Journal of clinical lipidology最新文献

Background: Alzheimer's disease (AD) is the leading cause of dementia, with an increasing incidence due to population aging. Approximately two-thirds of the people affected are women, possibly due to biological and hormonal factors. Also, lipids could play an important role in AD and show associations with cognitive impairment. Apolipoprotein E allele 4 (ApoE ε4) genotype and cardiovascular (CV) risk lipid ratios could be relevant in lipidomic studies.

Objective: This work aims to identify specific alterations in plasma lipid profiles associated with AD in women and to explore these alterations related to ApoE and 2 CV risk lipid ratios.

Methods: A lipidomic mass spectrometry-based method was applied to plasma samples from a clinical cohort of women. The patients were accurately classified into AD (n = 76) and non-AD (n = 74) groups by cerebrospinal fluid amyloid beta (Aβ)42/Aβ40 levels. The identified lipid species were evaluated and grouped into families and subfamilies. The lipids with significant differences between groups were examined in relation to ApoE genotype and 2 CV risk ratios (total cholesterol/high-density lipoprotein [HDL], triglycerides/HDL).

Results: Fatty acyls and monoacylglycerols showed higher levels in AD compared with non-AD, while diacylglycerols showed lower levels in AD. Also, specific subfamilies correlated with aging, CV risk, AD biomarkers, and cognitive status. Of the 627 lipid species detected, 45 showed statistically significant differences between groups, and some of them [lysophosphatidylcholine (24:1), diacylglycerol (18:0/18:1), and triacylglycerol (50:3)] showed significant associations with ApoE genotype and CV risk.

Conclusion: This study identified associations between lipid profiles in women and AD pathology, ApoE ε4 genotype, and high CV risk ratios.

Background: Ongericimab, a novel proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody, has recently been approved in China for hypercholesterolemia management but remains unapproved by major global regulatory agencies. This systematic review and meta-analysis provides the first pooled evidence on its efficacy and safety in participants with high cholesterol level.

Objective: To evaluate the efficacy of ongericimab to reduce lipid levels compared with placebo, assess its effects on other atherogenic and antiatherogenic lipid parameters, and determine its safety profile in randomized controlled trials (RCTs).

Methods: A comprehensive search of databases such as PubMed, Embase, and Cochrane Library from start to July 2025 identified RCTs comparing ongericimab with placebo. Primary outcome was percentage change in low-density lipoprotein cholesterol (LDL-C). Secondary outcomes included changes in other lipid parameters and safety endpoints. Data were pooled using a random-effects model, with heterogeneity assessed via the I² statistic.

Results: Four double-blind, placebo-controlled RCTs (n = 736) conducted in China were included. Ongericimab produced a profound reduction in LDL-C (mean difference: -68.74%; 95% CI, -72.22% to -65.26; I² = 0%) and significantly lowered total cholesterol, apolipoprotein (Apo) B, non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides, and lipoprotein(a), with the latter showing a robust -54.66% reduction after sensitivity analysis. HDL-C (+10.87%) and ApoA1 (+8.12%) were modestly increased. Safety analyses showed no significant differences in rates of upper respiratory tract infections, urinary tract infections, hyperuricemia, hepatic enzyme elevations, cardiovascular events, or severe adverse events compared with placebo. Only injection site erythema was significantly higher (odds ratios: 5.57; P = .02), though events were mild and transient.

Conclusion: Ongericimab is a potent lipid-lowering agent with a favorable short-term safety profile, offering potential for patients requiring intensive LDL-C reduction. While findings are consistent and clinically compelling, they are derived solely from short-duration trials in Chinese populations and are limited to surrogate endpoints. Large, multiethnic cardiovascular outcomes trials are essential to confirm long-term benefits, assess rare adverse events, and establish its position among global lipid-lowering strategies.

Background: Familial hypercholesterolemia (FH) is a genetic disorder characterized by impaired clearance of low-density lipoprotein cholesterol (LDL-C), leading to severe hypercholesterolemia and increased risk of premature cardiovascular disease (CVD). Our study aims to describe and compare the clinical, biochemical, and genetic profiles of pediatric patients diagnosed with FH based on LDL-C levels exceeding 400 mg/dL (10.4 mmol/L) and confirmed by biallelic pathogenic variants in low-density lipoprotein receptor (LDLR) or low-density lipoprotein receptor adapter protein-1 (LDLRAP1) genes.

Methods: This retrospective cohort study included 39 pediatric patients diagnosed with FH at a tertiary care center. Clinical data were analyzed, including age at diagnosis, family history, lipid profile, presence of xanthomas, and cardiovascular complications. Molecular analysis was conducted using next-generation sequencing (NGS) and Sanger sequencing to confirm pathogenic variants. Statistical comparisons were performed between the LDLR and LDLRAP1 variant groups regarding lipid profiles, treatment response, and cardiovascular outcomes.

Results: Among 39 patients, 32 and 7 had pathogenic variants in LDLR and LDLRAP1 genes, respectively. Genetic analysis identified 27 unique pathogenic variants in LDLR (including 5 novel mutations) and 4 in LDLRAP1 causal for autosomal recessive hypercholesterolemia (ARH), highlighting the molecular diversity of FH. Compared to the LDLR variant group, LDLRAP1 variant patients had significantly lower untreated LDL-C levels (640.0 ± 155.6 mg/dL [16.6 ± 4.0 mmol/L] vs 506.9 ± 130.1 mg/dL [13.1 ± 3.4 mmol/L], P = .026] and showed a superior response to lipid-lowering therapy (LLT), with a greater percentage (70.6% ± 12.0%) reduction in LDL-C levels (P = .015). While xanthomas were present in 62.5% of LDLR variant patients, they were less frequent (42.9%) in the LDLRAP1 group (P = .107). Cardiovascular complications were observed exclusively in LDLR variant patients. Fourteen patients required lipoprotein apheresis (LA), and one underwent liver transplantation due to severe aortic stenosis.

Conclusion: This study highlights the importance of genetic testing in differentiating classical semidominant homozygous FH from ARH, given their phenotypic overlap but distinct treatment responses. LDLRAP1 variant patients with ARH exhibit better LDL-C reductions with conventional LLT, suggesting a milder phenotype. Early diagnosis, aggressive LLT, and novel treatments are essential to mitigate cardiovascular risk. Future studies with larger cohorts and long-term follow-ups are needed to refine treatment strategies for pediatric FH.

Background: The effects of lipid traits on colorectal cancer (CRC) risk and the extent to which obesity may modify these effects remain unclear.

Objective: To examine the associations between lipid traits and CRC risk using an observational study and Mendelian randomization (MR) analyses, and the role of weight status in the potential associations.

Methods: In the Guangzhou Biobank Cohort Study (GBCS), lipid profiles were measured during 2003-2008, and CRC events were identified through record linkage with the cancer registry. MR analyses assessed the causal effects of lipid traits on CRC using a genome-wide association study meta-analysis of 185,616 Europeans.

Results: Among 28,576 GBCS participants followed until 2020, 599 CRC events occurred. Participants in the highest quartile of apolipoprotein B (apoB) had a higher CRC risk (hazard ratio [HR] 1.43, 95% CI 1.02-2.01). This association remained in those with overweight/obesity (HR 2.21, 95% CI 1.28-3.83). MR analyses supported a detrimental effect of apoB on CRC (odds ratio 1.12 per 1 SD, 95% CI 1.02-1.22). MR analyses also showed positive associations for total cholesterol and the apoB/apolipoprotein A-I ratio, which were not significant in the observational study.

Conclusion: Higher apoB levels were associated with an increased CRC risk in both observational and MR analyses, suggesting a potential role of apoB in CRC prevention, especially among participants with overweight/obesity. However, the limitations of single-time lipid measurements and the use of different ancestries across study designs indicate the need for further research to confirm the robustness and generalizability of the findings.

Background: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by extreme hypertriglyceridemia (>1000 mg/dL), recurrent pancreatitis, and lipoprotein lipase (LPL) deficiency. FCS is caused by biallelic loss-of-function variants in LPL or in 4 other genes encoding its cofactors and regulators, including LMF1 (lipase maturation factor 1). Variants in LMF1 are rare and present only in 1% to 2% of the FCS cases.

Objective: To assess in 3 patients with severe hypertriglyceridemia and recurrent pancreatitis and in whom a homozygous LMF1 duplication, initially classified as a variant of uncertain significance (VUS) was identified, post-heparin LPL activity.

Methods: We collected demographics, fasting lipid profiles, and body mass index, and performed next-generation sequencing using a targeted panel that included canonical FCS genes. A homozygous in-frame duplication in LMF1 (c.914_928dup; p.Ser309_Phe310dup) was identified. Variants were classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines and cross-referenced with public archive of reports of the relationships among human variations and phenotypes (ClinVar), The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff (HGMD), Leiden Open Variation Database (LOVD), The Single Nucleotide Polymorphism database (dbSNP), The Genome Aggregation Database (gnomAD), and in-house databases. LPL activity was assessed in post-heparin plasma using a radiometric assay.

Results: All 3 patients were homozygous for c.914_928dup (this variant was classified as a VUS) and exhibited markedly reduced LPL activity (<20% of normal). Clinical manifestations were consistent with FCS, including extreme triglyceride elevations and recurrent pancreatitis. One patient died from fulminant pancreatitis.

Conclusion: The combined clinical, biochemical, and genetic evidence supports the reclassification of LMF1 c.914_928dup (p.Ser309_Phe310dup) as likely pathogenic according to ACMG/AMP guidelines and indicates its association with severe pancreatitis.

Background: Elevated lipoprotein(a) [Lp(a)] is an independent and causal risk factor for atherosclerotic cardiovascular disease. Increasingly, prevention societies recommend testing Lp(a) at least once for all adults.

Objective: A quality improvement (QI) initiative aimed to increase the rates of Lp(a) ordering for patients was piloted in the general cardiology fellows' clinic at an urban academic medical center.

Methods: QI project interventions focused on provider education and inclusion of electronic health record-based tools.

Results: Over a period of 10 months, the proportion of patients with an Lp(a) order increased from 10.1% to 20.9%, and the proportion of patients with an Lp(a) result increased from 7.0% to 11.2%.

Conclusion: Ahead of results from ongoing clinical trials testing Lp(a)-targeted therapies, health systems can use QI methods to assess current Lp(a) ordering practices, identify patients who may benefit from future Lp(a)-targeted therapy, and plan for rapid expansion of Lp(a) testing.

Background: The size, composition, and functionality of high-density lipoprotein cholesterol (HDL-C) are potential biomarkers for predicting atherosclerosis, representing a major advance in the prevention and treatment of cardiovascular diseases.

Objective: This study aims to explore HDL-C concentrations and a derived HDL functionality score (HFS), and to investigate suggestive genetic associations in a representative Brazilian population.

Methods: This is an observational cross-sectional study. Plasma lipid profiles were analyzed using an automated system. The Lipoprint System determined HDL particle sizes. HFS was calculated using a composite based on the large HDL particle concentration combined with relevant cardiovascular data from demographic and clinical parameters. After DNA extraction, genotyping, and quality control, information on 330,656 single-nucleotide polymorphisms (SNPs) was available for genome-wide association studies (GWAS) of HFS.

Results: Among 345 participants, HDL functionality was impaired in 38%. Those with low functionality exhibited higher average waist circumference, systolic blood pressure, and glucose, as well as lower HDL-C concentrations, compared with those with high HDL functionality (P < .05). GWAS revealed suggestive associations for 5 SNPs and HFS, including rs11730709, rs78565063, and rs11786395 (P < 1 × 10^-5), as well as rs12734338 and rs36019094 (P < 1 ×10^-8). Additional regression analyses showed that SNPs rs12734338 and rs36019094 were positively associated with HFS, while rs11730709 showed an inverse association. Furthermore, rs12734338 increased the prevalence of low HFS by 41%, whereas rs11730709 reduced it by 34%.

Conclusion: These findings suggest potential genetic loci associated with the HFS, creating an opportunity for further investigations. Replication in larger and independent cohorts is warranted to confirm and extend these observations.

Background: The genetic and phenotypic spectrum of homozygous familial hypercholesterolemia (HoFH) in Han Chinese populations remains insufficiently defined.

Objective: To delineate the nationwide genetic and clinical features of HoFH in Taiwan, including true HoFH, double heterozygous FH (HeFH), and compound HeFH.

Methods: Patients with clinically diagnosed probable or definite FH enrolled in the Taiwan FH Registry who underwent genetic testing between 2006 and 2025 were analyzed. A comprehensive workflow integrating microarray assay, mass spectrometry, targeted next-generation sequencing, and multiplex ligation-dependent probe amplification was implemented. Variants were classified using American College of Medical Genetics and Genomics guidelines.

Results: Of 1479 screened individuals, 63 were genetically confirmed to have HoFH (mean age, 32.8 ± 22.7 years), including 28.6% with atherosclerotic vascular disease. The cohort comprised 14 true HoFH (including homozygous APOB variants), 6 double HeFH, and 43 compound HeFH. The highest documented low-density lipoprotein cholesterol (LDL-C) levels were 357.3 ± 123.5 mg/dL in true HoFH, 347.3 ± 39.2 mg/dL in double HeFH, and 443.5 ± 170.9 mg/dL in compound HeFH. The most frequent genotypes were LDLR [IVS2+4A>T];[IVS2+4A>T] in true HoFH, [APOB p.R3527W];[LDLR IVS2+4A>T] and [APOB p.R3527W];[LDLR p.D90N] in double HeFH, and LDLR [p.D90N];[p.C329Y] in compound HeFH. Patients with double HeFH had lower LDL-C levels and fewer xanthomas than those with LDLR homozygosity or compound mutations, while individuals with homozygous LDLR exon deletions/duplications had the highest LDL-C levels.

Conclusion: This nationwide study provides the first comprehensive genetic and clinical characterization of HoFH in Taiwan. Our findings highlight the importance of precise genetic diagnosis and early detection strategies in improving outcomes for this high-risk population.

Background: Ischemic stroke is a life-threatening condition, with high serum cholesterol recognized as a major risk factor. Recent studies suggest that vitamin B12 (VB12) deficiency is associated with changes in lipid metabolism, but its specific role remains unclear.

Objective: This study aims to explore the relationship between VB12 levels and lipid metabolism in patients diagnosed with acute ischemic stroke.

Methods: This cross-sectional study included 328 patients with acute ischemic stroke hospitalized at the First Affiliated Hospital of Chongqing Medical University or the First Branch of Chongqing Medical University in Chongqing, China, between January 2023 and December 2023. The results of laboratory assays were measured to examine the association between VB12 levels and lipid metabolism. The analysis utilized chi-square tests, Mann-Whitney U tests, 2-sample t-tests, Kruskal-Wallis H-tests, Spearman rank correlation, and binary logistic regression.

Results: Patients with VB12 levels below 300 pg/mL had significantly higher levels of triglycerides, low-density lipoprotein cholesterol (LDL-C), and total cholesterol compared to those with VB12 levels above 300 pg/mL. Furthermore, significant changes in LDL-C levels were observed with varying concentrations of VB12, and VB12 deficiency was significantly associated with atherosclerosis-related lipid risk factors (LDL-C above 1.8 mmol/L and high-density lipoprotein cholesterol below 1.04 mmol/L), indicating a potential link between VB12 levels and lipid metabolism in patients with ischemic stroke.

Conclusion: This study highlights the association between VB12 and lipid metabolism in patients with ischemic stroke, suggesting the importance of considering VB12 levels in clinical practice. These findings provide new insights into the potential role of VB12 in lipid metabolism, which may inform future research on atherosclerosis.