[1]李广政,周忠起,丁浩秦,等.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(06):8-18.
　LI Guangzheng,ZHOU Zhongqi,DING Haoqin,et al.Causal relationships of blood and urinary biomarkers with osteonecrosis:a bidirectional mendelian randomization analysis and meta-analysis[J].The Journal of Traditional Chinese Orthopedics and Traumatology,2025,37(06):8-18.
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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()

《中医正骨》[ISSN:1001-6015/CN:41-1162/R]

卷:
第37卷
期数:
2025年06期
页码:
8-18
栏目:
数据库研究
出版日期:
2025-06-20

文章信息/Info

Title:
Causal relationships of blood and urinary biomarkers with osteonecrosis:a bidirectional mendelian randomization analysis and meta-analysis
作者:
李广政1; 周忠起2; 丁浩秦1; 张歆雨2; 李刚3; 梁学振3
1.山东中医药大学第一临床医学院,山东 济南 250014; 2.山东中医药大学中医学院,山东 济南 250355; 3.山东中医药大学附属医院,山东 济南 250014
Author(s):
LI Guangzheng1; ZHOU Zhongqi2; DING Haoqin1; ZHANG Xinyu2; LI Gang3; LIANG Xuezhen3
1.The First Clinical Medical College of Shandong University of Traditional Chinese Medicine,Jinan 250014,Shandong,China 2.College of Traditional Chinese Medicine,Shandong University of Traditional Chinese Medicine,Jinan 250355,Shandong,China 3.The Affiliated Hospital of Shandong University of Traditional Chinese Medicine,Jinan 250014,Shandong,China
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
Keywords:
osteonecrosis;  biomarkers;  blood;  urine;  Mendelian randomization analysis;  meta-analysis as topic
摘要:
目的:探讨血液和尿液生物标志物指标与骨坏死的因果关系。方法:获取1项包含35种血液和尿液生物标志物指标的全基因组关联研究(genome-wide association study,GWAS)数据及3项骨坏死GWAS数据[finngen_R9_M13_OSTEONECROSIS(以下简称R9数据)、finngen_R10_M13_OSTEONECROSIS(以下简称R10数据)和finngen_R11_M13_OSTEONECROSIS(以下简称R11数据)]。基于上述GWAS数据分别筛选血液和尿液生物标志物指标的单核苷酸多态性(single nucleotide polymorphism,SNP)位点为正向孟德尔随机化(Mendelian randomization,MR)分析的工具变量,筛选骨坏死的SNP位点为反向MR分析的工具变量。以骨坏死为结局(分别使用R9数据、R10数据、R11数据)进行两样本正向MR分析,以35种血液和尿液生物标志物指标为结局进行两样本反向MR分析。采用Cochran's Q检验评估工具变量的潜在异质性,采用MR-Egger回归和MR-PRESSO分析评估工具变量的水平多效性。将与骨坏死存在因果关系的血液和尿液生物标志物指标的3次正向MR分析和3次反向MR分析所得的OR/β(95%CI)数据分别进行汇总,采用R studio软件进行Meta分析。结果:①工具变量筛选结果。基于包含35种血液和尿液生物标志物指标的GWAS数据和骨坏死的R9数据、R10数据、R11数据,分别筛选血液和尿液生物标志物指标SNP位点5931个、4385个、5931个,分别筛选骨坏死SNP位点9个、56个、9个。②正向MR分析及敏感性分析结果。基于R9数据的正向MR分析结果显示,血液天冬氨酸转氨酶(aspartate transaminase,AST)水平与丙氨酸转氨酶(alanine transaminase,ALT)水平的比值与骨坏死呈正向因果关系,血液白蛋白水平、C反应蛋白水平、胱抑素C水平、胰岛素样生长因子(insulin-like growth factor,IGF)-1水平与骨坏死均呈负向因果关系; 基于R10数据的正向MR分析结果显示,血液胱抑素C水平、IGF-1水平与骨坏死均呈负向因果关系; 基于R11数据的正向MR分析结果显示,血液C反应蛋白水平与骨坏死呈正向因果关系,血液白蛋白水平、胱抑素C水平、IGF-1水平、维生素D水平与骨坏死均呈负向因果关系。敏感性分析结果显示,各项血液生物标志物指标的工具变量均不存在异质性和水平多效性。③反向MR分析及敏感性分析结果。基于R9数据的反向MR分析结果显示,骨坏死与血液白蛋白水平、钙水平呈正向因果关系,与尿液尿素水平呈负向因果关系; 基于R10数据的反向MR分析结果显示,骨坏死与血液白蛋白水平、总蛋白水平呈正向因果关系; 基于R11数据的反向MR分析结果显示,骨坏死与血液白蛋白水平、钙水平、睾酮水平、总蛋白水平呈正向因果关系,与血液载脂蛋白B水平、总胆红素水平呈负向因果关系。敏感性分析结果显示,骨坏死的工具变量均不存在异质性和水平多效性。④正向MR分析结果的Meta分析结果。血液AST水平与ALT水平的比值、C反应蛋白水平与骨坏死呈正向因果关系[OR=1.25,95%CI(1.08,1.45); OR=1.20,95%CI(1.08,1.34)],血液白蛋白水平、IGF-1水平、维生素D水平与骨坏死均呈负向因果关系[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)]; 血液胱抑素C水平与骨坏死不存在因果关系[OR=0.91,95%CI(0.68,1.22)]。⑤反向MR分析结果的Meta分析结果。骨坏死与血液白蛋白水平、钙水平、总蛋白水平存在正向因果关系[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)],与血液载脂蛋白B水平、睾酮水平、总胆红素水平和尿液尿素水平不存在因果关系[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)]。结论:血液AST水平与ALT水平的比值、C反应蛋白水平、白蛋白水平、IGF-1水平、维生素D水平与骨坏死存在可靠的因果关系,且骨坏死与血液白蛋白水平、钙水平、总蛋白水平存在可靠的因果关系; 这为探寻诊断骨坏死的生物标志物指标提供了参考。
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 conducted 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 osteonecrosis 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 identified,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)level 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 pleiotropy in the instrumental variables of all serum biomarkers.③Reverse MR and sensitivity analyses.The R9 dataset-based reverse MR analyses 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 protein,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-Analysis 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.

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备注/Memo

备注/Memo:
基金项目:国家自然科学基金项目(82205154,82074453); 山东省自然科学基金项目(ZR2024MH156); 山东省中医药科技项目(MR20241837)
通讯作者:梁学振 E-mail:liangxz0429@163.com
更新日期/Last Update: 1900-01-01