OBJECTIVE: We describe the varied clinical presentations, barriers in diagnosis and outcomes of anti-HMGCR myopathy in a large national cohort.
METHODS: Adults found positive for serum anti-HMGCR autoantibodies via line blot or enzyme-immunoassay followed by immunoprecipitation were included in the study.
RESULTS: Of 75 patients identified, the records of 72 (96 %) described weakness as the presenting symptom. The records of 65 gave a reliable description of proximal weakness. In 22/65 (33.8 %) the weakness was described as predominantly or solely lower limb weakness. Forty-five of 75 (60 %) presented with a subacute onset (duration of symptoms >4 weeks -≤6 months), whilst 22/75 (29.3 %) presented with a more indolent chronic onset (duration of symptoms >6 months). Eighteen of 75 (24 %) suffered falls and 2/75 (2.7 %) had \"general decline\". In three patients no weakness was described: two presented with myalgia and one with a skin rash characterized as Jessner lymphocytic skin rash. Median creatine kinase at presentation was 7337 U/L (range 1050-25,500). Muscle biopsy was performed in 38 (50.7 %). Associated malignancy was infrequent. Four patients recovered without immunosuppression. Five-year and 10-year survival was 92.7 % (95 % CI 80.6-97.4 %), and 82.5 % (95 % CI 61.2-92.8 %) respectively.
CONCLUSIONS: Recurrent falls, a long prodrome and dominant lower limb proximal weakness were common in this anti-HMGCR myopathy cohort. These features overlap with frailty syndrome and sporadic inclusion body myositis emphasizing the importance of considering anti-HMGCR myopathy in that clinical context. A minority of patients recover after statin withdrawal alone.

There is no reliable causal evidence for the effect of statins on diabetic nephropathy (DN) and diabetic retinopathy (DR), and the results of previous observational studies are contradictory. Genetic variants linked to low-density lipoprotein cholesterol (LDL-C) from a UK biobank genome-wide association study and located within a 100kb window around HMGCR were used to proxy statins, comparing with PCSK9 inhibitors (control). DN and DR genome-wide association study summary statistics were obtained from the FinnGen study. Secondary MR analyses and NHANES cross-sectional data were used for validation. Drug-target Mendelian randomization (MR) was applied to investigate the association between the genetically proxied inhibition of HMGCR and PCSK9 with DN and DR, p < 0.0125 was considered significant after Bonferroni Correction. To triangulate the findings, genetic variants of whole blood-derived targets gene expression (cis-eQTL) and plasma-derived protein (cis-pQTL) levels were used to perform secondary MR analyses and data from the National Health and Nutrition Examination Survey were used for cross-sectional analysis. Genetically proxied inhibition of HMGCR was associated with higher risks of DN and DR (DN: OR = 1.79, p = 0.01; DR: OR = 1.41, p = 0.004), while no such association was found for PCSK9. Secondary MR analyses confirmed these associations. Cross-sectional analysis revealed a positive link between statin use and DR incidence (OR = 1.26, p = 0.03) and a significant negative association with glomerular filtration rate (Beta = - 1.9, p = 0.03). This study provides genetic evidence that genetically proxied inhibition of HMGCR is associated with increased risks of DN/DR, and this effect may not be attributed to their LDL-C-lowering properties. For patients with diabetic dyslipidemia, PCSK9 inhibitors may be a preferable alternative.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent an effective strategy for reducing cardiovascular disease risk. Yet, PCSK9\'s impact on osteoporosis remains unclear. Hence, we employed Mendelian randomization (MR) analysis for examining PCSK9 inhibitor effects on osteoporosis.
METHODS: Single nucleotide polymorphisms (SNPs) for 3-hydroxy-3-methylglutaryl cofactor A reductase (HMGCR) and PCSK9 were gathered from available online databases for European pedigrees. Four osteoporosis-related genome-wide association studies (GWAS) data served as the main outcomes, and coronary artery disease (CAD) as a positive control for drug-targeted MR analyses. The results of MR analyses examined by sensitivity analyses were incorporated into a meta-analysis for examining causality between PCSK9 and HMGCR inhibitors and osteoporosis.
RESULTS: The meta-analysis involving a total of 1,263,102 subjects, showed that PCSK9 inhibitors can increase osteoporosis risk (P < 0.05, I2, 39%). However, HMGCR inhibitors are not associated with osteoporosis risk. Additionally, a replication of the analysis was conducted with another exposure-related GWAS dataset, which led to similar conclusions.
CONCLUSIONS: PCSK9 inhibitors increase osteoporosis risk. However, HMGCR inhibitors are unremarkably linked to osteoporosis.

Colorectal cancer (CRC) presents a complex landscape, characterized by both inter-tumor and intra-tumor heterogeneity. RUNX1, a gene implicated in modulating tumor cell growth, survival, and differentiation, remains incompletely understood regarding its impact on CRC prognosis. In our investigation, we discerned a positive correlation between elevated RUNX1 expression and aggressive phenotypes across various CRC subtypes. Notably, knockdown of RUNX1 demonstrated efficacy in restraining CRC proliferation both in vitro and in vivo, primarily through inducing apoptosis and impeding cell proliferation. Mechanistically, we unveiled a direct regulatory link between RUNX1 and cholesterol synthesis, mediated by its control over HMGCR expression. Knockdown of RUNX1 in CRC cells triggered HMGCR transcriptional activation, culminating in elevated cholesterol levels that subsequently hindered cancer progression. Clinically, heightened RUNX1 expression emerged as a prognostic marker for adverse outcomes in CRC patients. Our findings underscore the pivotal involvement of RUNX1 in CRC advancement and its potential as a therapeutic target. The unique influence of RUNX1 on cholesterol synthesis and HMGCR transcriptional regulation uncovers a novel pathway contributing to CRC progression.

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.

Idiopathic inflammatory myopathy (IIM) represents a rare group of autoimmune conditions resulting in muscle weakness and includes polymyositis, dermatomyositis, immune-mediated necrotizing myopathy (IMNM), overlap myositis, and inclusion body myositis. Anti-3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) antibody IMNM represents a rare but increasingly recognized subtype of IIM. Here we report a case of a 65-year-old woman on rosuvastatin who presented with two months of progressive proximal muscle weakness, significant truncal weakness, and elevated creatine kinase concerning for rhabdomyolysis and inflammatory myopathy. The patient was eventually diagnosed on day 8 of her hospital stay with anti-HMGCR antibody IMNM after delayed testing for this specific myopathy. Increased awareness of this IIM subtype, as well as its risk factors and presenting features, might improve rapidity of testing and shorten hospital stays if the diagnosis is considered in the emergency department or early in the hospital course.

OBJECTIVE: Dysregulated cholesterol metabolism is a hallmark of atherosclerotic cardiovascular diseases, yet our understanding of how endogenous cholesterol synthesis affects atherosclerosis is not clear. The energy sensor AMP-activated protein kinase (AMPK) phosphorylates and inhibits the rate-limiting enzyme in the mevalonate pathway HMG-CoA reductase (HMGCR). Recent work demonstrated that when AMPK-HMGCR signaling was compromised in an Apoe-/- model of hypercholesterolemia, atherosclerosis was exacerbated due to elevated hematopoietic stem and progenitor cell mobilization and myelopoiesis. We sought to validate the significance of the AMPK-HMGCR signaling axis in atherosclerosis using a non-germline hypercholesterolemia model with functional ApoE.
METHODS: Male and female HMGCR S871A knock-in (KI) mice and wild-type (WT) littermate controls were made atherosclerotic by intravenous injection of a gain-of-function Pcsk9D374Y-adeno-associated virus followed by high-fat and high-cholesterol atherogenic western diet feeding for 16 weeks.
RESULTS: AMPK activation suppressed endogenous cholesterol synthesis in primary bone marrow-derived macrophages from WT but not HMGCR KI mice, without changing other parameters of cholesterol regulation. Atherosclerotic plaque area was unchanged between WT and HMGCR KI mice, independent of sex. Correspondingly, there were no phenotypic differences observed in hematopoietic progenitors or differentiated immune cells in the bone marrow, blood, or spleen, and no significant changes in systemic markers of inflammation. When lethally irradiated female mice were transplanted with KI bone marrow, there was similar plaque content relative to WT.
CONCLUSIONS: Given previous work, our study demonstrates the importance of preclinical atherosclerosis model comparison and brings into question the importance of AMPK-mediated control of cholesterol synthesis in atherosclerosis.

BACKGROUND: The objective of this research was to elucidate the hypocholesterolemic effects of a bioactive compound extracted from buckwheat, and to delineate its influence on the regulatory mechanisms of cholesterol metabolism. The compound under investigation was identified as quercetin.
RESULTS: In vitro experiments conducted on HepG2 cells treated with quercetin revealed a significant reduction in intracellular cholesterol accumulation. This phenomenon was rigorously quantified by assessing the transcriptional activity of key genes involved in the biosynthesis and metabolism of cholesterol. A statistically significant reduction in the expression of HMG-CoA reductase (HMGCR) was observed, indicating a decrease in endogenous cholesterol synthesis. Conversely, an upregulation in the expression of cholesterol 7 alpha-hydroxylase (CYP7A1) was also observed, suggesting an enhanced catabolism of cholesterol to bile acids. Furthermore, the study explored the combinatory effects of quercetin and simvastatin, a clinically utilized statin, revealing a synergistic action in modulating cholesterol levels at various dosages.
CONCLUSIONS: The findings from this research provide a comprehensive insight into the mechanistic pathways through which quercetin, a phytochemical derived from buckwheat, exerts its hypocholesterolemic effects. Additionally, the observed synergistic interaction between quercetin and simvastatin opens up new avenues for the development of combined therapeutic strategies to manage hyperlipidemia.

BACKGROUND: In addition to lowering cholesterol levels, the proprotein convertase subtilis kexin 9 (PCSK9) inhibitor has a variety of effects, including anti-neuroapoptosis. However, the effects of PCSK9 inhibitors on neurodegenerative diseases are controversial. Therefore, we used drug-targeted Mendelian randomization (MR) analysis to investigate the effects of PCSK9 inhibitors on different neurodegenerative diseases.
METHODS: We collected single nucleotide polymorphisms (SNPs) of PCSK9 from published statistics of genome-wide association studies and performed drug target MR analyses to detect a causal relationship between PCSK9 inhibitors and the risk of neurodegenerative diseases. We utilized the effects of 3-Hydroxy -3- methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitors (statin targets) for comparison with PCSK9 inhibitors. Coronary heart disease risk was used as a positive control, and primary outcomes included amyotrophic lateral sclerosis (ALS), Parkinson\'s disease (PD), and Alzheimer\'s disease (AD).
RESULTS: PCSK9 inhibitors marginally reduced the risk of ALS (OR [95%] = 0.89 [0.77 to 1.00], p = 0.048), while they increased the risk of PD (OR [95%] = 1.417 [1.178 to 1.657], p = 0.004). However, HMGCR inhibitors increased the risk of PD (OR [95%] = 1.907 [1.502 to 2.312], p = 0.001).
CONCLUSIONS: PCSK9 inhibitors significantly reduce the risk of ALS but increase the risk of PD. HMGCR inhibitors may be the risk factor for PD.

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.
CONCLUSIONS: 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.