中医正骨2025，Vol.37Issue(6)：8-18,11.
血液和尿液生物标志物指标与骨坏死因果关系的双向孟德尔随机化分析及Meta分析
Causal relationships of blood and urinary biomarkers with osteonecrosis:a bidirectional mendelian randomiza-tion analysis and meta-analysis
摘要
Abstract
Objective:To explore the causal relationships of blood and urinary biomarkers(BUBs)with osteonecrosis.Methods:One genome-wide association study(GWAS)data about 35 BUBs and 3 GWAS datasets(finngen_R9_M13_OSTEONECROSIS,finngen_R10_M13_OSTEONECROSIS,and finngen_R11_M13_OSTEONECROSIS(hereinafter referred to as R9,R10,and R11 datasets,respectively))about osteonecrosis were obtained.Based on the aforementioned GWAS datasets,the single nucleotide polymorphisms(SNPs)associated with the 35 BUBs were screened and selected as the instrumental variables for forward Mendelian randomization(MR)analysis,while the ones for osteonecrosis were identified as the instrumental variables for reverse MR analysis.After that,the forward two-sample MR analyses were con-ducted with osteonecrosis as the outcome using the R9,R10,and R11 datasets,respectively,while the reverse two-sample MR analyses were subsequently performed with 35 BUBs as the outcomes.The potential heterogeneity of instrumental variables was evaluated using Cochran's Q test,supplemented by MR-Egger regression and MR-PRESSO analysis for horizontal pleiotropy assessment.The effect estimates(OR/β(95％CI))derived from the three forward and three reverse MR analyses examining the BUBs demonstrating causal relationships with osteo-necrosis were pooled,respectively,and the meta-analyses were performed using R studio software.Results:①Instrumental variables.Based on the 35 BUBs-comprised GWAS data and osteonecrosis R9,R10,R11 datasets,5931,4385,and 5931 BUBs-associated SNPs were identi-fied,and 9,56,and 9 osteonecrosis-associated SNPs were screened,respectively.②Forward MR and sensitivity analyses.The R9 dataset-based forward MR analyses indicated a positive causal effect of serum aspartate transaminase(AST)level to alanine transaminase(ALT)lev-el ratio,and inverse causal effects of serum albumin,C-reactive protein(CRP),cystatin C,and insulin-like growth factor(IGF)-1 levels on osteonecrosis.Analyses with R10 dataset revealed inverse causal effects of serum cystatin C and IGF-1 levels on osteonecrosis.Furthermore,analyses with R11 dataset showed a positive causal effect of serum CRP level,alongside inverse causal effects of serum albumin,cystatin C,IGF-1,and vitamin D levels on osteonecrosis.Sensitivity analyses demonstrated that there was no significant heterogeneity or horizontal plei-otropy in the instrumental variables of all serum biomarkers.③Reverse MR and sensitivity analyses.The R9 dataset-based reverse MR ana-lyses revealed osteonecrosis exerted positive causal effects on serum albumin and calcium levels,with an inverse effect observed on urinary urea level.Analyses with R10 dataset demonstrated positive causalities between osteonecrosis and the serum levels of albumin and total pro-tein,and analyses with R11 dataset further identified positive causalities of serum albumin,calcium,testosterone,and total protein levels with osteonecrosis,alongside the inverse causalities of serum apolipoprotein B and total bilirubin levels.Sensitivity analyses showed that there was no significant heterogeneity or horizontal pleiotropy in the instrumental variables of osteonecrosis.④Meta-Analysis of forward MR results.The pooled estimates showed the positive causal effects of serum AST level to ALT level ratio and serum CRP level on osteonecrosis(OR=1.25,95％CI(1.08,1.45);OR=1.20,95％CI(1.08,1.34)),while the inverse effects of serum albumin,IGF-1,and vitamin D levels on osteonecrosis(OR=0.77,95％CI(0.66,0.88);OR=0.82,95％CI(0.74,0.91);OR=0.78,95％CI(0.67,0.91)),with no significant causal associations detected between serum cystatin C level and osteonecrosis(OR=0.91,95％CI(0.68,1.22)).⑤Meta-Anal-ysis of reverse MR results.The pooled estimates revealed that osteonecrosis exerted positive causal effects on serum albumin,calcium,and total protein levels(β=0.007,95％CI(0.004,0.009);β=0.007,95％CI(0.003,0.011);β=0.005,95％CI(0.003,0.008)),with no significant causal associations detected between osteonecrosis and serum apolipoprotein B,testosterone,total bilirubin,or urinary urea levels(β=-0.004,95％CI(-0.008,0.001);β=0.000,95％CI(-0.006,0.007);β=-0.002,95％CI(-0.006,0.002);β=-0.003,95％CI(-0.007,0.000)).Conclusion:The serum AST to ALT ratio,CRP,albumin,IGF-1,and vitamin D levels show reliable causal effects on osteonecrosis.Conversely,osteonecrosis exerted reliable causal effects on the serum albumin,calcium,and total protein levels.These findings provide a reference for exploring biomarkers for diagnosis of osteonecrosis.关键词
骨坏死/生物标志物/血液/尿/孟德尔随机化分析/专题Meta分析Key words
osteonecrosis/biomarkers/blood/urine/Mendelian randomization analysis/meta-analysis as topic引用本文复制引用
李广政,周忠起,丁浩秦,张歆雨,李刚,梁学振..血液和尿液生物标志物指标与骨坏死因果关系的双向孟德尔随机化分析及Meta分析[J].中医正骨,2025,37(6):8-18,11.基金项目
国家自然科学基金项目(82205154,82074453) （82205154,82074453）
山东省自然科学基金项目(ZR2024MH156) （ZR2024MH156）
山东省中医药科技项目(MR20241837) （MR20241837）
