Introduction:
The relationship between inflammatory response and osteoporosis has been the subject of extensive research; yet, their genetic link remains unclear. This study utilized IR-related genes as instrumental variables to represent IR, while summary data of OP served as the outcome to explore their genetic relationship.

Material and methods:
IR-related genes were retrieved from the GeneCards database. OP transcriptome datasets were collected from the Gene Expression Omnibus database and meta-analyzed to identify differentially expressed genes related to IR in OP. Genetic proxy instruments for IR-related genes were derived from studies of corresponding gene expressionand DNA methylation quantitative trait loci, respectively. Aggregated data for OP were extracted from the largest genome-wide association study of OP. We integrated QTL data with OP GWAS data to estimate their genetic associations using summary data-based Mendelian randomization analysis. Additionally, Bayesian colocalization analysis was employed to reveal the potential relationships between IR gene expression and inflammatory factors, as well as various hormones. Finally, to further validate whether the statistical evidence provided in GWAS were true-positive findings, a replication study was conducted here through genotype-phenotype associations.

Results:
Through SMR analysis, we found that the expression levels of two IR-related genes were associated with OP risk. Specifically, elevated gene expression levels of FAS increased the risk of OP. Conversely, increased expression levels of CHUK decreased the risk of OP.

Conclusions:
In summary, this multi-omics integration study reveals a genetic link between IR and OP, as represented by IR-related genes, and provides new insights into the potential pathogenic mechanisms of OP.