Causal relationship between PCSK9 inhibitor and primary glomerular disease: a drug target Mendelian randomization study
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PROVIDER: S-EPMC10951069 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundIn addition to decreasing the level of cholesterol, proprotein convertase subtilis kexin 9 (PCSK9) inhibitor has pleiotropic effects, including immune regulation. However, the impact of PCSK9 on autoimmune diseases is controversial. Therefore, we used drug target Mendelian randomization (MR) analysis to investigate the effect of PCSK9 inhibitor on different autoimmune diseases.MethodsWe collected single nucleotide polymorphisms (SNPs) of PCSK9 from published genome-wide association studies statistics and conducted drug target MR analysis to detect the causal relationship between PCSK9 inhibitor and the risk of autoimmune diseases. 3-Hydroxy-3-methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitor, the drug target of statin, was used to compare the effect with that of PCSK9 inhibitor. With the risk of coronary heart disease as a positive control, primary outcomes included the risk of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), myasthenia gravis (MG), multiple sclerosis (MS), asthma, Crohn's disease (CD), ulcerative colitis (UC), and type 1 diabetes (T1D).ResultsPCSK9 inhibitor significantly reduced the risk of SLE (OR [95%CI] = 0.47 [0.30 to 0.76], p = 1.74 × 10-3) but increased the risk of asthma (OR [95%CI] = 1.15 [1.03 to 1.29], p = 1.68 × 10-2) and CD (OR [95%CI] = 1.38 [1.05 to 1.83], p = 2.28 × 10-2). In contrast, HMGCR inhibitor increased the risk of RA (OR [95%CI] = 1.58 [1.19 to 2.11], p = 1.67 × 10-3), asthma (OR [95%CI] = 1.21 [1.04 to 1.40], p = 1.17 × 10-2), and CD (OR [95%CI] = 1.60 [1.08 to 2.39], p = 2.04 × 10-2).ConclusionsPCSK9 inhibitor significantly reduced the risk of SLE but increased the risk of asthma and CD. In contrast, HMGCR inhibitor may be a risk factor for RA, asthma, and CD.
| S-EPMC10424393 | biostudies-literature
Project description:BackgroundHigh LDL-cholesterol (LDL-C) is a well-known risk factor for coronary artery disease (CAD). PCSK9, HMGCR, NPC1L1, ACLY, and LDLR gene have been reported as lipid lowering drug genes related to LDL-C lowering. However relevant Asian studies were rare.MethodsWe examined the causality between LDL-c drug target genes and CAD using Korean and Japanese data using the two sample Mendelian Randomization (MR) method. We conducted two-sample MR analysis of LDL-c lowering drug target genes (7 Single-nucleotide polymorphisms (SNP) in PCSK9, 6 SNPs in HMGCR, 5 SNPs in NPC1L1, 9 SNPs in ACLY, 3 SNPs in LDLR) and CAD. We used summary statistics data from the Korean Genome Epidemiology Study (KOGES) for LDL-C data, and Biobank of Japan (BBJ) for CAD data.ResultsFor every 10 mg/dl decrease in LDL-C determined by four significant SNPs in the PCSK9 gene, the risk of CAD decreased by approximately 20% (OR = 0.80, 95% CI: 0.75-0.86). The risk of CAD decreased by 10% for every 10 mg/dl decrease in LDL-C due to the six significant SNPs in the HMGCR gene (OR = 0.90, 95% CI: 0.86-0.94). Due to the two significant SNPs in the gene LDLR, the risk of CAD decreased by approximately 26% for every 10 mg/dl decrease in LDL-C (OR = 0.74, 95% CI: 0.66-0.82). The combined effect on CAD showed the largest effect size for the PCSK9 gene and LDLR gene, and the reduced CAD risk induced by these two genes together was OR = 0.78 (95%CI, 0.74-0.83). Finally, the combined effect of all three genes (PCSK9, HMGCR, and LDLR) was OR = 0.85 (95%CI, 0.79-0.91).ConclusionLDL-C reduction estimated by SNPs in LDL-C lowering drug target genes significantly reduced the risk of CAD. We found the potential of using of proxy research design for clinical trials using LDL-C lowering drugs.
| S-EPMC11905656 | biostudies-literature
Project description:Introduction and objectivesRecent studies have indicated a potential association of hypertension with Hashimoto's thyroiditis (HT) and other autoimmune diseases, yet the impact of antihypertensive drugs on HT risk is not well understood.MethodsWe employed a drug-target Mendelian randomization approach to investigate the prolonged impact of 9 classes of antihypertensive medications on HT susceptibility in European and Asian populations. Genetic variants close to or within genes associated with the drug targets and systolic blood pressure (SBP) were utilized to mimic the effects of antihypertensive medications. We focused on drugs linked to a lower risk of coronary artery disease for our main analysis. We gathered genetic data on SBP and HT risk from comprehensive genome-wide association studies available for European and Asian groups. For a supplementary analysis, we used expression quantitative trait loci (eQTLs) related to drug target genes as proxies.ResultsOur analysis revealed that the use of calcium channel blockers (CCBs) is linked to a reduced risk of HT in both European (OR [95% CI]: 0.96 [0.95 to 0.98] per 1 mmHg decrease in SBP; p = 3.51×10-5) and Asian populations (OR [95% CI]: 0.28 [0.12, 0.66]; p = 3.54×10-3). Moreover, genetically mimicking the use of loop diuretics (OR [95% CI]: 0.94 [0.91, 0.97]; p = 3.57×10-5) and thiazide diuretics (0.98 [0.96, 0.99]; p = 3.83×10-3) showed a significant association with a decreased risk of HT only in European population. These outcomes were confirmed when eQTLs were employed to represent the effects of antihypertensive medications.ConclusionThe study suggests that CCBs and diuretics could potentially reduce the risk of HT in different populations. Additional research is needed to assess the feasibility of repurposing antihypertensive medications for the prevention of HT.
| S-EPMC11491371 | biostudies-literature
Project description:BackgroundPrevious research has yielded conflicting results on the link between epilepsy risk and lipid-lowering medications. The aim of this study is to determine whether the risk of epilepsy outcomes is causally related to lipid-lowering medications predicted by genetics.MethodsWe used genetic instruments as proxies to the exposure of lipid-lowering drugs, employing variants within or near genes targeted by these drugs and associated with low-density lipoprotein cholesterol (LDL cholesterol) from a genome-wide association study. These variants served as controlling factors. Through drug target Mendelian randomization, we systematically assessed the impact of lipid-lowering medications, including HMG-CoA reductase (HMGCR) inhibitors, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and Niemann-Pick C1-like 1 (NPC1L1) inhibitors, on epilepsy.ResultsThe analysis demonstrated that a higher expression of HMGCR was associated with an elevated risk of various types of epilepsy, including all types (OR = 1.17, 95% CI:1.03 to 1.32, p = 0.01), focal epilepsy (OR = 1.24, 95% CI:1.08 to 1.43, p = 0.003), and focal epilepsy documented with lesions other than hippocampal sclerosis (OR = 1.05, 95% CI: 1.01 to 1.10, p = 0.02). The risk of juvenile absence epilepsy (JAE) was also associated with higher expression of PCSK9 (OR = 1.06, 95% CI: 1.02 to 1.09, p = 0.002). For other relationships, there was no reliable supporting data available.ConclusionThe drug target MR investigation suggests a possible link between reduced epilepsy vulnerability and HMGCR and PCSK9 inhibition.
| S-EPMC10957583 | biostudies-literature
Project description:BackgroundColorectal cancer is influenced by several factors such as unhealthy habits and genetic factors. C1QB has been linked to a number of malignancies. However, uncertainty surrounds the connection between C1QB and CRC. Therefore, this study aimed to explore a bidirectional causal relationship of C1QB as a drug target in CRC through Mendelian randomization (MR) analysis.MethodsThe GWASs for C1QB and CRC were obtained from the Integrative Epidemiology Unit Open GWAS database. There were five strategies to investigate MR. Sensitivity analysis was carried out via tests for heterogeneity, horizontal pleiotropy and leave-one-out effects to evaluate the dependability of the MR analysis results. Furthermore, colocalization analysis of C1QB and CRC, protein-protein interaction network and drug prediction according to exposure factors as well as phenotype scanning were performed.ResultsThe results of forward MR analysis demonstrated that C1QB was a risk factor for CRC (OR = 1.104, p = 0.033). However, we did not find a causal relationship between CRC and C1QB (reverse MR). Rs294180 and rs291985 corresponded to the same linkage interval and had the potential to influence C1QB and CRC, respectively. The PPI results demonstrated that C1QB interacted with 10 genes (C1QA, C1QC, C1R, C1S, C2, C4A, C4B, CALR, SERPING1, and VSIG4). Additionally, 21 medications were predicted to match C1QB. Molecular docking data, including for benzo(a)pyrene, 1-naphthylisothiocyanate, calcitriol and medroxyprogesterone acetate, revealed excellent binding for drugs and proteins. Moreover, we identified 29 diseases that were associated with C1QB and related medicines via disease prediction and intersection methods. As a therapeutic target for CRC, phenotypic scanning revealed that C1QB does not significantly affect weight loss, liver cirrhosis, or nonalcoholic fatty liver disease, but might have protective impacts on ovarian cancer and melanoma.ConclusionThe results highlight a causal relationship between C1QB and CRC and imply an oncogenic role for C1QB in CRC, as potential drug targets. Drugs designed to target C1QB have a greater chance of success in clinical trials and are expected to help prioritize CRC drug development and reduce drug development costs. That provided a theoretical foundation and reference for research on CRC and C1QB in MR.
| S-EPMC11300244 | biostudies-literature
Project description:BackgroundPrevious Mendelian studies identified a causal relationship between renal function, as assessed by estimated glomerular filtration rate (eGFR), and severe infection with coronavirus disease 2019 (COVID-19). However, much is still unknown because of the limited number of associated single nucleotide polymorphisms (SNPs) of COVID-19 and the lack of cystatin C testing. Therefore, in the present study, we aimed to determine the genetic mechanisms responsible for the association between eGFR and COVID-19 in a European population.MethodsWe performed bidirectional Mendelian randomization (MR) analysis on large-scale genome-wide association study (GWAS) data; log-eGFR was calculated from the serum levels of creatinine or cystatin C by applying the Chronic Kidney Disease Genetics (CKDGen) Meta-analysis Dataset combined with the UK Biobank (N = 1,004,040) and on COVID-19 phenotypes (122,616 COVID-19 cases and 2,475,240 controls) from COVID19-hg GWAS meta-analyses round 7. The inverse-variance weighted method was used as the main method for estimation.ResultsAnalyses showed that the genetically instrumented reduced log-eGFR, as calculated from the serum levels of creatinine, was associated with a significantly higher risk of severe COVID-19 (odds ratio [OR]: 2.73, 95% confidence interval [CI]: 1.38-5.41, P < 0.05) and significantly related to COVID-19 hospitalization (OR: 2.36, 95% CI: 1.39-4.00, P < 0.05) or infection (OR: 1.24, 95% CI: 1.01-1.53, P < 0.05). The significance of these associations remained when using log-eGFR based on the serum levels of cystatin C as genetically instrumented. However, genetically instrumented COVID-19, regardless of phenotype, was not related to log-eGFR, as calculated by either the serum levels of creatinine or cystatin C.ConclusionsOur findings suggest that genetical predisposition to reduced kidney function may represent a risk factor for COVID-19. However, a consistent and significant effect of COVID-19 on kidney function was not identified in this study.
| S-EPMC10790484 | biostudies-literature
Project description:IntroductionAtrial fibrillation (AF) is a prevalent cardiac arrhythmia with significant clinical implications. The potential influence of lipid-lowering therapies, specifically PCSK9 inhibitors (PCSK9i) and HMG-CoA reductase inhibitors (statins), on AF risk remains a topic of interest. This mendelian randomization (MR) study aimed to elucidate the causal relationship between genetically predicted inhibition of PCSK9 and HMG-CoA reductase and the risk of AF.MethodsUtilizing publicly available, summary-level genome-wide association study data, we employed single-nucleotide polymorphisms associated with lower LDL-C levels as instruments for gene-simulated inhibition of PCSK9 and HMG-CoA reductase. Multiple MR techniques were applied to estimate the causal effects, and sensitivity analyses were conducted to validate the results.ResultsGenetically predicted inhibition of PCSK9 demonstrated a reduced risk of AF, with an odds ratio (OR) of 0.92 (95% CI: 0.85-0.99, p = 0.01) using the inverse variance-weighted (IVW) method. In contrast, the inhibition of HMG-CoA reductase did not exhibit a statistically significant association with AF risk (IVW: OR = 1.11, 95% CI: 1.00-1.22, p = 0.05).ConclusionOur MR study suggests that genetically predicted inhibition of PCSK9, but not HMG-CoA reductase, is associated with a lower risk of AF. These findings provide evidence for a causal protective effect of PCSK9i on AF and support the use of PCSK9i for AF prevention in patients with dyslipidemia. Further studies are needed to elucidate the mechanisms underlying the differential effects of PCSK9i and statins on AF and to confirm the clinical implications of our findings.
| S-EPMC11449189 | biostudies-literature
Project description: Not available
| S-EPMC11926596 | biostudies-literature
Project description: Not available
| S-BSST1516 | biostudies-other
Project description:BackgroundDepression ranks as a leading contributor to the global disease burden. The potential causal relationship between the use of antihypertensive medications and depression has garnered significant interest. Despite extensive investigation, the nature of this relationship remains a subject of ongoing debate. Therefore, this study aims to evaluate the influence of antihypertensive medications on depression by conducting a Mendelian randomization study focused on drug targets.MethodWe focused on the targets of five antihypertensive drug categories: ACE Inhibitors (ACEIs), Angiotensin II Receptor Antagonists (ARBs), Calcium Channel Blockers (CCBs), Beta-Blockers (BBs), and Thiazide Diuretics (TDs). We collected single-nucleotide polymorphisms (SNPs) associated with these drug targets from genome-wide association study (GWAS) statistics, using them as proxies for the drugs. Subsequently, we conducted a Mendelian randomization (MR) analysis targeting these drugs to explore their potential impact on depression.ResultsOur findings revealed that genetic proxies for Beta-Blockers (BBs) were associated with an elevated risk of depression (OR [95%CI] = 1.027 [1.013, 1.040], p < 0.001). Similarly, genetic proxies for Calcium Channel Blockers (CCBs) were linked to an increased risk of depression (OR [95%CI] = 1.030 [1.009, 1.051], p = 0.006). No significant associations were identified between the genetic markers of other antihypertensive medications and depression risk.ConclusionThe study suggests that genetic proxies associated with Beta-Blockers (BBs) and Calcium Channel Blockers (CCBs) could potentially elevate the risk of depression among patients. These findings underscore the importance of considering genetic predispositions when prescribing these medications, offering a strategic approach to preventing depression in susceptible individuals.
| S-EPMC11344258 | biostudies-literature