Dataset Information

PCSK9 inhibitors and osteoporosis: mendelian randomization and meta-analysis.

ABSTRACT:

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.

Conclusion

PCSK9 inhibitors increase osteoporosis risk. However, HMGCR inhibitors are unremarkably linked to osteoporosis.

SUBMITTER: Chen DQ

PROVIDER: S-EPMC11251371 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Publications

PCSK9 inhibitors and osteoporosis: mendelian randomization and meta-analysis.

Chen Ding-Qiang DQ Xu Wen-Bin WB Xiao Ke-Yi KY Que Zhi-Qiang ZQ Feng Jin-Yi JY Sun Nai-Kun NK Cai Di-Xin DX Rui Gang G

BMC musculoskeletal disorders 20240716 1

<h4>Background</h4>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.<h4>Methods</h4>Single nucleotide polymorphisms (SNPs) for 3-hydroxy-3-methylglutaryl cofactor A reductase (HMGCR) and PCSK9 were gathered from available online databases for Eur ...[more]

PMID: 39010016

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Project description:ObjectiveDisuse osteoporosis is known to be primarily caused by a lack of exercise. However, the causal relationships between zinc and immunity and disuse osteoporosis remain unknown. This study investigated these relationships and their potential mechanisms.MethodsThis study was an integrative study combining genome-wide association studies and transcriptomics. Two-sample Mendelian randomization analysis (MR) was used to analyze the causal relationships between exposures (zinc, immunity, physical activity) and the outcome (osteoporosis) with the aid of single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs). Four models, MR-Egger, inverse variance weighted, weighted median and MR-Pleiotrophy RESidual Sum and Outlier (MRPRESSO), were used to calculate odds ratio values. Sensitivity and heterogeneity analyses were also performed using MRPRESSO and MR-Egger methods. The mRNA transcriptomic analysis was subsequently conducted. Zinc metabolism scores were acquired through single-sample Gene Set Enrichment Analysis algorithms. Stromal scores were obtained using the R Package "estimate" algorithms. Important Kyoto Encyclopedia of Genes and Genomes and Gene Ontology pathways were also derived through gene set variation analysis. Cytoscape software helped construct the transcription factor (TF)-mRNA-microRNA (miRNA) network. Virtual screening and molecular docking were performed. Polymerase chain reaction validation was also carried out in vivo.ResultsCausal relationships were demonstrated between zinc and exercise (95% confidence interval [CI] = 1.30-2.95, p = 0.001), exercise and immunity (95% CI = 0.36-0.80, p = 0.002), exercise and osteoporosis (95% CI = 0.97-0.99, p = 0.0007), and immunity disorder and osteoporosis (95% CI = 1.30-2.03, p = 0.00002). One hundred and seventy-nine mRNAs in important modules were screened. Combining the differential expressional genes (DEGs) and the Boruta selection, six DEGs were screened (AHNAK, CSF2, ADAMTS12, SRA1, RUNX2, and SLC39A14). TF HOXC10 and miRNA hsa-miR-204 were predicted. Then, the TF-mRNA-miRNA network was successfully constructed. RUNX2 and SLC39A14 were identified as hub mRNAs in the TF-mRNA-miRNA network. Eventually, the novel small drug C6O4NH5 was designed according to the pharmacophore structure of SLC39A14. The docking energy for the novel drug was -5.83 kcal/mol. SLC39A14 and RUNX2 were downregulated (of statistical significance p-value < 0.05) in our animal experiment.ConclusionThis study revealed that zinc had a protective causal relationship with disuse osteoporosis by promoting exercise and immunity. SLC39A14 and RUNX2 mRNA participated in this zinc-related mechanism.

Dataset Information

PCSK9 inhibitors and osteoporosis: mendelian randomization and meta-analysis.

Background

Methods

Results

Conclusion

Publications

PCSK9 inhibitors and osteoporosis: mendelian randomization and meta-analysis.

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