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At least 19 recordsLinked to original sources
PubMed2026

Genetic evidence supports the combined targeting of lipoprotein(a) and LDL cholesterol to reduce coronary artery disease risk.

Distinct genetic mechanisms govern how lipoprotein(a) (Lp(a)) and low-density lipoprotein cholesterol (LDL-C) promote atherosclerosis. It remains unclear whether targeting both provides additive cardiovascular benefits. Here we use coding loss-of-function variants in LPA and PCSK9 and genetic scores associated with Lp(a) and LDL-C levels to evaluate the effects of lowering Lp(a) and LDL-C on coronary artery disease (CAD) risk. Among 408,039 individuals from the UK Biobank, LPA or PCSK9 loss-of-function carriers have lower CAD risk than noncarriers (odds ratio (OR) 0.91 and 0.81). Carriers of both variants have even lower CAD risk (OR 0.73). Genetic lowering of Lp(a) and LDL-C showed a stronger reduction of CAD risk (OR 0.70) than either trait individually (OR 0.85 and 0.81) in the two-factor genetic score analysis. Among statin users, Lp(a) reduction was linearly associated with CAD risk. A phenome-wide association study revealed that combined therapy was associated with cardiometabolic benefits without adverse effects. The additive benefits were replicated in 65,171 individuals from the Mass General Brigham Biobank.

Humans↗
PubMed1979

HDL- and LDL-cholesterol in normal weight healthy children 13 years of age.

From 108 healthy 13 years old school children who took part on a longitudinal study in regard to serum lipids and lipoproteins 64 with normal body weight were examined. Lipoproteins were estimated by means of preparative ultracentrifuge and polyanionprecipitation (Heparin and Manganese-chloride) according to the Lipid Research Clinics Methods, NIH, Bethesda. Mean values and S.D. were calculated as: Total cholesterol: 155 +/- 29, 150 +/- 35 mg/dl; LDL-cholesterol 98 +/- 21 and 96 +/- 34 mg/dl; HDL-cholesterol 44 +/- 13 and 44 +/- 13 mg/dl for males and females respectively. The few data from the literature showing wide variations in LDL- and HDL-cholesterol concentrations are compared with our results; methodological considerations indicate that for further epidemiological studies concerning the possible risk factors for premature atherosclerosis standaradized laboratory tests should be provided.

Adolescent↗
PubMed1979

Effect of polyenyl phosphatidyl choline on clofibrate-induced increase in LDL cholesterol.

In a double-blind, randomised, cross-over trial clofibrate and a combination of polyenyl phosphatidyl choline (PPC) plus clofibrate were tested in 67 patients with hyperlipoproteinemia. Each treatment lasted for 4 weeks and was separated by a 4 week placebo period. The daily doses were clofibrate 1.2 g and PPC 1.8 g + clofibrate 1.2 g. respectively. The results revealed that polypenyl phosphatidyl choline prevented the elevation of LDL-cholesterol induced by clofibrate treatment, and that the lipid-lowering potency of the combination did not differ significantly from that of clofibrate. Since elevation of LDL-cholesterol is considered to increase the risk of coronary heart disease, the combination appears to offer a therapeutic advantage. Despite the significance of this clinical observation, a final decision may only be obtained from a prospective, long term investigation in patients with coronary heart diseases and hyperlipoproteinemia.

Adult↗
PubMed1979

Screening for hyperlipoproteinemia in 10,000 Danish newborns. Follow-up studies in 522 children with elevated cord serum VLDL-LDL-cholesterol.

Among 10 440 newborns, 522 with upper 5 percentile values for very low-low density lipoprotein cholesterol in cord serum were selected for follow-up studies. Follow-up was possible in 446 of these 522 families (85%) and familial hypercholesterolemia (FH) was diagnosed in 11. In 273 of the 522 children, serum lipids were determined between the ages of 1 and 2 years and were now found to be normal, except in the 11 children with FH. Furthermore the serum lipids were compared in subgroups of these 273 children divided according to obstetric complications (i.e. low birth-weight, perinatal asphyxia and antepartum betamethasone treatment), which may cause a rise in serum lipids at birth. No differences were found between these subgroups at the age of 1--2 years.

Cholesterol↗
PubMedDate not supplied

[Hyperlipoproteinemia in children. Correlation between changes in the parents and newborn infant].

The families of 13 children who had presented hyperlipoproteinemia at birth were studied. Total cholesterol, LDL cholesterol, triglycerides and electrophoresis of LP were performed. The parameters studied were divided in three groups: a) Inespecific indicators (alpha-LP, betas/alphas relation). b) Indicators of the beta-LP group (total and LDL cholesterol and beta-LP). c) Indicators of the prebeta-LP group (TG, prebeta-LP and prebeta-1). In all cases at least one of the parents had hyperlipoproteinemia. All the parents, but one, showed alterations in the same group of indicators as their children. Obesity, diabetes mellitus, arterial hypertension, coronary insufficiency, myocardial infarction and cerebrovascular accident where observed in the families of the hiperlipidemic parents, but not on those of the normolipemic parents.

Adult↗
PubMed2026

Source- and Solubility-specific Choline, Gut Microbiota, and Dyslipidemia Risk: Trimethylamine N-oxide-associated and Non-trimethylamine N-oxide-Associated Patterns in a Prospective Cohort Study.

BACKGROUND: Dietary choline, a major precursor of the gut microbial metabolite trimethylamine N-oxide (TMAO), is implicated in dyslipidemia risk; however, source- and form-specific associations and interactions with gut microbiota remain unclear. OBJECTIVES: The aim of this study was to examine longitudinal associations of source- and form-specific dietary choline with plasma TMAO and dyslipidemia and to identify gut microbiota interactions. METHODS: Using data from the China Health and Nutrition Survey (2018-2023), dietary intake was assessed via 3 consecutive 24-h recalls in this prospective cohort study. Two-level generalized linear mixed-effects models were applied in 4828 adults (mean age: 55.9 ± 12.6 y, 56.6% females) to assess choline-dyslipidemia associations. Choline-TMAO and TMAO-dyslipidemia analyses were conducted in 1091 participants free of dyslipidemia at baseline. Among 7169 adults with gut microbiome data, Least Absolute Selection and Shrinkage Operator and logistic regression identified lipid-associated gut genera; TMAO relationships were examined in a subset of 693 participants. RESULTS: Higher intakes of total [Q4 compared with Q1: odds ratio (OR) = 1.261; 95% confidence interval (CI): 1.007, 1.580], red meat-derived (OR: 1.753; 95% CI: 1.196, 2.568), and lipid-soluble choline (OR: 1.304; 95% CI: 1.047, 1.624) were associated with higher risk of elevated low-density lipoprotein cholesterol (LDL cholesterol), whereas vegetable-derived choline was inversely associated. Egg-derived and lipid-soluble choline were positively associated with plasma TMAO, which was prospectively associated with 5-y incident dyslipidemia (Q4 compared with Q1-OR: 1.620; 95% CI: 1.047, 2.509), elevated LDL cholesterol (Q3 compared with Q1-OR: 2.478; 95% CI: 1.187, 5.174), and hypertriglyceridemia (Q4 compared with Q1-OR: 1.829; 95% CI: 1.028, 3.225). Three TMAO-associated genera were identified: Lachnospiraceae and Phascolarctobacterium as pro-risk taxa and Turicibacter as protective. The adverse LDLcholesterol association of egg-derived choline was observed exclusively in Phascolarctobacterium-enriched individuals. CONCLUSIONS: Dietary choline source and solubility differentially associated with dyslipidemia risk through TMAO-associated and non-TMAO-associated patterns, with gut microbiota as key modulators.

Humans↗
PubMed1979

Plasma lipoproteins and coronary arteriography in subjects in the program on the surgical control of the hyperlipidemias. Preliminary report.

Coronary arteriographic findings, plasma lipid and lipoprotein levels, and cigarette smoking history are reported for the first 101 male post myocardial infarction survivors who have been entered into the POSCH clinical trial. Estimates of the extent of stenosis in the major coronary arteries were made using 4 models ranging from a simple determination of the number of the 3 major vessels having significant (i.e. 50% or greater stenosis) disease to more complex methods of determining overall extent of disease in 14 major segments of the coronary arteries. Age was shown to be an important factor in the extent of vessel disease. When controlling for age, plasma cholesterol and LDL-cholesterol levels were shown to be related to the extent of disease, especially in Type II hyperlipoproteinemia subjects. Multiple linear regression analysis demonstrated that age and LDL-cholesterol had positive associations and HDL-cholesterol had an inverse association with the coronary artery disease indices. In this comparatively "healthy" subgroup of the overall population of first MI survivors the major CHD risk factors are limited to plasma lipids and cigarette smoking. This preliminary report of 10% of the recruitment objective of the project supports the currently held views of the lipid--atherosclerosis hypothesis regarding the effects of age-total plasma cholesterol, LDL--cholesterol, and HDL--cholesterol on the extent of coronary atherosclerotic plaques, as determined by coronary arteriography.

Adult↗
PubMed1975

Colestipol, clofibrate, cholestyramine and combination therapy in the treatment of familial hyperbetalipoproteinaemia.

Fifty-seven patients, mean age 26 years, suffering from familial hyperbetalipoproteinaemia (Fredrickson type lla and llb), were treated on a low cholesterol, modified polyunsaturated fat diet for a period of 6-12 weeks prior to the introduction of drug therapy. No significant reduction in the serum levels of total cholesterol, low density lipoprotein (LDL) cholesterol or triglyceride was found. Fifty patients were then treated with colestipol for 6 weeks; total and LDL cholesterol decreased by 23%, but triglyceride levels were unaffected. During the following 6 weeks, placebo was administered, and total and LDL cholesterol returned to pretreatment levels. The patients were then randomly allocated into two groups of 16. The first group continued with clofibrate therapy, while the second group received cholestyramine. In the clofibrate group a reduction in total and LDL cholesterol of the order of 17% was noted, similar to cholestethat achieved in this group on colestipol. Triglyceride levels were 15% lower on clofibrate therapy than on colestipol. In the cholestyramine group, there was a 25% decrease in total and LDL cholesterol, compared with pretreatment levels. This reduction was similar to that found when colestipol was administered. Triglyceride values were significantly raised during cholestyramine therapy. Thirteen patients were then subjected to a 6-week period of combination therapy, either clofibrate or colestipol, or clofibrate and cholestyramine. Total and LDL cholesterol were reduced by 32% on combination therapy compared with 18% on colestipol and 23% on either clofibrate or cholestyramine alone. Furthermore, on combined therapy, triglyceride concentrations fell by 20% when compared with the levels found when colestipol, clofibrate or cholestyramine were administered on their own.

Adolescent↗
PubMed1976

Lipoprotein levels in apparently healthy men and women in the west of Scotland.

Lipoprotein typing was undertaken in apparently healthy women (419) and men (103) in whom measurements of fasting total cholesterol, triglycerides, and cholesterol content of the major lipoprotein fractions were made. In the female group (30 to 59 years) there was a significant rise in total cholesterol, low density lipoprotein (LDL) cholesterol, and triglycerides with age. Using total cholesterol and triglyceride levels for classification, type II hyperlipoproteinaemia was present in 1 per cent and type IV in 6-7 per cent. When LDL cholesterol levels were also considered, type II occurred in 9-8 per cent ( 8-4% type IIA and 1-4% type IIB). In the male group ( 40 to 59 years) there was no increase in cholesterol or triglyceride levels with age: II per cent had type IV hyperlipoproteinaemia and none had a type II abnormality. When LDL cholesterol levels were also considered, type II occurred in 3 per cent ( 2% type IIA and 1% IIB). The apparent increase in LDL cholesterol frequency of type IIA abnormality in women could be merely the consequence of arbitrary selection of upper limits of normality for LDL cholesterol, but may signify improved detection of a high risk group.

Adult↗
PubMed1976

Effect of gemfibrozil on lipoprotein concentrations in different types of hyperlipoproteinaemia.

The lipoprotein lowering effect of gemfibrozil, 400 mg twice daily, was studied for 24 weeks in 26 subjects with primary hyperlipoproteinaemia (type IIa, 5; IIb, 3; III, 3; and IV, 15). Maximum effects were noted after four weeks on very low density lipoproteins (VLDL) and after 12 weeks on low density lipoproteins (LDL), these effects remaining throughout the study. Gemfibrozil decreased VLDL triglycerides (TG) in all types of hyperlipoproteinaemia according to the equation: deltaVLDL TG (mmol/l) = -0.80 X initial VLDL TG concentration + 0.68 The drug affected the low density lipoprotein (LDL) cholesterol= -0.45 X initial LDL cholesterol + 61 This means that LDL cholesterol on average decreased if the initial LDL concentration was above 135 mg/100 ml and increased below that concentration. LDL TG and high density lipoprotein (HDL) TG concentrations also decreased significantly. A slight increase in HDL cholesterol concentration occurred after administration of gemfibrozil. Two subjects had to stop treatment because of nausea and abdominal pain respectively, attributed to the drug. No biochemical side effects were noted.

Cholesterol↗
PubMed2026

Current and Future Perspectives of LDL-C Lowering Therapies 2026.

LDL cholesterol (LDL-C) is the central causal factor for atherosclerotic cardiovascular disease (ASCVD), and its reduction is a cornerstone of both primary and secondary prevention. Since the introduction of statins more than three decades ago, LDL-C-lowering therapy has expanded substantially, now encompassing ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9)-targeting agents, bempedoic acid, and other emerging modalities. This expanding therapeutic landscape has improved the feasibility of achieving guideline-recommended LDL-C targets, but it has also increased the complexity of clinical decision making. This review provides a contemporary and practical overview of the LDL-C-lowering strategies, beginning with the initial evaluation of patients with elevated LDL-C, including differentiation between primary and secondary causes and the identification of familial hypercholesterolemia (FH). We summarize the current treatment targets for primary and secondary prevention, highlight the optimal selection and use of statins, and discuss the assessment and management of statin intolerance, including the role of the nocebo effect. Non-statin therapies, including ezetimibe, bile acid sequestrants, PCSK9 inhibitors, inclisiran, and bempedoic acid, are reviewed with an emphasis on their mechanisms, efficacy, and clinical positioning. Advanced therapies for severe dyslipidemia, such as lipoprotein apheresis, lomitapide, and evinacumab, are also discussed in this review. Finally, we outline the future directions, including oral PCSK9 inhibitors, next-generation cholesteryl ester transfer protein (CETP) inhibitors, lipoprotein(a)-lowering agents, and genome-editing approaches. Collectively, these developments offer new opportunities to address unmet clinical needs, particularly in patients with FH, statin intolerance, and residual cardiovascular risk. A comprehensive understanding of these therapies is essential for further reducing the burden of ASCVD in the coming decades.

Humans↗
PubMed1977

Characterization of plasma low density lipoproteins on nonhuman primates fed dietary cholesterol.

LDL from animals of three nonhuman primate species, Macaca mulatta, Macaca fascicularis, and Cercopithecus aethiops, were studied. A standard preparation of 125I-LDL was added to isolated lipoprotein mixtures just prior to separation of plasma lipoproteins by agarose gel chromatography. A relative size index, rI, was determined by dividing the elution volume of the iodinated LDL by the elution volume of the sample LDL, both volumes being determined simultaneously during chromatographic elution. Comparison of rI with molecular weights measured by flotation equilibrium analysis in the analytical ultracentrifuge showed a linear relationship across a molecular weight range of 2.5-8.0 X 10(6), r = 0.985. A regression equation describing this relationship was used to calculate molecular weights of LDL from a group of M. fascicularis that were fed cholesterol-containing diets. In these animals, plasma cholesterol concentration ranged from 100 to over 700 mg/dl and was highly correlated with LDL molecular weight and with the micromolar concentration of the LDL. Using multiple regression analyses, the two variables of plasma LDL could be shown to account for 94% of the variation in plasma cholesterol concentration in the M. fascicularis of this study. Micromolar concentration and molecular weight of LDL were not correlated with each other, suggesting that in M. fascicularis at least two independent types of controls are operative in the response of plasma LDL to dietary cholesterol. The increase in LDL molecular weight was associated with a large increase in cholesteryl ester content and concomitant smaller increases in protein, phospholipid, and free cholesterol. As molecular weight increased, these components appeared to be added to the LDL particles together as discrete increments of fixed composition. The data are consistent with a spherical model of LDL structure with a core of cholesteryl ester and triglyceride and a 21.3 A-thick coat of phospholipid, free cholesterol, and protein.

Animals↗
PubMed2026

LDLR Variant Classification Through Activity-Normalized Prime Editing Screening.

BACKGROUND: Inherited variants in the LDL (low-density lipoprotein) receptor (LDLR) gene are the most common cause of familial hypercholesterolemia, significantly increasing coronary artery disease risk. Early identification of pathogenic LDLR variants enables prompt lipid-lowering therapy and cascade testing of at-risk relatives; however, most LDLR variants observed in the population have uncertain or absent clinical classifications, leaving many patients without actionable information. METHODS: We developed the first activity-normalized prime editing screening pipeline to measure the impact of 5184 LDLR coding variants on LDL-cholesterol (LDL-C) uptake. Each prime editing guide RNA is paired with a genotypic outcome reporter to correct for variable editing efficiency, overcoming a key limitation of previous pooled genome editing screens. A statistical framework further improves variant effect estimates by jointly analyzing all missense variants at each amino acid position. RESULTS: We show that prime editing of the reporter construct correlates with endogenous variant installation frequency, validating the activity normalization approach. The resulting scores capture a continuous spectrum of functional effects, robustly separate pathogenic versus benign ClinVar variants, and show concordance with LDL-C levels in UK Biobank participants. We calibrate functional evidence strengths to the ACMG/AMP variant interpretation framework, enabling integration into a clinical variant classification workflow. By combining functional, computational, population, and contextual evidence, 322 of 434 LDLR variants currently classified as variants of uncertain significance, conflicting, or absent from ClinVar appear to meet evidence thresholds for reclassification and can be prioritized for expert review, substantially expanding the pool of actionable variant classifications. The screen also reveals a cluster of gain-of-function variants in LDLR class A repeat 5, at least some of which enhance LDL-C uptake through increased apolipoprotein B interaction, with implications for therapeutic genome editing. Last, prime editing uniquely detects splice-altering coding variants missed by cDNA-based screens and pathogenicity predictors, revealing an advantage of endogenous variant installation. CONCLUSIONS: Altogether, activity-normalized prime editing provides a scalable framework for LDLR variant classification that substantially expands the proportion of variants with evidence for genetic diagnosis and reveals novel biology with therapeutic relevance.

CRISPR screening↗
PubMed2026

Variant harmonization critically determines polygenic score transferability for lipid traits in Samoan populations.

Dyslipidemia is a significant risk factor for cardiovascular disease (CVD), the leading cause of death in Samoa. Polygenic scores (PGSs) for lipid traits offer promise for improved CVD risk prediction; however, their performance in Pacific Islander populations-comprising only 0.002% of genome-wide association study (GWAS) participants as of 2024-remains unknown. We evaluated the transferability of multi-ancestry PGS for LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), triglycerides (TGs), and total cholesterol (TC) in 4,342 Samoan adults across five cohorts spanning 1990-2010. PGSs from Graham et al. and Kanoni et al. multi-ancestry meta-analyses were harmonized with genome-wide imputed genotypes using a Samoan-specific reference panel, and performance was assessed via incremental R2 from linear mixed models with bootstrapped confidence intervals. HDL-C showed the highest performance (incremental R2 5.0%-15.0%), followed by TC (5.0%-10.7%), LDL-C (5.7%-8.6%), and TG (3.5%-7.0%). Critically, meaningful LDL-C performance was achieved only with the genome-wide PRS-CS score (99.6%-99.7% variant matching), while a curated pruning-and-thresholding score achieved ∼9% matching and near-zero performance. These findings establish systematic lipid PGS benchmarks in Samoans, demonstrating meaningful transferability when genome-wide variant coverage is ensured, and highlight variant harmonization as a critical precondition for PGS deployment in underrepresented populations.

Pacific Islanders↗
PubMed1979

Psychologic correlates of serum indicators of stress in man: a longitudinal study.

Correlations between serum uric acid, cortisol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol and psychometric indices of stress--namely, anxiety, hostility, and depression--were investigated in 20 students over a 2 1/2 month academic quarter. There were three peak periods of stress, with two occurring during midterm and final exams. The observed changes in serum cortisol were highly correlated with changes in anxiety and depression. Serum uric acid was significantly depressed during the first half of the quarter, but returned to control levels after midterm exams. Serum cholesterol and the LDL cholesterol subfraction were significantly elevated above control levels and remained elevated throughout the quarter after the first day of classes. Absolute levels of HDL cholesterol varied little throughout the quarter, however, the ratio of HDL cholesterol/total cholesterol was significantly depressed twice in the quarter, each time following approximately 10 days after the peak period of stress.

Adolescent↗
PubMed1976

Inheritance of xanthomatosis and hyper-beta-lipoproteinaemia. A study of 7 large kindreds.

In a study of xanthomatosis in the county of Ostfold, Norway (approximately 220,000 inhabitants), it was found that 20% (37 out of 185) of the probands belonges to seven large kindreds where xanthomatosis and hyper-beta-lipoproteinaemia segregated. Almost complete ascertainment (99%) of living subjects in the sibships in these families was obtained. Within each kindred, the frequency distribution of age- and sex-adjusted cholesterol and LDL cholesterol were discontinuous; the xanthomatosis patients all had values corresponding to the upper mode, whereas no person without xanthomatosis had such values. The combined results showed a slight overlap. Triglyceride concentrations were unimodally distributed. The genetics of the disorder in the seven families was analysed on the basis of 270 individuals. The segregation pattern satisfied the criteria for autosomal dominant inheritance, but not those for a polygenic trait. Thus, xanthomatosis with hyper-beta-lipoproteinaemia segregates as an autosomal dominant trait in these seven kindreds. No evidence of reduced penetrance was found. Since both IIA and IIB lipoprotein patterns were observed within the same family, there is no evidence that the two patterns reflect the presence of different genes in these kindreds.

Adolescent↗