关键词: 骨折, 孟德尔随机化分析, 体质量指数, 腰臀比, 血脂异常, 糖尿病, 2型

Abstract: Objective To investigate the causal relationship between metabolic factors and fracture risk utilizing a two-sample Mendelian randomization (MR) approach, based on publicly available genome-wide association study (GWAS) summary statistics from the China Kadoorie Biobank (CKB). Methods Body mass index (BMI), waist-hip ratio (WHR), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), fasting blood glucose (FBG), glycated hemoglobin (HbA1c), and type 2 diabetes mellitus (T2DM) were designated as exposure variables, with overall fracture incidence serving as the outcome variable. Independent single nucleotide polymorphisms (SNPs) strongly associated with the exposures were selected as instrumental variables. The inverse-variance weighted (IVW) method was utilized as the primary analytical approach, complemented by MR-Egger regression and the weighted median method to evaluate causal effects. Multivariable MR was employed to adjust for confounding variables, and bidirectional MR was conducted to rule out reverse causation. The robustness of the findings was assessed using Cochran's Q test, the MR-Egger intercept test, and the MR-PRESSO method. Results The IVW analysis revealed no significant causal association between fracture risk and either BMI (OR=0.999, P=0.932) or WHR (OR=1.003, P=0.783). Conversely, significant causal associations with fracture risk were observed for LDL-C (OR=1.105, P=0.039), HDL-C (OR=0.902, P=0.029), TG (OR=1.082, P=0.044), FBG (OR=1.153, P=0.034), HbA1c (OR=1.121, P=0.021), and T2DM (OR=1.180, P=0.009). Following adjustment for BMI and WHR via multivariable MR, the independent causal effects of the aforementioned metabolic parameters remained statistically significant (all P<0.05). Bidirectional MR yielded no evidence of reverse causality (all P>0.05). Sensitivity analyses indicated an absence of heterogeneity and horizontal pleiotropy (all P>0.05). Conclusion Impaired glucose metabolism and dyslipidemia constitute independent causal factors for fractures within the Chinese population, whereas adiposity indices such as BMI and WHR demonstrate no independent causal association with fracture risk. These findings suggest that distinct metabolic pathways exert differential effects on fracture susceptibility.

Key words: Fractures, Mendelian randomization analysis, Body mass index, Waist-hip ratio, Dyslipidemias, Diabetes mellitus, type 2