Association of lipid lowering drugs and the risk of systemic lupus erythematosus: a drug target Mendelian randomization
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SUBMITTER: Wu T
PROVIDER: S-EPMC10642506 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundInflammatory bowel disease (IBD) has been associated with lipid-lowering drugs in observational studies. Drug-target Mendelian randomization (MR) was utilized in this study to examine the causal relationship between lipid-lowering drugs and incidence of IBD, aiming to identify new preventive uses for the drugs.MethodsWe identified instrumental variables for three classes of lipid-lowering drugs: HMGCR inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitors, using data from the Global Lipids Genetics Consortium. Summary statistics of IBD were obtained from UK Inflammatory Bowel Disease Genetics. The summary-data-based MR (SMR) and the inverse-variance weighted (IVW) MR were used for analysis. Sensitivity analyses were performed by conventional MR methods.ResultsThe SMR analysis showed no significant genetic association between increased gene expression of HMGCR, PCSK9, and NPC1L1 and IBD, Crohn's disease (CD) and ulcerative colitis (UC). According to IVW-MR analysis, increased HMGCR expression is associated with a reduced risk of IBD (OR = 0.73, 95% confidence interval (CI) 0.59-0.90, P = 0.003) and CD (OR = 0.75, 95% CI 0.57-0.97, P = 0.03), but not with UC. Additionally, increased NPC1L1 gene expression was associated with elevated risk of IBD (OR = 1.60, 95% CI 1.07-2.40, P = 0.023), but not with CD and UC. However, no significant causal relationships were found between PCSK9 gene expression and IBD, CD, and UC. The sensitivity analysis demonstrated no evidence of heterogeneity or pleiotropy among the reported results.ConclusionsThe heightened expression of genetic variations in HMGCR inhibitor targets could potentially reduce the risk of IBD and CD, while genetic variation in the expression of NPC1L1 targets was positively associated with IBD.
| S-EPMC10775535 | biostudies-literature
Project description:BackgroundOsteoarthritis (OA), a prevalent musculoskeletal disorder, has been suggested to have a potential association with metabolic syndrome, particularly lipid metabolism. Studies exploring the effects of lipid-lowering drugs on OA have yielded conflicting results.ObjectiveThis study employed a drug-targeted Mendelian randomization approach to investigate the association between genetically predicted lipid-modulating effects of commonly targeted lipid-lowering agents and the risk of OA, with the aim of providing a theoretical foundation for the use of lipid-lowering drugs in OA treatment.MethodsEmploying Mendelian randomization (MR) analysis, we examined the potential causal relationship between lipid-lowering drugs and OA. Genetic variants associated with LDL cholesterol levels were selected from the GWAS summary data, and a series of statistical analyses, including inverse-variance weighted (IVW), weighted median (WM), and MR-Egger, were performed to estimate causal effects.ResultsWe observed significant associations between genetically proxied lipid-lowering drug targets and OA risk. Notably, HMGCR-mediated LDL cholesterol showed an association with overall OA of the hip or knee (OR = 0.865, 95%CI: 0.762 to 0.983, p = 0.026, q = 0.07) and knee osteoarthritis specifically (OR = 0.746, 95%CI: 0.639 to 0.871, p = 2.180×10-4, q = 0.004). PCSK9-mediated LDL cholesterol also demonstrated an association with OA of the hip or knee (OR = 0.915, 95%CI: 0.847 to 0.988, p = 0.023, q = 0.07) and knee osteoarthritis (OR = 0.901, 95%CI: 0.821 to 0.990, p = 0.03, q = 0.07). NPC1L1-mediated LDL cholesterol showed a positive association with OA of the hip or knee (OR = 1.460, 95%CI: 1.127 to 1.890, p = 0.004, q = 0.033). Furthermore, LDLR-mediated LDL cholesterol demonstrated an association with OA of the hip or knee (OR = 0.882, 95%CI: 0.788 to 0.988, p = 0.03, q = 0.07) and hip osteoarthritis (OR = 0.867, 95%CI: 0.769 to 0.978, p = 0.02, q = 0.07).ConclusionsThese findings provide preliminary evidence for the potential therapeutic use of lipid-lowering drugs in OA treatment. Further investigation is needed to validate these findings and explore the precise mechanisms underlying the observed associations.
| S-EPMC10901306 | biostudies-literature
Project description:Background: The causal relationship between lipid-lowering drug (LLD) use and lung cancer risk is controversial, and the role of sphingolipid metabolism in this effect remains unclear. Methods: Genome-wide association study data on low-density lipoprotein (LDL), apolipoprotein B (ApoB), and triglycerides (TG) were used to develop genetic instrumental variables (IVs) for LLDs. Two-step Mendelian randomization analyses were performed to examine the causal relationship between LLDs and lung cancer risk. The effects of ceramide, sphingosine-1-phosphate (S1P), and ceramidases on lung cancer risk were explored, and the proportions of the effects of LLDs on lung cancer risk mediated by sphingolipid metabolism were calculated. Results: APOB inhibition decreased the lung cancer risk in ever-smokers via ApoB (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.70-0.92, p = 0.010), LDL (OR 0.82, 95% CI 0.71-0.96, p = 0.040), and TG (OR 0.63, 95% CI 0.46-0.83, p = 0.015) reduction by 1 standard deviation (SD), decreased small-cell lung cancer (SCLC) risk via LDL reduction by 1 SD (OR 0.71, 95% CI 0.56-0.90, p = 0.016), and decreased the plasma ceramide level and increased the neutral ceramidase level. APOC3 inhibition decreased the lung adenocarcinoma (LUAD) risk (OR 0.60, 95% CI 0.43-0.84, p = 0.039) but increased SCLC risk (OR 2.18, 95% CI 1.17-4.09, p = 0.029) via ApoB reduction by 1 SD. HMGCR inhibition increased SCLC risk via ApoB reduction by 1 SD (OR 3.04, 95% CI 1.38-6.70, p = 0.014). The LPL agonist decreased SCLC risk via ApoB (OR 0.20, 95% CI 0.07-0.58, p = 0.012) and TG reduction (OR 0.58, 95% CI 0.43-0.77, p = 0.003) while increased the plasma S1P level. PCSK9 inhibition decreased the ceramide level. Neutral ceramidase mediated 8.1% and 9.5% of the reduced lung cancer risk in ever-smokers via ApoB and TG reduction by APOB inhibition, respectively, and mediated 8.7% of the reduced LUAD risk via ApoB reduction by APOC3 inhibition. Conclusion: We elucidated the intricate interplay between LLDs, sphingolipid metabolites, and lung cancer risk. Associations of APOB, APOC3, and HMGCR inhibition and LPL agonist with distinct lung cancer risks underscore the multifaceted nature of these relationships. The observed mediation effects highlight the considerable influence of neutral ceramidase on the lung cancer risk reduction achieved by APOB and APOC3 inhibition.
| S-EPMC10687161 | biostudies-literature
Project description:So far, there is no clear pathogenesis and no cure for systemic lupus erythematosus (SLE). The therapeutic benefits of existing drug therapies are far from ideal. The proteome is a major source of therapeutic targets. Therefore, new drug targets for SLE need to be discovered. Based on the STROBE-Mendelian randomization (MR) checklist, we performed MR to explore potential drug targets for SLE, using genome-wide association study summary statistics of plasma and cerebrospinal fluid (CSF) and further replicated in the external validation. Bidirectional MR, reverse causality testing by Steiger filtering, Bayesian co-localization were used. In addition, protein-protein interaction networks (PPI) were performed to reveal potential associations between proteins and current SLE drugs. At false discovery rate (FDR) significance (PFDR < .05), MR analysis revealed 8 proteins. Five proteins decreased the SLE risks, whereas the other 3 proteins increased the SLE risks. None of the 8 proteins had reverse causality except sICAM-1. Bayesian co-localization suggested that 5 proteins shared the same variant with SLE. PPI network suggested that intercellular adhesion molecular 1 (ICAM-1), Fc-gamma-RIIb (FCG2B) and N-terminal pro-B-type natriuretic peptide (N-terminal pro-BNP) interacted with targets of current SLE medications. Our integrative analysis revealed that SLE risk is causally associated with ICAM-1, FCG2B, and N-terminal pro-BNP. These 3 proteins have the potential to become drug targets of SLE, especially for ICAM-1 and FCG2B. More further studies are also warranted to support this finding.
| S-EPMC11835111 | biostudies-literature
Project description:IntroductionLarge observational and Mendelian randomization (MR) studies have demonstrated a strong association between both elevated LDL cholesterol (LDL-c) and triglycerides (TG) with risk of aortic stenosis (AS), although randomized trials showed no benefit of statins for AS. It consequently remains uncertain whether lipid-lowering therapies have a role to prevent or treat AS. We used a drug-target MR approach to investigate the genetically predicted effect of lipid-lowering therapies on risk of AS.Methods and resultsWe collected summary statistics for LDL-c, TG, and AS from genome-wide association studies (GWAS) including 1 320 016, 1 253 277, and 412 181 European participants from the Global Lipids Genetics Consortium and FinnGen study, respectively. We identified genetic proxies for PCSK9 inhibitors, statins, bempedoic acid, and ezetimibe as single nucleotide polymorphisms in or within 200 kb of the target genes (PCSK9, HMGCR, ACLY, and NPC1L1, respectively), which were also significantly associated with LDL-c at P < 5 × 10-8. We used a similar approach to identify genetic proxies for the TG-lowering agents fenofibrates, APOC3 inhibitors, and ANGPTL3 inhibitors using the target genes PPARA, APOC3, and ANGPTL3, respectively. Inverse variance-weighted was the primary analysis method. Sensitivity analyses included weighted median, weighted mode, and MR-Egger, followed by the outlier-exclusion approaches MR-PRESSO and Cook's distance. We also performed multivariable analyses to evaluate whether the predicted effect of PCSK9 inhibition may be mediated by lipoprotein(a). We performed replication and negative control analyses using GWAS of AS and height including 653 867 and 408 112 participants, respectively. Genetically proxied PCSK9 inhibition was significantly associated with reduced AS risk (odds ratio [OR] 0.61, 95% confidence interval [CI] 0.52-0.72, P < 0.0001) on main, replication, and all sensitivity analyses. Genetically proxied ezetimibe (OR 0.49, 95% CI 0.31-0.78, P = 0.003), bempedoic acid (OR 0.0054, 95% CI 0.0002-0.12, P = 0.0009), and statins (OR 0.61, 95% CI 0.46-0.81, P = 0.0006) were similarly associated with reduced AS risk, although the latter were not significant on replication analyses. Amongst the TG-lowering agents, genetically proxied APOC3 inhibition was associated with reduced AS risk (OR 0.78, 95% CI 0.70-0.88, P < 0.0001), but fenofibrate (OR 0.64, 95% CI 0.09-4.53, P = 0.65) and ANGPTL3 inhibitors (OR 1.05, 95% CI 0.77-1.43, P = 0.74) were not.ConclusionsGenetically proxied lipid-lowering therapies are significantly associated with reduced risk of AS. Early initiation and sustained administration of lipid-lowering therapies may prevent AS progression and warrants further research in the clinical trial setting.
| S-EPMC11905763 | biostudies-literature
Project description:ObjectiveNumerous observational studies have found a relationship between systemic lupus erythematosus (SLE) and epilepsy; however, their causal relationship remains unclear. This study aimed to investigate the causal role of SLE in epilepsy or any of its subtypes using a two-sample Mendelian randomization (MR) analysis.MethodsSingle nucleotide polymorphisms (SNPs) linked to SLE were utilized as instrumental variables in MR analysis to assess their causal impact on epilepsy. The primary MR findings were derived using the inverse variance weighted (IVW) method, which was further supported by the weighted median and MR-Egger regression techniques. Additionally, sensitivity analyses, including Cochran's Q test and pleiotropy tests, were conducted to evaluate the influence of these SNPs on epilepsy, particularly looking for signs of horizontal pleiotropy and heterogeneity.ResultsWe selected 43 SNPs that reached genome-wide significance from genome-wide association studies (GWASs) on SLE to serve as instrumental variables in this study. The IVW method showed no evidence to support a causal association between SLE and epilepsy (all epilepsy: odds ratio (OR) = 1.006, 95% confidence interval (CI) = 0.994-1.018; focal epilepsy: OR = 1.006, 95% CI = 0.994-1.019; generalized epilepsy: OR = 1.015, 95% CI = 0.996-1.035). Other MR complementary methods revealed consistent results. Furthermore, there was no evidence indicating heterogeneity or horizontal pleiotropy.SignificanceThe findings of MR analysis did not support a genetically predicted causal relationship between SLE and epilepsy, but emphasized the need for further research on shared pathophysiological mechanisms, particularly the role of immune system abnormalities and potential influences such as chronic inflammation and therapeutic interventions.Plain language summaryThe etiology of epilepsy is complex and diverse, including immune factors. Through a Mendelian randomization analysis, we did not find evidence of a genetic causal relationship between systemic lupus erythematosus and epilepsy. However, this does not invalidate epidemiological evidence, and further exploration is needed to investigate factors influencing the relationship between the two.
| S-EPMC11633673 | biostudies-literature
Project description:BackgroundLipid-lowering drugs are widely used among the elderly, with some studies suggesting links to muscle-related symptoms. However, the causality remains uncertain.MethodsUsing 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.ResultsUsing 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.ConclusionsGenetically 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.
| S-EPMC11223278 | biostudies-literature
Project description:Dyslipidemia has been established as a potential risk factor for venous thromboembolism (VTE) in several observational studies. Statins and novel lipid-modifying agents are being explored for their potential in VTE prevention, encompassing deep vein thrombosis (DVT), and pulmonary embolism (PE). Nonetheless, conclusive evidence supporting the effectiveness remains uncertain. Without definitive proof, the current recommendation of lipid-lowering drugs (LLDs) for preventing VTE, either primarily or secondarily, is not support. An investigation into the impact of 8 classes of LLDs on VTE was conducted using a drug-target Mendelian randomization approach. The drug categories examined included 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), apolipoprotein B, proprotein convertase subtilisin/kexin type 9, Niemann-Pick C1-like 1, lipoprotein lipase (LPL), angiopoietin-like 3, apolipoprotein C3 (APOC3), and peroxisome proliferator-activated receptor alpha. Leveraging genetic variants situated proximate to or within drug-target genes linked with low-density lipoprotein and triglycerides, we acted as proxies for LLDs. The UK Biobank study was the source of data on VTE, PE, and DVT of lower extremities (LEDVT). We employed the inverse-variance weighted method for the core analysis in Mendelian randomization, complemented by sensitivity analysis to investigate horizontal pleiotropy and heterogeneity. Employing genetic proxies to inhibit HMGCR revealed a notable correlation with reduced LEDVT risk (odds ratio [OR]: 0.995, 95% CI: 0.992-0.998, P = .002), VTE (OR: 0.994, 95% CI: 0.988-1.000, P = .033), but a no significant association with PE (OR: 1.000, 95% CI: 0.994-1.002, P = .246). The suppression of APOB was linked with an elevated risk of experiencing LEDVT (OR: 1.002, 95% CI: 1.001-1.004, P = .006), VTE (OR: 1.005, 95% CI: 1.002-1.007, P < .001), and PE (OR: 1.002, 95% CI: 1.000-1.004, P = .031). Similarly, the activation of LPL was associated with increased risks for VTE (OR: 1.003, 95% CI: 1.001-1.005, P = .003) and PE (OR: 1.003, 95% CI: 1.002-1.005, P < .001). Additionally, the inhibition of APOC3 was linked to a higher DVT risk (OR: 1.002, 95% CI: 1.000-1.004, P = .038). Research has shown that HMGCR, out of 8 lipid-lowering drug-targets evaluated, exhibited a significant correlation with VTE and LEDVT, highlighting its potential as an effective target for the treatment or prevention of these conditions. In contrast, APOB, LPL, and APOC3 each contribute to an increased risk of VTE, PE, and LEDVT in various degrees, pharmacovigilance for VTE, PE, and LEDVT risk among users of APOB inhibitors, LPL activation, and APOC3 inhibitors may be warranted.
| S-EPMC11666180 | biostudies-literature
Project description:Observational studies suggest dyslipidemia as an atopic dermatitis (AD) risk factor and posit that lipid-lowering drugs may influence AD risk, but the causal link remains elusive. Mendelian randomization was applied to elucidate the causal role of serum lipids in AD and assess the therapeutic potential of lipid-lowering drug targets. Genetic variants related to serum lipid traits and lipid-lowering drug targets were sourced from the Global Lipid Genetics Consortium GWAS data. Comprehensive AD data were collated from the UK Biobank, FinnGen, and Biobank Japan. Colocalization, Summary-data-based Mendelian Randomization (SMR), and mediation analyses were utilized to validate the results and pinpoint potential mediators. Among assessed targets, only Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) was significantly linked to a reduced AD risk, corroborated across three separate AD cohorts. No association between serum lipid concentrations or other lipid-lowering drug targets and diminished AD risk was observed. Mediation analysis revealed that beta nerve growth factor (b-NGF) might mediate approximately 12.8% of PCSK9's influence on AD susceptibility. Our findings refute dyslipidemia's role in AD pathogenesis. Among explored lipid-lowering drug targets, PCSK9 stands out as a promising therapeutic agent for AD.
| S-EPMC11300444 | biostudies-literature
Project description: Not available
| S-EPMC11328884 | biostudies-literature