Association of PCSK9 inhibitors with bone disease: A comprehensive drug-target Mendelian randomization study
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Background
Emerging research indicates that PCSK9 inhibitors, which originally developed for lowering LDL cholesterol, may positively impact bone skeletal system. By potentially enhancing bone density and strength, PCSK9 inhibitors offer a promising new avenue in bone disease management, signaling a significant shift in therapeutic strategies.
Methods
This study employed a comprehensive approach involving the extraction of single-nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS), followed by rigorous quality checks. PCSK9 instrumental variables were utilized to evaluate the effect of cholesterol-lowering drugs on osteoporosis, osteoarthritis, and rheumatoid arthritis. Cross-Phenotype Association Analysis (CPASSOC) and colocalization analysis were conducted to identify overlapping genetic sites
Results
Our analysis did not reveal a significant causal relationship between lower BMD and the predicted risk of FCHL. However, there was an observed association between an increased genetic risk of FCHL and reduced BMD, particularly in younger individuals (TB-BMD (age 15-30): OR = 0.922, 95% CI: 0.844-0.993, P = 0.032). PCSK9 inhibitors were found to increase BMD while reducing the risk of FCHL. Notably, rs998584 in the VEGFA gene emerged as a shared locus in both CPASSOC and colocalization analyses, with high expression in Adipo-CAR cells in the bone marrow.
Conclusions
This study’s cross-trait analysis uncovers a shared genetic basis between FCHL and BMD, elucidating the causal relationship between genetic predisposition to FCHL and the likelihood of reduced BMD. Our findings contribute to a more nuanced understanding of the genetic factors influencing bone health in European populations and highlight potential therapeutic targets for improving BMD in individuals with FCHL.
