转录组和多变量孟德尔随机化分析:2型糖尿病与骨折的关系

Transcriptome and Multivariate Mendelian Randomized Interpretation:Relationship Between Type 2 Diabetes and Fractures

郝丽美 ¹任文清 ²秦林 ¹李慧慧 ¹王艺璇¹

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作者信息

1. 定州市人民医院内分泌科,定州 073000
2. 定州市人民医院骨科,定州 073000
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摘要

目的:利用生物信息学与孟德尔随机化分析方法结合,确定导致2型糖尿病患者骨折风险增加的危险因素,为建立后续的临床预测模型奠定理论基础.方法:使用Gene Expression Omnibus(GEO)数据库中的2型糖尿病数据集(GSE38642)和骨折数据集(GSE30159),进行差异分析并筛选关键基因.然后利用Genecards建立共有主要基因的桑基图,揭示它们与相关疾病的联系.在转录组学中,选取有意义的危险因素作为暴露因素,将2型糖尿病和骨折作为结局因素,进行孟德尔随机化(Mendelian randomization,MR)分析.采用逆方差加权(IVW)作为主要方法,并使用MR-Egger回归法评估水平多效性的截距项,使用Cochran Q统计量评估异质性(Cochran Q P<0.05表示结果具有异质性).同时,通过留一法分析验证整体效果的可靠性.最后,对在MR中显示因果效应的危险因素进行多变量孟德尔随机化分析.结果:在转录组学中,共筛选出14个与2型糖尿病患者发生骨折事件相关的危险因素,包括身高、枸橼酸盐水平、丙氨酸水平、糖化血红蛋白水平、肾小球滤过率状态、IL-1R2水平、血液蛋白质水平、静息心率、心率、脉压状态、心房颤动、慢阻肺病、急性骨髓性白血病和收缩压.经过MR和多变量孟德尔随机化分析后,确定了糖化血红蛋白水平和身高是2型糖尿病患者发生骨折风险的危险因素.结论:在2型糖尿病患者中,糖化血红蛋白水平的上升会引发骨代谢相关功能的改变,进而增加骨质疏松的风险,导致患者身高下降,最终促成2型糖尿病患者发生骨折事件.

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 pri-mary 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 iden-tified.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.Conclusions In patients with type 2 diabetes,an elevation in glycated hemoglobin levels triggers alterations in bone metabo-lism-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.

关键词

2型糖尿病/骨折/影响因素/多变量孟德尔随机化/基因表达综合数据库

Key words

type 2 diabetes/fracture/influencing factors/multivariate mendelian randomization/gene expression omnibus

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基金项目

河北省2022年度医学科学研究课题计划(20220434)

出版年

2024

湖南师范大学学报(医学版)

湖南师范大学

湖南师范大学学报(医学版)

CSTPCD

影响因子：1.389

ISSN：1673-016X

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