, the SG showed significant reductions in total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, very low-density lipoprotein, apolipoprotein-A (Apo-A), apolipoprotein-B (Apo-B), and lipoprotein-A (Lp-A) (p < 0.001) compared to the CG. Also, the change was observed after 9 months in Apo-A, Apo-B, and Lp-A significantly (p < 0.001). These findings underscore the potential of naturopathic and yogic interventions in improving lipid profiles in hypertensive patients, thereby contributing to the current literature. In conjunction with conventional management, these specific interventions could be considered as a safer form of complementary therapy in the treatment of dyslipidemia among hypertensive patients. Thus, these findings hold promise for the integration of naturopathic and yogic therapies in the standard care of hypertensive patients. Show less

In the PEMA-FL study in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), pemafibrate was shown to significantly decrease low-density lipoprotein cholesterol (LDL-C) levels. We aimed to investigate the mechanisms of pemafibrate-induced LDL-C reduction in patients with MASLD by conducting an additional sub-analysis of the PEMA-FL study. The PEMA-FL study randomized 118 patients with MASLD to receive pemafibrate or placebo for 72 weeks. This sub-analysis examined the percentage change in LDL-C and related lipid markers by tertile of baseline LDL-C levels and the correlation between these changes in the pemafibrate group. Pemafibrate significantly decreased LDL-C levels approximately 25% (p＜0.001 at all timepoints) from baseline in the highest tertile of baseline LDL-C levels (≥ 137.5 mg/dL), with similar trends for non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (ApoB) levels. Lipoprotein (a) [Lp(a)] levels decreased only in patients with the highest baseline LDL-C levels. Regardless of the baseline LDL-C levels, pemafibrate altered the LDL particle profile (increased LDL particle size and decreased the number); reduced lathosterol, β-sitosterol, and campesterol; and increased angiopoietin-like protein 3 (ANGPTL3). The percentage change in LDL-C positively correlated with that in ApoB, non-HDL-C, Lp(a), lathosterol, β-sitosterol, and campesterol but not HDL-C and ANGPTL3. Pemafibrate reduced LDL-C, ApoB, and non-HDL-C levels in patients with MASLD, and the effect was greater in those with higher baseline LDL-C levels. Pemafibrate may clinically benefit patients with MASLD by improving LDL-C levels and the LDL particle profile. Show less

Adverse drug responses (ADRs) result in over 7,000 deaths annually. Pharmacogenomic studies have shown that many ADRs are partially attributable to genetics. However, emerging data suggest that epigenetic mechanisms, such as DNA methylation (DNAm) also contribute to this variance. Understanding the impact of DNA methylation on drug response may minimize ADRs and improve the personalization of drug regimens. In this work, we identify DNA methylation sites that likely impact drug response phenotypes for anticoagulant and cardiometabolic drugs. We use instrumental variable analysis to integrate genome-wide association study (GWAS) summary statistics derived from electronic health records (EHRs) within the U.K. Biobank (UKBB) with methylation quantitative trait loci (mQTL) data from the Genetics of DNA Methylation Consortium (GoDMC). This approach allows us to achieve a robust sample size using the largest publicly available pharmacogenomic GWAS. For warfarin, we find 71 DNAm sites. Of those, 8 are near the gene VKORC1 and 48 are on chromosome 6 near the human leukocyte antigen (HLA) gene family. We also find 2 warfarin DNAm sites near the genes CYP2C9 and CYP2C19. For statins, we identify 17 DNAm sites. Eight are near the APOB gene, which encodes a carrier protein for low-density lipoprotein cholesterol (LDL-C). We find no novel significant epigenetic results for metformin. Show less

Atherosclerosis, the major underlying cause of cardiovascular disease, is believed to arise from the accumulation of low-density lipoprotein (LDL) in the arterial subendothelial space, ultimately leading to plaque formation. It is proposed that the accumulation of LDL is linked to its intrinsic aggregation propensity. Although the native LDL is not prone to aggregation, LDL(-), an electronegative LDL characterized in the plasma, has been shown to prime LDL aggregation in a domino-like behavior similar to amyloidogenic proteins. LDL(-) has also been observed to have a misfolded apolipoprotein B-100 (apo B-100), a huge protein consisting of 4563 amino acid residues. As misfolding of proteins is commonly associated with amyloid formation, apo B-100 is therefore being considered as the possible triggering factor in LDL aggregation. Previous computational studies have implicated the α2 domain to be the aggregation-prone region of apo B-100. In this study, the amyloidogenic properties of the α2 domain of apo B-100 were interrogated using both in silico and in vitro techniques. Since the crystal structure of the 570-amino acid α2 domain of apo B-100 is yet to be solved, we used several secondary structure prediction tools to model putative helical regions that make up the α2 domain. The stability of each of the 17 helices thus identified was further probed using molecular dynamics (MD), with the least stable of the helices considered as potentially amyloidogenic. In a 100 ns simulation window, helices k (YFEKLVGFIDDAVK), m (YHQFVDETNDKIREVTQRLNGEIQA), and p (QQELQRYLSLVGQVYS) were the least stable and appeared to transition to β-structures, the hallmark of amyloidogenesis. When the simulation was extended to longer times, only helices k and p formed stable β-sheets that persisted. Analysis of the data indicates that the final β-sheet conformation was stabilized by the π-π stacking interactions between the aromatic rings of Tyr-1 and Phe-8 for helix k and likely π-π stacking contacts between Arg-6 guanidino group and Tyr-15 ring for helix p. Based on the in silico work, we proceeded to synthesize and spectroscopically characterize helices k, m Show less

To evaluate the efficacy and safety of inclisiran in the treatment of hypercholesterolemia. Randomized controlled trials comparing inclisiran with a placebo were searched until April 2024. Overall, 8 studies involving 4947 patients were included. Inclisiran reduced low-density lipoprotein cholesterol (mean difference [MD]: -46.95 %; 95 % confidence interval [CI]: -53.26 to -40.46; P < 0.05), proprotein convertase subtilisin/kexin type 9 (MD: -70.80 %; 95 % CI: -76.52 to -65.08; P < 0.05), serum total cholesterol (MD: -29.47 %; 95 % CI: -32.56 to -26.39; P < 0.05), non-high-density lipoprotein cholesterol (MD: -40.46 %; 95 % CI: -45.24 to -35.68; P < 0.05), apolipoprotein B (MD: -36.77 %; 95 % CI: -40.94 to -32.61; P < 0.05), and lipoprotein(a) (MD: -20.04 %; 95 % CI: -24.2 to -15.87; P < 0.05) levels but increased high-density lipoprotein cholesterol level (MD: 6.09 %; 95 % CI: 3.63 to 8.55; P < 0.05). The incidences of adverse events, serious adverse events, headache, nasopharyngitis, and muscular adverse reactions were not significantly different between the inclisiran and placebo groups. Inclisiran reduced the incidence of cardiovascular adverse reactions (odds ratio [OR] = 0.79; 95 % CI: 0.65 to 0.96; P = 0.02) and increased the incidence of injection-site reactions (OR = 4.79; 95 % CI: 2.18 to 10.52; P < 0.05). Inclisiran is effective in treating hypercholesterolemia and has a good safety profile. Show less

Microsomal triglyceride transfer protein (MTP) plays crucial roles in the assembly and secretion of apolipoprotein B-containing lipoproteins and loss of function MTP variants are associated with abetalipoproteinemia, a disease characterized by the absence of these lipoproteins. MTP is a heterodimeric protein of two subunits, MTP and protein disulfide isomerase (PDI). In this study, we report a proband with abetalipoproteinemia who was monitored annually for 10 years in her third decade and had very low plasma lipids and undetectable apoB-containing lipoproteins. Genetic testing revealed biallelic variants in the MTTP gene. She has a well-documented nonsense mutation Gly865∗ that does not interact with the PDI subunit. She also has a novel missense MTP mutation, Ile344Asn. We show that this mutation abrogates lipid transfer activity in MTP and does not support apolipoprotein B secretion. This residue is present in the central α-helical domain of MTP and the substitution of Ile with Asn at this position disrupts interactions between MTP and PDI subunits. Ile344 is away from the known MTP:PDI interacting sites identified in the crystal structure of MTP suggesting that MTP:PDI interactions are more dynamic than previously envisioned. Identification of more missense mutations will enhance our understanding of the structure-function of MTP and the role of critical residues in these interactions between the two subunits. This knowledge may guide us in developing novel treatment modalities to reduce plasma lipids and atherosclerosis. Show less

Most studies found that apolipoprotein B (apo B)-100 is a superior marker for coronary risk to non-high-density lipoprotein (HDL) cholesterol (C). Usually, studies use multivariant analysis with single-point odds/risk ratios. In multivariant analysis, when variables are highly correlated they are difficult to interpret. Effects cannot be well discriminated. Brief review and examination of diagnostic sensitivity and specificity by receiver operator characteristic (ROC) curves at decision levels so that discrimination can be well compared. Since apo B has additional expense, clinical value should be compared in an appropriate format. Apo B and cholesterols were measured in 382 angiographically defined patients. Non-HDLC and apo B were stronger markers than low-density lipoprotein (LDL)C, when examined by logistic regression, but as a result of strong collinearity, non-HDLC appeared weaker than LDLC in the presence of apo B, based on P values. This was true when analyzed with and without nonlipid risk factors. On ROC analysis, apo B and non-HDLC showed stronger C statistics than LDLC and total C. When analyzed alone apo B showed about 6.1% greater sensitivity than non-HDLC. After adjustment for nonlipid risk factors, the C statistics for apo B and non-HDLC were 0.74 and 0.73, and there was little difference in diagnostic specificity. Risk is calculated from an algorithm that includes nonlipid risk factors similar to those examined here along with cholesterols. When assessed by the 10-year screening algorithm, these data support the view that non-HDLC would be less expensive than apo B with similar clinical efficacy. Show less

Aging-related lipid metabolic disorder is related to oxidative stress. Selenium (Se)-enriched Cardamine violifolia (SEC) is known for its excellent antioxidant function. The objective of this study was to evaluate the effects of SEC on antioxidant capacity and lipid metabolism in the liver of aged laying hens. A total of 450 sixty-five-wk-old Roman laying hens were randomly divided into 5 treatments: a basal diet (without Se supplementation, CON) and basal diets supplemented with 0.3 mg/kg Se from sodium selenite (SS), 0.3 mg/kg Se from Se-enriched yeast (SEY), 0.3 mg/kg Se from SEC (SEC), or 0.3 mg/kg Se from SEC and 0.3 mg/kg Se from SEY (SEC + SEY). The experiment lasted for 8 wk. The results showed that dietary SEC + SEY supplementation decreased (P < 0.05) triglyceride (in the plasma and liver) and total cholesterol levels (in the plasma), and increased (P < 0.05) HDL-C concentration in plasma compared to CON diet. Compared with CON diet, SEC and/or SEY supplementation decreased (P < 0.05) the mRNA expression of hepatic ACC, FAS and HMGCR, and increased (P < 0.05) PPARα, VTG-II, Apo-VLDL II and ApoB expression. Dietary SEC + SEY and SEY supplementation increased (P < 0.05) Se content in egg yolk and breast muscle compared to CON diet. Dietary SEC, SEY or SEC + SEY supplementation increased (P < 0.05) the activity of antioxidant enzymes (GSH-PX, T-AOC and T-SOD) in the plasma and liver and decreased (P < 0.05) MDA content in the plasma compared to CON diet. Dietary Se supplementation promoted (P < 0.05) mRNA expression of Nrf2 in the liver. In contrast, dietary SEY and SEC supplementation resulted in a decrease (P < 0.05) of hepatic Keap1 mRNA expression compared to CON diet. Dietary SEC + SEY and/or SEC supplementation increased (P < 0.05) mRNA expression of Selenof, GPX1 and GPX4 in the liver compared with CON diet. In conclusion, dietary SEC (0.3 mg/kg Se) or SEC (0.3 mg/kg Se) + SEY (0.3 mg/kg Se) improved the antioxidant capacity and the lipid metabolism in the liver of aged laying hens, which might be associated with regulating Nrf2/Keap1 signaling pathway. Show less

Vitamin A is an essential nutrient crucial to ensuring proper mammalian embryonic development. β-Carotene is the most prevalent form of vitamin A in food that, when transferred in its intact form from mother to the developing tissues, can serve as an in situ source of retinoic acid, the active form of vitamin A. We have previously provided evidence that the maternal-fetal transfer of β-carotene across the placenta is mediated by lipoproteins and that β-carotene itself regulates placenta lipoprotein biogenesis by means of its derivatives β-apo-10'-carotenoids and retinoic acid. These metabolites exert antagonistic transcriptional activity on placental microsomal triglyceride transfer protein (MTP) and apolipoprotein B (APOB), two key players of lipoprotein biosynthesis. Here, we analyzed the time-dependency of this regulation over the course of 24 h upon a single maternal administration of β-carotene. We also tested the hypothesis that the transcriptional repressor intestine-specific homeobox (ISX) plays a role in the regulation of Mttp in placenta. We observed that ISX is expressed in placenta of mouse dams and is regulated by β-carotene availability. Furthermore, we demonstrated that the absence of Isx disrupts the β-carotene-mediated regulation of placental MTP. We also showed that this mechanism is organ-specific, as it was not observed in enterocytes of the intestine, a major place of Isx expression. Therefore, we identified ISX as a "master" regulator of a placental β-carotene-dependent transcriptional regulatory cascade that fine-tunes the flux of provitamin A carotenoid towards the developing fetus. Show less