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PubMed2025

Genetic Predisposition to Low-Density Lipoprotein Cholesterol and Incident Type 2 Diabetes.

IMPORTANCE: 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. OBJECTIVE: To investigate the association of genetic predisposition to increased LDL-C levels with incident T2D risk. DESIGN, SETTING, AND PARTICIPANTS: 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. EXPOSURES: LDL-C level, LDL-C PRS, FH, or pLOF variant status. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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.

Humans↗

PubMed2026

Management and Consequences of Genotype-Positive Familial Hypercholesterolemia.

IMPORTANCE: Familial hypercholesterolemia (FH) is a common genetic condition that causes hypercholesterolemia and increased risk for premature atherosclerotic cardiovascular disease (ASCVD). The prevalence, management, and consequences of genetically confirmed FH across the US are poorly understood. OBJECTIVE: To identify genotype-positive FH in a national US cohort and describe its prevalence, consequences, and lipid-lowering management. DESIGN, SETTING, AND PARTICIPANTS: In the All of Us (AoU) cohort study, whole-genome sequencing and phenotypic data from US adult participants enrolled between May 2018 and July 2022 were analyzed to identify and study genotype-positive FH. Data were analyzed between May 2024 and May 2025. EXPOSURE: FH variants (pathogenic or likely pathogenic) in LDLR, APOB, and PCSK9 genes were manually classified with standard criteria. MAIN OUTCOMES AND MEASURES: The primary outcomes were demographic characteristics, lipid measurements, ASCVD, and prevalence of FH and noncarriers in AoU. Lipid management was then characterized among individuals with FH through lipid-lowering therapy (LLT) documentation and guideline-based low-density lipoprotein cholesterol (LDL-C) targets. RESULTS: A total of 245 388 participants were included, with mean (SD) age of 56.5 (16.9) years and 145 563 female participants (59.3%). Genotype-positive FH was identified in 865 participants (prevalence, 0.35%; 95% CI, 0.33%-0.38%; 1 in 287 participants). Among individuals with genotype-positive FH, 349 (40%) were prescribed statins, and 332 (38.4%) had LDL-C measured. Coronary artery disease, peripheral artery disease, and transient ischemic attack or stroke were significantly more common in genotype-positive FH carriers compared to noncarriers (coronary artery disease: odds ratio [OR], 2.91; 95% CI, 2.34-3.58; peripheral artery disease: OR, 1.51; 95% CI, 1.16-1.96; and transient ischemic attack or stroke: OR, 1.54; 95% CI, 1.11-2.09). Only 30.1% of participants positive for FH variants had LDL-C less than 100 mg/dL at their most recent result compared to 48.2% of noncarriers (P < .001). Of the total participants with ASCVD and LLT prescription, significantly fewer individuals with FH met the secondary prevention LDL-C target (<70 mg/dL; 19.33% vs 43.12%; P < .001) compared to noncarriers. CONCLUSIONS AND RELEVANCE: This cohort study finds a prevalence of genotype-positive FH in All of Us participants of 0.35% (95% CI, 0.33%-0.38%), with state-level variation. A minority of individuals with genotype-positive FH met guideline-recommended LDL-C targets and had increased rates of ASCVD.

Humans↗

PubMed2024

Mendelian randomization study of lipid metabolism characteristics and migraine risk.

BACKGROUND: The association between serum lipids and migraine is controversial. However, randomized controlled trials have suggested that statins may be efficacious for the prevention of migraine. In this study, we aim to investigate the relationship between lipids metabolism and migraine risk. METHODS: Single-nucleotide polymorphisms (SNPs), relating to the serum lipid traits and the effect of lipid-lowering drugs that target APOB, CETP, HMGCR, NPC1L1, and PCSK9, were extracted from genome-wide association studies (GWAS) summary data. The GWAS summary data were obtained from the Global Lipids Genetic Consortium (GLGC), the UK Biobank, and the FinnGen study, respectively. Mendelian randomization (MR) analysis was performed to evaluate the association between serum lipid traits and lipid-lowering drugs with migraine risk. RESULTS: Regarding serum lipids, it was found that SNPs related to high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), or triglycerides (TG) levels were not associated with migraine, migraine with aura (MA) or migraine without aura (MO). In addition, genotypes of HMGCR related to higher LDL-C levels were associated with increased risk of migraine (OR = 1.46, p = 0.035) and MA (OR = 2.03, p = 0.008); However, genotypes of PCSK9 related to higher LDL-C levels were associated with decreased risk of migraine (OR = 0.75, p = 0.001) and MA (OR = 0.69, p = 0.004); And genotypes of APOB related to higher LDL-C levels were associated with decreased risk of MO (OR = 0.62, p = 0.000). CONCLUSIONS: There is a relationship between lipid metabolism characteristics and migraine risk. SIGNIFICANCE: Based on the genome-wide association summary data, single-nucleotide polymorphisms (SNPs) related to high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), or triglycerides (TG) level were not associated with risk of migraine, migraine with aura (MA) or migraine without aura (MO). However, genotypes of HMGCR related to higher LDL-C levels have shown an increased risk on migraine and MA. And genotypes of APOB or PCSK9 related to higher LDL-C levels have shown a decreased risk on MO, or migraine and MA, respectively. These results suggested that there may be a relationship between lipid metabolism characteristics and the risk for migraine development.

Humans↗

PubMed2026

Proteomics-Based Identification of the Pyroptosis-Related Biomarker PCSK9 and Its Association With the Pathogenesis of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a common autoimmune disease, and early diagnosis is critical for effective treatment. This study aims to identify potential biomarkers related to pyroptosis through serum proteomics analysis, offering new insights for the early diagnosis of RA. We enrolled 100 participants, including 50 patients with RA and 50 healthy controls. Serum samples were collected and analyzed using high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) for proteomics profiling. Differential protein expression analysis and functional annotation revealed significant upregulation of pyroptosis-related proteins in the serum of patients with RA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, along with protein-protein interaction (PPI) network analysis, showed that these proteins are involved in inflammation and immune pathways, particularly the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome. Enzyme-linked immunosorbent assay (ELISA) validation confirmed a significant increase in PCSK9 levels in patients with RA, suggesting that PCSK9 may play a key role in the pathogenesis of RA. This study provides new directions for biomarker research in RA, particularly regarding the potential involvement of the pyroptosis pathway, with significant clinical application prospects.

Humans↗

PubMed2026

The Impact of PCSK9 Inhibitors on Development of Retinal Vascular Occlusions.

PURPOSE: PCSK9 inhibitors (PCSK9i) are a newer class of lipid-lowering drug that may be effective at lowering risk for retinal artery occlusion (RAO) and retinal vein occlusion (RVO). This study aims to investigate the relationship between PCSK9i use and retinal vascular occlusion among patients with hyperlipidemia. DESIGN: Retrospective, comparative clinical cohort study SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: Patients with hyperlipidemia, defined as serum low-density lipoprotein level of ≥130 mg/dL and total cholesterol level of ≥220 mg/dL, prescribed a lipid-lowering medication were identified. Patients prescribed a PCSK9i were included in the study group and compared with control patients prescribed any other type of lipid-lowering drug. METHODS: This study was conducted using electronic health record data from health organizations in the United States through the TrinetX platform. Propensity score matching was completed based on relevant patient demographics, comorbidities, and laboratory values. Comparison of main outcomes between the PCSK9i and non-PCSK9i groups was performed using measures of association analysis to determine risk ratio (RR) with 95% CI. MAIN OUTCOME MEASURES: The outcomes measured consisted of occurrence of retinal vascular occlusion, RAO, RVO, central RAO, and central RVO at 3-year, 5-year, and 7-year time points. RESULTS: After propensity score matching, a total of 12,960 patients were included in each cohort. The analysis revealed that the PCSK9i cohort had a significantly lower risk for development of retinal vascular occlusions at multiple points, including 3-year (RR = 0.56, CI = 0.39-0.79), 5-year (RR = 0.50, CI = 0.37-0.67), and 7-year (RR = 0.46, CI 0.35-0.61) time points. This lower risk was also found in the PCSK9i group for an outcome of RVO at 5 years (RR = 0.50, CI = 0.34-0.73) and 7 years (RR = 0.47, CI = 0.33-0.67). For occurrence of RAOs (RR = 0.47, CI = 0.30-0.76) and central RVO (RR = 0.46, CI = 0.29-0.74) separately, the PCSK9i cohort had a lower risk at 7 years. CONCLUSION: These findings suggest that PCSK9i may reduce the risk of retinal vascular occlusion compared with other classes of lipid-lowering medications.

Humans↗

PubMed2025

Cost-effectiveness of alternative cascade screening strategies for familial hypercholesterolemia with realistic cascade screening acceptance rates and use of novel treatment.

BACKGROUND AND AIMS: Cascade screening (CS) for familial hypercholesterolemia (FH) has been found to be cost-effective in many published studies. However, most existing studies (i) ignored or overstated first-degree relative (FDR) participation rate (as 60-100 %), (ii) did not consider novel and expensive therapies, e.g. PCSK9 inhibitors (PCSK9i), and (iii) were conducted outside of Asia. This study, conducted in Singapore, where FDR participation rate is about 25 % among probands who have known pathogenic variants, aims to identify drivers of cost-effectiveness of CS protocols for FH. METHODS: Four CS protocols, which vary in the application of genetic tests, were examined using a hybrid decision tree-Markov model. Sensitivity analyses were conducted to identify drivers of cost-effectiveness. RESULTS: Cascade acceptance rates are key drivers of cost-effectiveness. Other drivers include age of proband, prevalence of FH among probands, health-related quality of life loss with cardiovascular disease, timeliness of starting treatment post-screening, treatment effectiveness, cost of PCSK9i and discount rate for cost and QALY. With cascade acceptance rates observed in Singapore, among various screening protocols examined, probabilities of being cost-effective ranged from 86 % to 95 % when no access to PCSK9i and ranged from 75 % to 98 % when PCSK9i are provided. The most cost-effective protocol differs depending on cascade acceptance rates and whether PCSK9i is provided. CONCLUSION: For better cost-effectiveness of CS for FH, health systems need to look for ways to improve proband's willingness to share contact of their relatives and relatives' willingness to be screened and to lower the cost of novel treatment. Other ways to improve cost-effectiveness include to select age groups for proband screening, improve screening detection rate among probands, and start timely treatment post-screening.

Humans↗

PubMed2026

In vivo epigenome editing reduces circulating lipids and attenuates atherosclerosis in mice.

Atherosclerotic cardiovascular disease remains the leading cause of global mortality, with hypercholesterolemia serving as a critical driver of atherogenesis. Although current lipid-lowering therapies substantially improve circulating lipid profiles, strategies that provide more durable, safe, and efficient control of lipid metabolism are still needed. Epigenome editing offers a promising approach for long-lasting repression of disease-modifying genes without altering the underlying DNA sequence. Here, we develop CRISPRoff platforms delivered by adeno-associated virus or lipid nanoparticle to epigenetically silence hepatic Hmgcr or Pcsk9 in vivo. In both C57BL/6J wild-type and ApoE-/- mice, CRISPRoff mediates robust and durable repression of these targets, leading to marked reductions in circulating total cholesterol, low-density lipoprotein cholesterol, and triglycerides. In the ApoE-/- context, epigenetic silencing of Pcsk9 confers pronounced vascular protection, including decreased lipid accumulation in the liver and aortic root, reduced necrotic core formation, diminished macrophage infiltration, and enhanced plaque stability. Together, these results provide proof of principle that CRISPRoff-based epigenome editing enables stable repression of clinically relevant targets and ameliorates key features of atherosclerotic disease. This work lays the foundation for broader therapeutic applications of epigenetic modulation in cardiovascular disorders.

Animals↗

PubMed2026

Comparative safety of lipid-lowering drugs alone or in combination: insights from a systematic review and network meta-analysis.

BACKGROUND AND AIMS: Although the safety profile of lipid-lowering therapies (LLTs) is known, there are no comprehensive comparative assessments. We aimed to compare the risk of muscle-related events, diabetes, liver dysfunction, and cognitive disorders among LLTs through a network meta-analysis. METHODS AND RESULTS: Databases were searched from inception to May 2025. Eligible studies included adult patients, using statins, ezetimibe, PCSK9 monoclonal antibodies (PCSK9mAbs), inclisiran, bempedoic acid, or their combinations as intervention, reporting the information about any of the selected adverse events, a total sample size of ≥200 subjects, and had ≥1 month of intervention. Pooled estimates were assessed by fixed effects model within a frequentist setting. Pooled relative risks (RR) and their 95% confidence interval were estimated. A total of 303,397 subjects from 153 RCTs were included. Bempedoic acid ranked the lowest risk of myalgia (vs PCSK9mAbs, RR 0.80 [0.69, 0.93]). PCSK9mAbs were associated with lower incidence of creatine kinase (CK) elevation, diabetes, and liver dysfunction comparing to statins (statins vs PCSK9mAbs, RR 1.44 [1.14, 1.81], RR 1.13 [1.05, 1.22], and RR 1.38 [1.17, 1.62], respectively). In terms of muscle-related events and cognitive disorders, no significant risk differences were found among treatments and their combinations. CONCLUSIONS: PCSK9mAbs appear to have a more favourable safety profile regarding the risk of CK elevation, diabetes, and liver dysfunction. Bempedoic acid seem to be a better choice for subjects with high risk of myalgia. This information can be valuable when selecting therapy for specific patient subgroups at higher risk of certain adverse events.

Humans↗

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↗

PubMed2026

Genetically Proxied Inhibition of Cholesterol-Lowering Drug Targets and Survival in HPV-Positive and Non-HPV-Driven Head and Neck Cancer: A Multicentre MR Study.

BACKGROUND: Cholesterol pathways may influence head and neck squamous cell carcinoma (HNSCC) progression, but evidence on prognosis is inconsistent. We used Mendelian randomization (MR) to test whether genetically proxied inhibition of major low-density lipoprotein cholesterol (LDL-C)-lowering drug targets and circulating lipid traits affects overall survival (OS) in HPV-positive and non-HPV-driven HNSCCs. METHODS: We proxied lifelong LDL-C lowering using 55 cis-acting single-nucleotide polymorphisms in HMGCR, NPC1L1, PCSK9, and LDL-receptor (LDLR) from the updated 2021 Global Lipids Genetics Consortium and instrumented circulating lipid traits. Two-sample MR estimated effects on OS in 4,869 multicentre HNSCC cases (1,291 HPV-positive; 3,578 non-HPV-driven) using minimally adjusted Cox models. Sensitivity analyses additionally adjusted for tumor stage and treatment, assessed collider bias using an external HNSCC incidence genome-wide association study, and examined between-center heterogeneity and colocalization. RESULTS: Using the updated Global Lipids Genetic Consortium 2021 instruments, genetically proxied HMGCR inhibition showed a directionally protective but nonsignificant association with OS in HPV-positive oropharyngeal HNSCC in the primary analysis [inverse variance weighted (IVW) HR = 0.19; 95% confidence interval (CI), 0.03-1.18; P = 0.08], with directionally concordant weighted median results. No corresponding protective association was observed for HMGCR in non-HPV-driven disease (IVW HR = 1.68; 95% CI, 0.78-3.63; P = 0.19). No clear evidence of association was observed for NPC1L1, PCSK9, LDLR, or circulating lipid traits in either HPV stratum. Colocalization did not support a shared causal variant. CONCLUSIONS: These analyses provide suggestive evidence that genetically proxied HMGCR inhibition may influence survival in HPV-positive oropharyngeal HNSCC. IMPACT: HMGCR-related pathways may be relevant to prognosis in HPV-positive oropharyngeal HNSCC, whereas clear survival effects of other cholesterol-lowering targets were not supported.

Humans↗

PubMed2024

Lipid-lowering drugs and risk of rapid renal function decline: a mendelian randomization study.

BACKGROUND: Chronic kidney disease (CKD) patients face the risk of rapid kidney function decline leading to adverse outcomes like dialysis and mortality. Lipid metabolism might contribute to acute kidney function decline in CKD patients. Here, we utilized the Mendelian Randomization approach to investigate potential causal relationships between drug target-mediated lipid phenotypes and rapid renal function decline. METHODS: In this study, we utilized two methodologies: summarized data-based Mendelian randomization (SMR) and inverse variance-weighted Mendelian randomization (IVW-MR), to approximate exposure to lipid-lowering drugs. This entailed leveraging expression quantitative trait loci (eQTL) for drug target genes and genetic variants proximal to drug target gene regions, which encode proteins associated with low-density lipoprotein (LDL) cholesterol, as identified in genome-wide association studies. The objective was to investigate causal associations with the progression of rapid kidney function decline. RESULTS: The SMR analysis revealed a potential association between high expression of PCSK9 and rapid kidney function decline (OR = 1.11, 95% CI= [1.001-1.23]; p = 0.044). Similarly, IVW-MR analysis demonstrated a negative association between LDL cholesterol mediated by HMGCR and kidney function decline (OR = 0.74, 95% CI = 0.60-0.90; p = 0.003). CONCLUSION: Genetically predicted inhibition of HMGCR is linked with the progression of kidney function decline, while genetically predicted PCSK9 inhibition is negatively associated with kidney function decline. Future research should incorporate clinical trials to validate the relevance of PCSK9 in preventing kidney function decline.

Mendelian Randomization Analysis↗

PubMed2026

PCSK9 as a Key Gene of Metastasis in Lung Adenocarcinoma: A Multi-omics and Experimental Validation Study.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common form of lung cancer. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is abnormally expressed in various tumor tissues and is associated with malignant phenotypes. However, the clinical significance, function, and mechanism of LUAD invasion and metastasis remain unclear. METHODS: We retrospectively enrolled 100 patients with LUAD in this study. Initially, qRT-PCR was performed to detect PCSK9 levels in clinical tissues. Subsequently, bioinformatics analysis of scRNA-seq and The Cancer Genome Atlas Program (TCGA) datasets was performed to predict the role of PCSK9 in tumor cell malignancy and its potential downstream pathways. These predictions were validated experimentally using the CCK-8 assay, TUNEL staining, wound healing, transwell invasion assay, and an in vivo lung metastasis model. Finally, Western blotting and an AKT inhibitor (MK2206) were used to verify the underlying mechanism. RESULTS: PCSK9 was significantly upregulated in LUAD tissues compared to paracancerous tissues and was associated with poorer OS and DFS. Bioinformatics analysis of scRNA-seq data and TCGA analysis predicted that PCSK9 is highly enriched in tumor cells and is involved in EMT, and that the PI3K/AKT pathway plays a significant role in LUAD development. Experiments confirmed that PCSK9 markedly promoted LUAD cell proliferation, migration, and invasion in vitro and lung metastasis in vivo. PCSK9 overexpression significantly upregulated p-AKT, p-PI3K, and p-mTOR levels. Furthermore, the AKT inhibitor, MK2206, reversed the promoting effects of PCSK9. CONCLUSIONS: PCSK9 expression is associated with the prognosis and diagnosis of LUAD. This molecule activates the PI3K/AKT signaling pathway, thereby driving invasion, metastasis, and proliferation in LUAD.

Humans↗

PubMed2025

Silencing FAF2 mitigates alcohol-induced hepatic steatosis by modulating lipolysis and PCSK9 pathway.

BACKGROUND: Chronic alcohol consumption leads to lipid accumulation, oxidative stress, cellular damage, and inflammation in the liver, collectively referred to as alcohol-associated liver disease (ALD). FAF2/UBXD8/ETEA (Fas-associated factor 2) is a ubiquitin ligase adaptor protein that plays a crucial role in the ubiquitin-mediated degradation of misfolded proteins in the endoplasmic reticulum. A recent genome-wide association study indicated an association between FAF2 and ALD; however, the exact contribution of FAF2 to ALD pathogenesis remains unclear. METHODS: FAF2 was knocked down using AAV-delivered shRNA in C57/BL6 mice. Mice were subjected to a chronic-plus-single binge ethanol feeding (NIAAA) model. Nine hours after gavage, liver, blood, and other organs of interest were collected for gene expression and biochemical analyses. RESULTS: We first observed a significant elevation in hepatic FAF2 protein expression in individuals with ALD and in mice subjected to an ethanol-binge model. Interestingly, knocking down FAF2 in the liver using adeno-associated virus serotype 8-delivered short hairpin RNA conferred a protective effect against alcohol-induced liver steatosis in ethanol-binged mice. Transcriptomic analysis revealed that differentially expressed genes were enriched in multiple lipid metabolism regulation pathways. Further analysis of transcription factors regulating these differentially expressed genes suggested potential regulation by SREBP1. Several SREBP1 target genes, including Fasn, Scd1, Lpin1, and Pcsk9 (proprotein convertase subtilisin/kexin type 9), were dysregulated in the livers of ethanol-fed FAF2 knockdown mice. Additionally, Pcsk9 could be regulated through the FOXO3-SIRT6 pathway in the livers of ethanol-fed FAF2 knockdown mice, leading to increased liver low-density lipoprotein receptor expression and reduced plasma LDL cholesterol levels. Furthermore, FAF2 knockdown in mouse liver enhanced adipose triglyceride lipase lipolytic activity by upregulating the adipose triglyceride lipase activator, comparative gene identification-58, and downregulating the adipose triglyceridelipase transport inhibitor, Elmod2, contributing to the alleviation of liver steatosis. CONCLUSIONS: Our study uncovers a novel mechanism involving FAF2 in the pathogenesis of ALD.

Animals↗

PubMed2025

Design of optimized epigenetic regulators for durable gene silencing with application to PCSK9 in nonhuman primates.

Epigenetic editing is a promising strategy for modifying gene expression while avoiding the permanent alterations and potential genotoxicity of genome-editing technologies. Here we designed optimized epigenetic regulators (EpiRegs) by testing combinations of transcription activator-like effector (TALE)-based and catalytically deactivated Cas9 (dCas9)-based epigenetic modification effectors and fusion protein structures. TALE-based EpiReg (EpiReg-T) achieved a final efficiency of 98% in mice, surpassing the initial dCas9-based efficiency of 64%. We demonstrated the approach in macaques by introducing DNA methylation and histone modifications to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) expression, thereby lowering low-density lipoprotein cholesterol levels. A single dose of EpiReg-T delivered with lipid nanoparticles achieved efficient (>90%) and long-lasting (343 days) silencing of PCSK9 in the liver. Integrative multiomic analyses revealed minimal off-target effects in EpiReg-T-treated monkeys, mice and human-derived cells. EpiReg can be redirected to other genes by reengineering the DNA-binding domain. Our findings represent a step toward the clinical application of epigenetic editing for the treatment of human diseases.

Animals↗

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↗

PubMed2026

Association of PCSK9 and CCL22 gene polymorphisms with myocardial infarction in a South Indian population.

Myocardial infarction (MI) remains a major global cause of morbidity and mortality, with a particularly high burden among individuals with type 2 diabetes mellitus (T2DM). Host genetic factors play a significant role in modulating individual susceptibility to MI by influencing lipid metabolism and immune-mediated inflammatory pathways. The proprotein convertase subtilisin/kexin type 9 (PCSK9) gene is a key regulator of cholesterol homeostasis, while C-C motif chemokine ligand 22 (CCL22) is involved in immune cell recruitment and vascular inflammation. In this study, we investigated the association of PCSK9 rs505151 and rs11591147 and CCL22 rs4359426 polymorphisms with MI risk in a South Indian population. This case-control study included 400 participants categorized into controls (n = 100), MI (n = 100), T2DM (n = 100), and MI with T2DM (n = 100). Significant differences in clinical and biochemical parameters, including lipid indices and cardiometabolic risk markers, were observed between groups (p < 0.05). Genetic analysis revealed a significant association between the PCSK9 rs505151 variant and MI susceptibility across allelic and genotypic distributions, with significant effects under dominant and recessive inheritance models. Multivariable logistic regression confirmed that the rs505151 risk genotype was independently associated with MI after adjustment for age, sex, body mass index, and smoking status. In contrast, PCSK9 rs11591147 was rare and showed no significant association. The CCL22 rs4359426 polymorphism showed limited evidence of association with MI, with a significant effect observed only under the dominant inheritance model. Furthermore, combined analysis using a genetic risk score suggested that cumulative genetic burden involving PCSK9 and CCL22 variants was associated with an increased risk of MI. Overall, our findings suggest that genetic variation in lipid-regulatory and immune-related pathways may contribute to MI susceptibility in South Indians. Further studies are warranted to validate these associations and clarify their biological and clinical relevance.

Humans↗

PubMed2026

Cross-Ancestry Proteogenomic Analyses Identified New Therapeutic Insights for Ischemic Heart Disease.

BACKGROUND: Most drugs target proteins, and proteome-wide genetic analyses in diverse populations could discover potential novel and repurposed targets for improved prevention and treatment of ischemic heart disease (IHD) beyond statin therapy. OBJECTIVES: The purposes of this study were to use cis-acting single nucleotide polymorphisms (cis-pQTLs) identified for plasma proteins in East Asians and Europeans to discover and validate potential drug targets for IHD. METHODS: We measured plasma levels of 9,520 (Olink/SomaScan: 2,923/7,297) proteins in a case-cohort study of IHD (1,976 incident cases and 2,001 subcohort controls) in statin-free individuals in the prospective China Kadoorie Biobank (CKB). Genome-wide association studies identified 2,895 (Olink/SomaScan: 1,301/1,594) cis-pQTLs for these proteins in CKB. Two-sample Mendelian randomization (MR) and colocalization analyses assessed associations of all available cis-pQTLs for these proteins with IHD in East Asians (n = 29,319 cases), with further replication in Europeans (n = 181,522 cases) and comparison with findings in previous MR studies. RESULTS: In CKB observational analyses, a total of 959 (Olink/SomaScan: 426/533) proteins were associated at false discovery rate-corrected P < 0.05 with IHD after adjusting for major IHD risk factors. Two-sample MR analyses provided genetic support for 54 unique (Olink/SomaScan: 36/28) proteins in IHD etiology. Colocalization analyses confirmed shared gene-protein-IHD associations (posterior probability of hypothesis 4 [PPH4] ≥0.8) for 15 unique (Olink/SomaScan: 10/10) proteins, including 8 lipid-related, 3 inflammation-related, 1 blood pressure-related, and 3 alcohol-related proteins in East Asians. In Europeans, MR analyses of 12 non-alcohol-related proteins showed directionally concordant results for 8 proteins, with 5 having strong colocalization evidence of shared gene-protein-IHD associations (PPH4 ≥0.8), including 4 lipid-related (proprotein convertase subtilisin/kexin type 9, LPA, APOE, cadherin-1) and 1 systolic blood pressure-related (fibroblast growth factor 5) protein. However, 4 proteins showed directionally discordant MR results, including 2 lipid-related (APOA5, SORT1) and 1 inflammation-related (transforming growth factor beta 1) proteins with strong colocalization evidence of shared gene-protein-IHD associations (PPH4 ≥0.8). Comparison with previous MR studies revealed little consistency across studies in the number and identity of target proteins for IHD beyond well-established lipid-related (low-density lipoprotein cholesterol, lipoprotein(a), and triglycerides) or inflammation-related (interleukin-6) protein targets. CONCLUSIONS: The findings support a role for lipid-driven chronic inflammation in IHD etiology, and treatment strategies simultaneously targeting multiple lipid and inflammation pathways should be prioritized for further research to improve drug treatment of IHD beyond statin therapy.

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PubMed2026

Engineered Transformer Base Editor with Enhanced Editing Efficiency.

Canonical cytosine base editors (CBEs) achieve precise C-to-T conversions without inducing DNA double-strand breaks (DSBs), yet their clinical potential remains hampered by substantial off-target (OT) mutations. The recently developed transformer base editor (tBE) significantly reduces both genomic and transcriptomic OT mutations by using a cleavable deoxycytidine deaminase inhibitor (dCDI) domain. However, the modest base editing efficiency limits its broader applications. Here, through rational deaminase engineering and fusion of a uracil DNA glycosylase inhibitor (UGI) domain, we developed the engineered tBE (etBE). The etBE exhibited substantially enhanced editing efficiencies compared with the parental tBE (up to 35.11-fold improvement), while maintaining high editing fidelity and background levels of OT mutations. As a therapeutic proof-of-concept, dual adeno-associated virus (AAV)-mediated delivery of etBE targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), a well-established therapeutic target for cardiovascular diseases, was evaluated in a humanized mouse model. The treatment achieved efficient in vivo base editing (up to 35.13%), resulting in substantial reductions in plasma PCSK9 protein (24%) and low-density lipoprotein cholesterol (LDL-C) levels (33%), while inducing only minimal OT mutations. Collectively, etBE represents a highly efficient and specific base editing platform with enormous potential for both basic research and clinical applications.

CRISPR‐Cas9↗