Discordance Between Circulating Atherogenic Cholesterol Mass and Lipoprotein Particle Concentration in Relation to Future Cardiovascular Disease in China Population

BackgroundIt is uncertain whether measurement of circulating total atherogenic lipoprotein particle cholesterol mass (non-high-density lipoprotein cholesterol [non-HDL-C]) or particle concentration (apolipoprotein B [Apo B]) more accurately reflects risk of incident cardiovascular disease (CVD). We evaluated CVD risk among China population in whom these markers where discordant.MethodsIn total, 7,117 initially healthy participants from the China Health and Nutrition Survey were included. Logistic regressions among Apo B, non-HDL-C, and LDL-C, respectively, were used to examined CVD risk by categories of concordant and discordant values defined by residual differences. Mediation analysis was performed to explore the intermediary effect of Apo B between the obesity and the risk of CVD.ResultsAlthough all 3 biomarkers were correlated (r ≥ 0.81), discordance occurred in approximately 16% of China participants. Participants with discordant high Apo B were more likely to have higher proportion of traditional risk factors and dyslipidemia. During a follow-up of 6 years, 207 CVD cases were identified. High LDL-C, non-HDL-C and Apo B were associated with increased risk of CVD. Participants with discordant high Apo B relative to LDL-C or non-HDL-C had increased CVD risk compared with concordant levels, odds ratios were 1.38 (95% CI: 1.01 to 1.87), 1.40 (95% CI: 1.01 to 1.94), respectively. Furthermore, mediation analyses revealed 16.67% of association between obesity with CVD was mediated by Apo B.ConclusionsDiscordance analysis demonstrates that Apo B is a more accurate marker of CVD risk in China healthy participants than LDL-C and non-HDL-C. Direct measurement of lipoprotein particle concentration might help better inform clinical risk assessment and guide clinical decision making.

Sleep and Alzheimer’s Disease: Shared Genetic Risk Factors, Drug Targets, Molecular Mechanisms, and Causal Effects

Background: Alzheimer’s disease (AD) was associated with sleep-related phenotypes (SRPs). Whether they share common genetic etiology remains largely unknown. We explored the shared genetics and causality between AD and SRPs by using high-definition likelihood (HDL), cross phenotype association study (CPASSOC), transcriptome wide association study (TWAS), and bidirectional Mendelian randomization (MR) in summary-level data for AD (n = 79145) and summary-level data for seven SRPs (sample size ranges from 345552 to 386577). Results: AD shared strong genetic basis with insomnia (rg = 0.20; P = 9.70×10-5), snoring (rg = 0.13; P = 2.45×10-3), and sleep duration (rg = -0.11; P = 1.18×10-3). CPASSOC identifies 31 independent loci shared between AD and SRPs, including four novel shared loci. Functional analysis and TWAS showed shared genes were enriched in liver, brain, breast, and heart tissues, and highlighted the regulatory role of immunological disorders, very-low-density lipoprotein particle clearance, triglyceride-rich lipoprotein particle clearance, chylomicron remnant clearance and positive regulation of T cell mediated cytotoxicity pathways. Protein-protein interaction analysis provided three potential drug target genes (APOE, MARK4 and HLA-DRA) that interacted with known FDA-approved drug target genes. CPASSOC and TWAS demonstrated three regions 11p11.2, 6p22.3 and 16p11.2 may account for the shared basis between AD and sleep duration or snoring. MR showed AD had causal effect on sleep duration (βIVW = -0.056, PIVW = 1.03×10-3). Conclusion: Our findings provide strong evidence of shared genetics and causation between AD and sleep, and advance our understanding the genetic overlap between them. Identifying shared drug targets and molecular pathways can be beneficial to treat AD and sleep disorders more efficiently.

The NIH Lipo-COVID Study: A Pilot NMR Investigation of Lipoprotein Subfractions and Other Metabolites in Patients with Severe COVID-19

A complex interplay exists between plasma lipoproteins and inflammation, as evidenced from studies on atherosclerosis. Alterations in plasma lipoprotein levels in the context of infectious diseases, particularly respiratory viral infections, such as SARS-CoV-2, have become of great interest in recent years, due to their potential utility as prognostic markers. Patients with severe COVID-19 have been reported to have low levels of total cholesterol, HDL-cholesterol, and LDL-cholesterol, but elevated levels of triglycerides. However, a detailed characterization of the particle counts and sizes of the different plasma lipoproteins in patients with COVID-19 has yet to be reported. In this pilot study, NMR spectroscopy was used to characterize lipoprotein particle numbers and sizes, and various metabolites, in 32 patients with severe COVID-19 admitted to the intensive care unit. Our study revealed markedly reduced HDL particle (HDL-P) numbers at presentation, especially low numbers of small HDL-P (S-HDL-P), and high counts of triglyceride-rich lipoprotein particle (TRL-P), particularly the very small and small TRL subfractions. Moreover, patients with severe COVID-19 were found to have remarkably elevated GlycA levels, and elevated levels of branched-chain amino acids and beta-hydroxybutyrate. Finally, we detected elevated levels of lipoproteins X and Z in most participants, which are distinct markers of hepatic dysfunction, and that was a novel finding.

Characterization of Particle Size Distribution of Plasma Lipoproteins in Dairy Cattle Using High-Resolution Polyacrylamide Electrophoresis

Plasma lipoproteins play critical roles in energy metabolism and inflammation. Concentrations of high-density lipoproteins (HDL) are linked to reproductive outcomes and milk yields in dairy cattle. Low-density lipoproteins (LDL), which are enzymatically formed in the blood from very low-density lipoproteins (VLDL) following secretion by the liver, have been used as a surrogate marker of liver function due to the rapid influx of circulating VLDL into the lactating mammary gland. In humans, the composition of plasma lipoproteins is reflected in lipoprotein particle size distribution, and both of these parameters are highly predictive of disease development and related health outcomes. Bovine HDL are overall larger, less dense particles compared to human HDL. Lipoprotein particle size distribution in both health and disease is understudied in the bovine. We hypothesize that a more detailed analysis of lipoproteins could hold diagnostic and/or prognostic value in the study of dairy cattle health and production. In this study, we took the first steps in this characterization and used a high-resolution polyacrylamide gel electrophoretic assay to better define LDL and HDL at the subfraction level in Holstein cows at different stages of lactation. We extensively characterized the lipoprotein particle size distribution in healthy lactating dairy cattle. We identified subfractions of LDL that were prominent only in the dry period and subfractions of HDL that were highest in cows during mid-lactation. Use of this method could be informative in the study of multiple herds and management strategies, including longitudinal evaluation of animals and production parameters.

Association of kidney function with NMR-quantified lipids, lipoproteins, and metabolic measures in Mexican adults

Context Chronic kidney disease (CKD) and diabetes are associated with dyslipidaemia, metabolic abnormalities, and atherosclerotic risk. Nuclear magnetic resonance (NMR) spectroscopy provides much more detail on lipoproteins than traditional assays. Methods In about 38,000 participants from the Mexico City Prospective Study, aged 35-84 years and not using lipid-lowering medication, NMR spectroscopy quantified plasma concentrations of lipoprotein particles, their lipidic compositions, and other metabolic measures. Linear regression related low eGFR (<60mL/min/1.73m2) to each NMR-measure after adjustment for confounders and for multiplicity. Analyses were done separately for those with and without diabetes. Results Among the 38,081 participants (mean age 52 years, 64% women), low eGFR was present for 4.8% (306/6,403) of those with diabetes and 1.2% (365/31,678) of those without diabetes. Among both those with and without diabetes, low eGFR was significantly associated with higher levels of 58 NMR-measures – including apolipoprotein B (Apo-B), the particle numbers of most Apo-B containing lipoproteins, the cholesterol and triglycerides carried in these lipoproteins, several fatty acids, total cholines and phosphatidylcholine, citrate, glutamine, phenylalanine, β-OH-butyrate, and the inflammatory measure glycoprotein-A – and significantly lower levels of 13 NMR-measures, including medium and small high-density lipoprotein particle measures, very low-density lipoprotein particle size, the ratio of saturated:total fatty acids, valine, tyrosine, and aceto-acetate. Conclusions In this Mexican population with high levels of adiposity and diabetes, low kidney function was associated with widespread alterations in lipidic and metabolic profiles, both in those with and without diabetes. These alterations may help explain the higher atherosclerotic risk experienced by people with CKD.