Genetically predicted KIR2DS4 mediate the association between gut microbe K10 and osteoporosis fractures: A mediation Mendelian randomization study

Background Osteoporosis fractures pose a significant public health concern, leading to substantial morbidity and mortality rates. The emerging evidence on the potential link between gut microbiota, proteins, and osteoporosis fractures suggests a complex relationship that warrants further investigation. Objective To investigate the bidirectional relationships between gut microbiota, proteins, and osteoporosis fractures. Design We leveraged genome‐wide association study (GWAS) data to perform two‐sample and reverse Mendelian randomization analyses. Setting This mediation Mendelian randomization analysis utilized publicly available GWAS summary statistics from the NHGRI‐EBI Catalog and the FinnGen consortium. Participants Analyses were based on genetic associations estimated from large cohorts including up to 5959 individuals for gut microbiota, 619 for plasma proteomics (Olink), and 1822 Finnish biobank participants for fracture outcomes (FinnGen). Interventions Not applicable. Main Outcome Measurements The causal relationship between gut microbiota and osteoporotic fractures, along with the mediating role of proteomics in this relationship. Results Our Mendelian randomization analysis identified 12 gut microbes and 194 proteins with potential causal effects on osteoporosis fractures. Notably, the gut microbial strain K10 was found to reduce the risk of osteoporosis fractures, whereas the KIR2DS4 protein was associated with an increased risk of osteoporosis fractures. Mediation analysis indicated that KIR2DS4 may mediate the effect of K10 on fracture risk. We observed no evidence of reverse causality in our analyses, which supports the validity of our findings. Conclusion This study provides compelling evidence supporting the causal involvement of specific gut microbiota and proteins in susceptibility to osteoporosis fractures. The identification of KIR2DS4 as a mediator in the K10–osteoporosis fractures relationship highlights a potential therapeutic target for osteoporosis management. These findings have significant implications for our understanding of the pathogenesis of osteoporosis, underscoring the importance of gut microbiota and protein metabolism in disease susceptibility.