Association of lipid-lowering drugs with risk of sarcopenia: a drug target mendelian randomization study and meta-analysis.

BACKGROUND: Lipid-lowering drugs are widely used among the elderly, with some studies suggesting links to muscle-related symptoms. However, the causality remains uncertain. METHODS: Using the Mendelian randomization (MR) approach, we assessed the causal effects of genetically proxied reduced low-density lipoprotein cholesterol (LDL-C) through inhibitions of hydroxy-methyl-glutaryl-CoA reductase (HMGCR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and Niemann-Pick C1-like 1 (NPC1L1) on sarcopenia-related traits, including low hand grip strength, appendicular lean mass, and usual walking pace. A meta-analysis was conducted to combine the causal estimates from different consortiums. RESULTS: Using LDL-C pooled data predominantly from UK Biobank, genetically proxied inhibition of HMGCR was associated with higher appendicular lean mass (beta = 0.087, P = 7.56 × 10- 5) and slower walking pace (OR = 0.918, P = 6.06 × 10- 9). In contrast, inhibition of PCSK9 may reduce appendicular lean mass (beta = -0.050, P = 1.40 × 10- 3), while inhibition of NPC1L1 showed no causal impact on sarcopenia-related traits. These results were validated using LDL-C data from Global Lipids Genetics Consortium, indicating that HMGCR inhibition may increase appendicular lean mass (beta = 0.066, P = 2.17 × 10- 3) and decelerate walking pace (OR = 0.932, P = 1.43 × 10- 6), whereas PCSK9 inhibition could decrease appendicular lean mass (beta = -0.048, P = 1.69 × 10- 6). Meta-analysis further supported the robustness of these causal associations. CONCLUSIONS: Genetically proxied HMGCR inhibition may increase muscle mass but compromise muscle function, PCSK9 inhibition could result in reduced muscle mass, while NPC1L1 inhibition is not associated with sarcopenia-related traits and this class of drugs may serve as viable alternatives to sarcopenia individuals or those at an elevated risk.

Repurposing lipid-lowering drugs on asthma and lung function: evidence from a genetic association analysis.

OBJECTIVE: To explore the correlation between asthma risk and genetic variants affecting the expression or function of lipid-lowering drug targets. METHODS: We conducted Mendelian randomization (MR) analyses using variants in several genes associated with lipid-lowering medication targets: HMGCR (statin target), PCSK9 (alirocumab target), NPC1L1 (ezetimibe target), APOB (mipomersen target), ANGPTL3 (evinacumab target), PPARA (fenofibrate target), and APOC3 (volanesorsen target), as well as LDLR and LPL. Our objective was to investigate the relationship between lipid-lowering drugs and asthma through MR. Finally, we assessed the efficacy and stability of the MR analysis using the MR Egger and inverse variance weighted (IVW) methods. RESULTS: The elevated triglyceride (TG) levels associated with the APOC3, and LPL targets were found to increase asthma risk. Conversely, higher LDL-C levels driven by LDLR were found to decrease asthma risk. Additionally, LDL-C levels (driven by APOB, NPC1L1 and HMGCR targets) and TG levels (driven by the LPL target) were associated with improved lung function (FEV1/FVC). LDL-C levels driven by PCSK9 were associated with decreased lung function (FEV1/FVC). CONCLUSION: In conclusion, our findings suggest a likely causal relationship between asthma and lipid-lowering drugs. Moreover, there is compelling evidence indicating that lipid-lowering therapies could play a crucial role in the future management of asthma.

[Pharmacological and clinical profile of inclisiran sodium, a long-acting LDL cholesterol lowering siRNA, LEQVIO for s.c. injection syringe 300†|mg].

Inclisiran sodium (Brand name: LEQVIO® for s.c. injection syringe 300 |mg, hereinafter referred to as inclisiran), a small interfering ribonucleic acid (siRNA) product that targets the mRNA that encodes the proprotein convertase subtilisin/kexin type 9 (PCSK9) protein was approved on September 25, 2023 for the indication of "Familial hypercholesterolemia, hypercholesterolemia" in Japan. Inclisiran is conjugated on the sense strand with triantennary N-acetylgalactosamine to facilitate uptake by hepatocytes. In vitro and in vivo pharmacology studies demonstrated the lowering effects of PCSK9 and LDL-C in hepatocytes and cynomolgus monkeys. It was considered unlikely to cause clinically significant risks due to toxicities arising from complementary binding to non-target RNA sequences (hybridization-dependent off-target effects). Clinical trials conducted globally including Japan in patients with familial hypercholesterolemia and hypercholesterolemia who did not reach the LDL-C target showed that inclisiran sodium 300 |mg dosed at Day 1, Day 90 and then every 6 months demonstrated significant LDL-C reduction and the efficacy sustained long. The majority of patients achieved the guideline recommended LDL-C targets. Inclisiran sodium 300 |mg was well tolerated and there were no specific safety concerns. Therefore, inclisiran is expected to be a new therapeutic option for the patients with familial hypercholesterolemia and hypercholesterolemia.

20( S )-Protopanaxatriol Improves Atherosclerosis by Inhibiting Low-Density Lipoprotein Receptor Degradation in ApoE KO Mice.

ABSTRACT: Atherosclerosis (AS) is a chronic progressive disease caused by various factors and causes various cerebrovascular and cardiovascular diseases (CVDs). Reducing the plasma levels of low-density lipoprotein cholesterol is the primary goal in preventing and treating AS. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in regulating low-density lipoprotein cholesterol metabolism. Panax notoginseng has potent lipid-reducing effects and protects against CVDs, and its saponins induce vascular dilatation, inhibit thrombus formation, and are used in treating CVDs. However, the anti-AS effect of the secondary metabolite, 20( S )-protopanaxatriol (20( S )-PPT), remains unclear. In this study, the anti-AS effect and molecular mechanism of 20( S )-PPT were investigated in vivo and in vitro by Western blotting, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, immunofluorescence staining, and other assays. The in vitro experiments revealed that 20( S )-PPT reduced the levels of PCSK9 in the supernatant of HepG2 cells, upregulated low-density lipoprotein receptor protein levels, promoted low-density lipoprotein uptake by HepG2 cells, and reduced PCSK9 mRNA transcription by upregulating the levels of forkhead box O3 protein and mRNA and decreasing the levels of HNF1α and SREBP2 protein and mRNA. The in vivo experiments revealed that 20( S )-PPT upregulated aortic α-smooth muscle actin expression, increased the stability of atherosclerotic plaques, and reduced aortic plaque formation induced by a high-cholesterol diet in ApoE -/- mice (high-cholesterol diet-fed group). Additionally, 20( S )-PPT reduced the aortic expression of CD68, reduced inflammation in the aortic root, and alleviated the hepatic lesions in the high-cholesterol diet-fed group. The study revealed that 20( S )-PPT inhibited low-density lipoprotein receptor degradation via PCSK9 to alleviate AS.

Improving the Detection of Potential Cases of Familial Hypercholesterolemia: Could Machine Learning Be Part of the Solution?

BACKGROUND: Familial hypercholesterolemia (FH), while highly prevalent, is a significantly underdiagnosed monogenic disorder. Improved detection could reduce the large number of cardiovascular events attributable to poor case finding. We aimed to assess whether machine learning algorithms outperform clinical diagnostic criteria (signs, history, and biomarkers) and the recommended screening criteria in the United Kingdom in identifying individuals with FH-causing variants, presenting a scalable screening criteria for general populations. METHODS AND RESULTS: Analysis included UK Biobank participants with whole exome sequencing, classifying them as having FH when (likely) pathogenic variants were detected in their LDLR, APOB, or PCSK9 genes. Data were stratified into 3 data sets for (1) feature importance analysis; (2) deriving state-of-the-art statistical and machine learning models; (3) evaluating models' predictive performance against clinical diagnostic and screening criteria: Dutch Lipid Clinic Network, Simon Broome, Make Early Diagnosis to Prevent Early Death, and Familial Case Ascertainment Tool. One thousand and three of 454 710 participants were classified as having FH. A Stacking Ensemble model yielded the best predictive performance (sensitivity, 74.93%; precision, 0.61%; accuracy, 72.80%, area under the receiver operating characteristic curve, 79.12%) and outperformed clinical diagnostic criteria and the recommended screening criteria in identifying FH variant carriers within the validation data set (figures for Familial Case Ascertainment Tool, the best baseline model, were 69.55%, 0.44%, 65.43%, and 71.12%, respectively). Our model decreased the number needed to screen compared with the Familial Case Ascertainment Tool (164 versus 227). CONCLUSIONS: Our machine learning-derived model provides a higher pretest probability of identifying individuals with a molecular diagnosis of FH compared with current approaches. This provides a promising, cost-effective scalable tool for implementation into electronic health records to prioritize potential FH cases for genetic confirmation.

Associations of lipids and lipid-modifying drug target genes with atrial fibrillation risk based on genomic data.

BACKGROUND: The causal associations of lipids and the drug target genes with atrial fibrillation (AF) risk remain obscure. We aimed to investigate the causal associations using genetic evidence. METHODS: Mendelian randomization (MR) analyses were conducted using summary-level genome-wide association studies (GWASs) in European and East Asian populations. Lipid profiles (low-density lipoprotein cholesterol, triglyceride, and lipoprotein[a]) and lipid-modifying drug target genes (3-hydroxy-3-methylglutaryl-CoA reductase, proprotein convertase subtilisin/kexin type 9, NPC1-like intracellular cholesterol transporter 1, apolipoprotein C3, angiopoietin-like 3, and lipoprotein[a]) were used as exposures. AF was used as an outcome. The inverse variance weighted method was applied as the primary method. Summary-data-based Mendelian randomization analyses were performed for further validation using expression quantitative trait loci data. Mediation analyses were conducted to explore the indirect effect of coronary heart disease. RESULTS: In the European population, MR analyses demonstrated that elevated levels of lipoprotein(a) increased AF risk. Moreover, analyses focusing on drug targets revealed that the genetically proxied target gene LPA, which simulates the effects of drug intervention by reducing lipoprotein(a), exhibited an association with AF risk. This association was validated in independent datasets. There were no consistent and significant associations observed for other traits when analyzed in different datasets. This finding was also corroborated by Summary-data-based Mendelian randomization analyses between LPA and AF. Mediation analyses revealed that coronary heart disease plays a mediating role in this association. However, in the East Asian population, no statistically significant evidence was observed to support these associations. CONCLUSIONS: This study provided genetic evidence that Lp(a) may be a causal factor for AF and that LPA may represent a promising pharmacological target for preventing AF in the European population.

Effects of genetically proxied lipid-lowering drugs on acute myocardial infarction: a drug-target mendelian randomization study.

OBJECTIVE: High low-density-lipoprotein (LDL) cholesterol has been associated with an increased risk of coronary artery diseases (CAD) including acute myocardial infarction (AMI). However, whether lipids lowering drug treatment is causally associated with decreased risk of AMI remains largely unknown. We used Mendelian randomization (MR) to evaluate the influence of genetic variation affecting the function of lipid-lowering drug targets on AMI. METHODS: Single-nucleotide polymorphisms (SNPs) associated with lipids as instruments were extracted from the Global Lipids Genetics Consortium (GLGC). The genome-wide association study (GWAS) data for AMI were obtained from UK Biobank. Two sample MR analysis was used to study the associations between high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG) with AMI (n = 3,927). Genetic variants associated with LDL cholesterol at or near drug target gene were used to mimic drug effects on the AMI events in drug target MR. RESULTS: Genetically predicted higher LDL-C (per one SD increase in LDL-C of 38.67 mg/dL, OR 1.006, 95% CI 1.004-1.007) and TG (per one SD increase in TG of 90.72 mg/dL, 1.004, 1.002-1.006) was associated with increased risk of AMI, but decreased risk for higher HDL-C (per one SD increase in HDL-C of 15.51 mg/dL, 0.997, 0.995-0.999) in univariable MR. Association remained significant for LDL-C, but attenuated toward the null for HDL-C and TG in multivariable MR. Genetically proxied lower LDL-C with genetic variants at or near the PCSK9 region (drug target of evolocumab) and NPC1L1 (drug target of ezetimibe) were associated with decreased risk of AMI (0.997, 0.994-0.999 and 0.986, 0.975-0.998, respectively), whereas genetic variants at HMGCR region (drug target of statin) showed marginal association with AMI (0.995, 0.990-1.000). After excluding drug target-related SNPs, LDL-C related SNPs outside the drug target region remained a causal effect on AMI (0.994, 0.993-0.996). CONCLUSIONS: The findings suggest that genetically predicted LDL-C may play a predominant role in the development of AMI. The drug MR results imply that ezetimibe and evolocumab may decrease the risk of AMI due to their LDL-C lowering effect, and there are other non-drug related lipid lowering pathways that may be causally linked to AMI.

Far-infrared irradiation increases the uptake of LDL cholesterol by downregulating PCSK9 through the activation of TRPV4 calcium channels in HepG2 cells.

This study investigated the effects of far-infrared (FIR) irradiation on low-density lipoprotein cholesterol (LDL-C) uptake by human hepatocellular carcinoma G2 (HepG2) cells via the regulation of proprotein convertase subtilisin/kexin type 9 (PCSK9). FIR irradiation for 30 min significantly decreased PCSK9 expression (p < 0.01) in HepG2 cells. FIR irradiation substantially increased the low-density lipoprotein receptor (p < 0.0001) and LDL-C uptake (p < 0.01). Activation of transient receptor potential vanilloid (TRPV) channels mimicked the effects of FIR irradiation, significantly decreasing the protein expression of PCSK9 (p < 0.05). Conversely, inhibition of TRP channels using ruthenium red reversed the reduction in PCSK9 protein expression following FIR irradiation (p < 0.01). The specific activation of TRPV4 using 4α-PDD mimicked the effect of FIR irradiation (p < 0.01), whereas PCSK9 reduction by FIR irradiation was significantly reversed by the inhibition of TRPV4 using RN1734 (p < 0.05). These findings implied that FIR irradiation emitted from a ceramic lamp specifically increased TRPV4 activity. These findings provide insights into a novel therapeutic approach using FIR irradiation for LDL-C regulation and its implications for cardiovascular health.

Association between Apo B, LDL-R and PCSK9 gene polymorphisms with coronary artery diseases in Egyptians.

BACKGROUND: Many studies have focused on the significance of lipid regulatory genes in the pathophysiology of Coronary artery disease (CAD). ApoB XbaI (rs693) and EcoRI (rs1042031) single nucleoid polymorphisms (SNPs) were investigated to detect whether they are risk factors for CAD. Till now, this association remains uncertain. SMARCA4 (rs1122608) SNP has directly related to dyslipidemia. Loss of function mutations (LOF) in PCSK9 result in a reduction in LDL cholesterol and are associated with protection from the development of CAD. METHODS: This study was conducted on 54 CAD patients who were admitted at Internal Medicine Specialized Hospital (Cardiology Department) and 47 healthy controls. Peripheral blood samples were taken from both groups. DNA was extracted from EDTA-blood samples, then PCR- RFLP for ApoB XbaI (rs693) and EcoRI (rs1042031), SMARCA4 (rs1122608) and PCSK9 (rs505151) SNPs was done. RESULTS: No statistically significant difference was found between patients and controls as regard EcoRI SNP. XbaI (rs693) X + X + genotype was significantly higher in control group (P = 0.0355). SMARCA4 (TT, GT + TT) genotypes, and T allele (P < 0.001); PCSK9 AG genotype and G allele (P = 0.027 and 0.032 respectively) were more frequent in CAD patients than controls. CONCLUSION: SMARCA4 (rs1122608) and PCSK9 (rs505151) SNPs are significantly accompanying with the risk of CAD development in the Egyptian population. X + X + genotype appeared to have a protective effect against CAD. However, no observed association between EcoRI (rs1042031) and the risk of CAD development was found.

PCSK9 aggravated carotid artery stenosis in ApoE-/- mice by promoting the expression of tissue factors in endothelial cells via the TLR4/NF-κB pathway.

Atherosclerosis, a chronic inflammatory disease, is the most relevant cause of carotid artery stenosis. Vascular endothelial cells (ECs) play a significant role in the development of atherosclerosis. In this chronic inflammatory environment, we aimed to investigate whether PCSK9 could mitigate atherosclerosis progression by reducing tissue factor expression in ECs via in vivo and in vitro assays. In vivo, we investigated the effect of PCSK9 inhibition on preventing atherosclerotic lesion formation in ApoE-/- mice fed a western diet. The results showed that inhibiting PCSK9 could significantly downregulate the protein expression of tissue factor (TF) in ECs to reduce the area of atherosclerotic plaques. In vitro, we incubated human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS). We found that LPS-induced TF elevation was suppressed by a PCSK9 inhibitor at both the mRNA and protein levels and that the TLR4/NF-κB pathway was also suppressed by a PCSK9 inhibitor. With respect to plasma samples from patients with carotid artery stenosis, we also demonstrated that the expression of TF was positively correlated with that of PCSK9. Thus, in addition to regulating lipid metabolism, the regulation of endothelial cell TF expression through the TLR4/NF-κB pathway may be a potential mechanism of PCSK9 in promoting atherosclerotic carotid stenosis.

Gallic Acid Can Promote Low-Density Lipoprotein Uptake in HepG2 Cells via Increasing Low-Density Lipoprotein Receptor Accumulation.

Gallic acid (GA) is a type of polyphenolic compound that can be found in a range of fruits, vegetables, and tea. Although it has been confirmed it improves non-alcoholic fatty liver disease (NAFLD), it is still unknown whether GA can improve the occurrence of NAFLD by increasing the low-density lipoprotein receptor (LDLR) accumulation and alleviating cholesterol metabolism disorders. Therefore, the present study explored the effect of GA on LDLR and its mechanism of action. The findings indicated that the increase in LDLR accumulation in HepG2 cells induced by GA was associated with the stimulation of the epidermal growth factor receptor-extracellular regulated protein kinase (EGFR-ERK1/2) signaling pathway. When the pathway was inhibited by EGFR mab cetuximab, it was observed that the activation of the EGFR-ERK1/2 signaling pathway induced by GA was also blocked. At the same time, the accumulation of LDLR protein and the uptake of LDL were also suppressed. Additionally, GA can also promote the accumulation of forkhead box O3 (FOXO3) and suppress the accumulation of hepatocyte nuclear factor-1α (HNF1α), leading to the inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) mRNA expression and protein accumulation. This ultimately results in increased LDLR protein accumulation and enhanced uptake of LDL in cells. In summary, the present study revealed the potential mechanism of GA's role in ameliorating NAFLD, with a view of providing a theoretical basis for the dietary supplementation of GA.

Targeting PCSK9 as a key player in lipid metabolism: exploiting the therapeutic and biosensing potential of aptamers.

The degradation of low-density lipoprotein receptor (LDLR) is induced by proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in elevated plasma concentrations of LDL cholesterol. Therefore, inhibiting the interactions between PCSK9 and LDLR is a desirable therapeutic goal for managing hypercholesterolemia. Aptamers, which are RNA or single-stranded DNA sequences, can recognize their targets based on their secondary structure. Aptamers exhibit high selectivity and affinity for binding to target molecules. The systematic evolution of ligands by exponential enrichment (SELEX), a combination of biological approaches, is used to screen most aptamers in vitro. Due to their unique advantages, aptamers have garnered significant interest since their discovery and have found extensive applications in various fields. Aptamers have been increasingly utilized in the development of biosensors for sensitive detection of pathogens, analytes, toxins, drug residues, and malignant cells. Furthermore, similar to monoclonal antibodies, aptamers can serve as therapeutic tools. Unlike certain protein therapeutics, aptamers do not elicit antibody responses, and their modified sugars at the 2'-positions generally prevent toll-like receptor-mediated innate immune responses. The focus of this review is on aptamer-based targeting of PCSK9 and the application of aptamers both as biosensors and therapeutic agents.

Effect of the PCSK9 R46L genetic variant on plasma insulin and glucose levels, risk of diabetes mellitus and cardiovascular disease: A meta-analysis.

BACKGROUND AND AIM: The impact of the loss-of-function (LOF) genetic variant PCSK9 R46L on glucose homeostasis and cardiovascular disease (CVD) remains uncertain, despite its established correlation with diminished blood cholesterol levels. This meta-analysis aimed at exploring the effect of the PCSK9 R46L genetic variant on plasma insulin and glucose levels, risk of diabetes mellitus and CVD. METHODS AND RESULTS: PubMed, Embase, and the Cochrane Library were searched for cohort and case-control studies published until October 1, 2023. The studies should report the association of the PCSK9 R46L genetic variant with one of the following: fasting plasma insulin, blood glucose levels, diabetes mellitus, and CVD risk. A dominant model of the PCSK9 R46L genetic variant was employed to statistical analysis. The meta-analyses were performed for continuous variables with standard mean difference (SMD), categorical variables with odds ratio (OR) using a random-effects model. A total of 17 articles with 20 studies engaging 1,186,861 population were identified and mobilized for these analyses. The overall results indicated that, compared with non-carriers of the PCSK9 R46L genetic variant, carriers of the PCSK9 R46L genetic variant did not increase or decrease the levels of fasting plasma insulin (3 studies with 7277 population; SMD, 0.08; 95% CI, -0.04 to 0.19; P = 0.270), and the levels of fasting plasma glucose (7 studies with 9331 population; SMD, 0.03; 95% CI, -0.08 to 0.13; P = 0.610). However, carriers of the PCSK9 R46L genetic variant indeed had 17% reduction in the risk of CVD (11 studies with 558,263 population; OR, 0.83; 95% CI, 0.71 to 0.98; P = 0.030), and 9% increase in the risk of diabetes mellitus (10 studies with 744,466 population; OR, 1.09; 95% CI, 1.04 to 1.14; P < 0.01). Meta-regression analyses indicated that the increased risk of diabetes mellitus and the reduced risk of CVD were positively correlated with reduction in LDL-C (P = 0.004 and 0.033, respectively). CONCLUSIONS: PCSK9 R46L genetic variant exhibited an elevated susceptibility to diabetes mellitus alongside a reduced vulnerability to CVD.

Analysis of the Correlation between FH and PCSK9 and APOB Gene Mutations in Han and Mongolian Populations of the Hulunbuir.

BACKGROUND: The goal of the study was to provide an individual and precise genetic and molecular biological basis for the early prevention, diagnosis, and treatment of local FH by analyzing the risk factors for the development of FH in Han and Mongolian patients in the Hulunbuir, comparing the lipid levels of FH patients of the two ethnicities, and assessing differences in mutations to two genes between the two ethnic groups. METHODS: Twenty cases each of Han Chinese and Mongolian healthy controls and fifty patients who each met the inclusion criteria from November 2021 to December 2022 in five general hospitals in Hulunbuir were selected. Multifactor logistic analysis was used to analyze the risk factors associated with the development of FH. We used t-tests to analyze statistical differences in lipid levels between the groups, and Sanger sequencing to detect the dis-tribution of common mutation sites of PCSK9 and APOB in all study subjects. The mutation rates and differences between regions and ethnic groups were summarized and compared. RESULTS: 1) Gender, age, alcohol consumption, dietary status, and a family history of FH were risk factors associated with the development of FH. 2) TC, LDL-C, and APOB were significantly higher in Mongolian cases than Han cases (p < 0.05). sdLDL-C was not statistically different between the two ethnicities (p > 0.05). 3) We detected four (8%) heterozygous mutations at the PCSK9 gene E670G mutation site in the Han case group and a total of nine (18%) mutations at this site in the Mongolian cases, including one (2%) homozygous and eight (16%) heterozygous mutations. One case of a heterozygous mutation was detected in the Mongolian control group. We detected a total of ten (20%) mutations at the APOB gene rs1367117 mutation site in the Han case group, including eight (16%) heterozygous and two (4%) homozygous mutations, 11 cases (22%) of heterozygous mutations in the Mongolian case group, two cases of heterozygous mutations in the Han control group, and one case of a heterozygous mutation in the Mongolian control group. 4) The D374Y and S127R mutation sites of PCSK9 and the R3500Q mutation site of APOB were not detected in any of the study subjects. CONCLUSIONS: The mutation sites of the PCSK9 and APOB genes in FH patients in Hulunbuir are different from other regions, and the mutation rate is higher than in other regions. Therefore, we recommend that the mutation sites of the PCSK9 and APOB genes described herein be used as clinical detection indicators to assist the diagnosis of FH in this region.

Association of lipid-lowering drug targets with risk of cutaneous melanoma: a mendelian randomization study.

BACKGROUND: Melanoma proliferation is partly attributed to dysregulated lipid metabolism. The effectiveness of lipid-lowering drugs in combating cutaneous melanoma (CM) is a subject of ongoing debate in both in vitro and clinical studies. METHOD: This study aims to evaluate the causal relationship between various lipid-lowering drug targets, namely 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR, targeted by statins), Proprotein convertase subtilisin/kexin type 9 (PCSK9, targeted by alirocumab and evolocumab), and Niemann-Pick C1-like 1 (NPC1L1, targeted by ezetimibe), and the outcomes of cutaneous melanoma. To mimic the effects of lipid-lowering drugs, we utilized two genetic tools: analysis of polymorphisms affecting the expression levels of drug target genes, and genetic variations linked to low-density lipoprotein cholesterol levels and drug target genes. These variations were sourced from genome-wide association studies (GWAS). We applied Summary-data-based Mendelian Randomization (SMR) and Inverse Variance Weighted Mendelian Randomization (IVW-MR) to gauge the effectiveness of these drugs. RESULTS: Our findings, with SMR results showing an odds ratio (OR) of 1.44 (95% CI: 1.08-1.92; P = 0.011) and IVW-MR results indicating an OR of 1.56 (95% CI: 1.10-2.23; P = 0.013), demonstrate a positive correlation between PCSK9 expression and increased risk of CM. However, no such correlations were observed in other analyses. CONCLUSION: The study concludes that PCSK9 plays a significant role in the development of CM, and its inhibition is linked to a reduced risk of the disease.

Insights into PCSK9-LDLR Regulation and Trafficking via the Differential Functions of MHC-I Proteins HFE and HLA-C.

PCSK9 is implicated in familial hypercholesterolemia via targeting the cell surface PCSK9-LDLR complex toward lysosomal degradation. The M2 repeat in the PCSK9's C-terminal domain is essential for its extracellular function, potentially through its interaction with an unidentified "protein X". The M2 repeat was recently shown to bind an R-x-E motif in MHC-class-I proteins (implicated in the immune system), like HLA-C, and causing their lysosomal degradation. These findings suggested a new role of PCSK9 in the immune system and that HLA-like proteins could be "protein X" candidates. However, the participation of each member of the MHC-I protein family in this process and their regulation of PCSK9's function have yet to be determined. Herein, we compared the implication of MHC-I-like proteins such as HFE (involved in iron homeostasis) and HLA-C on the extracellular function of PCSK9. Our data revealed that the M2 domain regulates the intracellular sorting of the PCSK9-LDLR complex to lysosomes, and that HFE is a new target of PCSK9 that inhibits its activity on the LDLR, whereas HLA-C enhances its function. This work suggests the potential modulation of PCSK9's functions through interactions of HFE and HLA-C.

Statin administration or blocking PCSK9 alleviates airway hyperresponsiveness and lung fibrosis in high-fat diet-induced obese mice.

BACKGROUND: Obesity is associated with airway hyperresponsiveness and lung fibrosis, which may reduce the effectiveness of standard asthma treatment in individuals suffering from both conditions. Statins and proprotein convertase subtilisin/kexin-9 inhibitors not only reduce serum cholesterol, free fatty acids but also diminish renin-angiotensin system activity and exhibit anti-inflammatory effects. These mechanisms may play a role in mitigating lung pathologies associated with obesity. METHODS: Male C57BL/6 mice were induced to develop obesity through high-fat diet for 16 weeks. Conditional TGF-ß1 transgenic mice were fed a normal diet. These mice were given either atorvastatin or proprotein convertase subtilisin/kexin-9 inhibitor (alirocumab), and the impact on airway hyperresponsiveness and lung pathologies was assessed. RESULTS: High-fat diet-induced obesity enhanced airway hyperresponsiveness, lung fibrosis, macrophages in bronchoalveolar lavage fluid, and pro-inflammatory mediators in the lung. These lipid-lowering agents attenuated airway hyperresponsiveness, macrophages in BALF, lung fibrosis, serum leptin, free fatty acids, TGF-ß1, IL-1ß, IL-6, and IL-17a in the lung. Furthermore, the increased RAS, NLRP3 inflammasome, and cholecystokinin in lung tissue of obese mice were reduced with statin or alirocumab. These agents also suppressed the pro-inflammatory immune responses and lung fibrosis in TGF-ß1 over-expressed transgenic mice with normal diet. CONCLUSIONS: Lipid-lowering treatment has the potential to alleviate obesity-induced airway hyperresponsiveness and lung fibrosis by inhibiting the NLRP3 inflammasome, RAS and cholecystokinin activity.

Causal relationship between lipid-lowering drugs and ovarian cancer, cervical cancer: a drug target mendelian randomization study.

BACKGROUND: The causal impact of lipid-lowering drugs on ovarian cancer (OC) and cervical cancer (CC) has received considerable attention, but its causal relationship is still a subject of debate. Hence, the objective of this study is to evaluate the impact of lipid-lowering medications on the occurrence risk of OC and CC through Mendelian randomization (MR) analysis of drug targets. METHODS: This investigation concentrated on the primary targets of lipid-lowering medications, specifically, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) and proprotein convertase kexin 9 (PCSK9). Genetic variations associated with HMGCR and PCSK9 were derived from published genome-wide association study (GWAS) findings to serve as substitutes for HMGCR and PCSK9 inhibitors. Employing a MR approach, an analysis was conducted to scrutinize the impact of inhibitors targeting HMGCR and PCSK9 on the occurrence of OC and CC. Coronary heart disease (CHD) risk was utilized as a positive control, and the primary outcomes encompassed OC and CC. RESULTS: The findings of the study suggest a notable elevation in the risk of OC among patients treated with HMGCR inhibitors (OR [95%CI] = 1.815 [1.316, 2.315], p = 0.019). In contrast, no significant correlation was observed between PCSK9 inhibitors and the occurrence of OC. Additionally, the analysis did not reveal any noteworthy connection between HMGCR inhibitors, PCSK9 inhibitors, and CC. CONCLUSION: HMGCR inhibitors significantly elevate the risk of OC in patients, but their mechanism needs further investigation, and no influence of PCSK9 inhibitors on OC has been observed. There is no significant relationship between HMGCR inhibitors, PCSK9 inhibitors, and CC.