Transcriptome and Multivariate Mendelian Randomized Interpretation: Relationship Between Type 2 Diabetes and Fractures
HAO Limei1, REN Wenqing2, QIN Lin1, LI Huihui1, WANG Yixuan1
1. Department of Endocrinology, Dingzhou People's Hospital, Dingzhou 073000, China; 2. Department of Orthopedics, Dingzhou People's Hospital, Dingzhou 073000, China
Abstract：Objective Using bioinformatics and Mendelian randomization analysis combined, we identified the risk factors contributing to increased fracture risk in patients with type 2 diabetes. This establishes the theoretical foundation for developing subsequent clinical prediction models. Methods Utilizing the Gene Expression Omnibus (GEO) databases GSE38642 for type 2 diabetes and GSE30159 for fractures, we conducted differential analysis and selected key genes. Subsequently, we employed Genecards to construct a Sankey diagram illustrating the interplay between these genes and associated diseases. Within the realm of transcriptomics, we identified significant risk factors as exposure variables and type 2 diabetes along with fractures as outcome variables for Mendelian randomization analysis. We employed the inverse variance-weighted (IVW) method as the primary approach and evaluated horizontal pleiotropy using the intercept term in MR-Egger regression, while Cochran's Q statistic assessed heterogeneity (Cochran Q P<0.05 indicates heterogeneity). Additionally, we validated overall effects through leave-one-out analysis. Finally, we performed multivariable Mendelian randomization analysis on risk factors displaying causal effects in MR. Results In transcriptomics, a total of 14 risk factors associated with fractures in patients with type 2 diabetes were identified. These factors include height, citrate levels, alanine levels, glycated hemoglobin levels, glomerular filtration rate status, IL-1R2 levels, blood protein levels, resting heart rate, heart rate, pulse pressure status, atrial fibrillation, chronic obstructive pulmonary disease, acute myeloid leukemia, and systolic blood pressure. Following Mendelian randomization and multivariable analysis, glycated hemoglobin levels and height were determined to be risk factors for fractures in patients with type 2 diabetes. Conclusion sIn patients with type 2 diabetes, an elevation in glycated hemoglobin levels triggers alterations in bone metabolism-related functions, thereby increasing the risk of osteoporosis. This, in turn, leads to a decrease in patient height, ultimately culminating in fractures among individuals with type 2 diabetes.
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2024, Vol. 21 
