2型糖尿病与骨质疏松因果关系的孟德尔随机化研究  

Mendelian randomization study on the causal relationship between type 2 diabetes and osteoporosis

作　　者：于涵 李宗宝 胡帆[1] 李楠[1] 卢艳慧[1] 李春霖[1] Yu Han;Li Zongbao;Hu Fan;Li Nan;Lu Yanhui;Li Chunlin(Department of Endocrinology,the Second Medical Center&National Clinical Research Center for Geriatric Disease,Chinese PLA General Hospital,Beijing 100853,China;Medical School of Chinese PLA,Beijing 100853,China)

机构地区：[1]解放军总医院第二医学中心内分泌科、国家老年疾病临床研究中心,北京100853 [2]解放军总医院研究生院,北京100853

出　　处：《中华内科杂志》2025年第3期225-233,共9页Chinese Journal of Internal Medicine

基　　金：国家重点研发计划(2020YFC2008905)。

摘　　要：目的分析2型糖尿病与腰椎骨密度、脊柱骨折之间的因果关系,并进一步剖析中心性肥胖在糖尿病骨悖论中产生的影响。方法孟德尔随机化(MR)研究。从全基因组关联分析研究数据中分别筛选与2型糖尿病相关的单核苷酸多态性(SNP)作为工具变量,以腰椎骨密度及脊柱骨折为结局变量,通过运用逆方差加权法、加权中位数法以及MR-Egger回归,从基因层面,评估2型糖尿病与骨质疏松之间的因果关联。此外,为剖析中心性肥胖在糖尿病骨悖论中产生的影响,引入腰臀比作为新的暴露变量,以2型糖尿病及腰椎骨密度为结局变量,应用MR方法进一步揭示其中的影响因素。结果以MR三大假设为前提设置筛选标准,最终筛选出与T2DM相关SNP 62个、与腰臀比相关SNP 241个。以逆方差加权法为主要分析方法,因果关联效应分析显示,2型糖尿病与腰椎骨密度(OR=1.0476,P=0.007)的升高及脊柱骨折(OR=1.0009,P=0.014)存在因果关系。腰臀比与2型糖尿病(OR=1.6386,P<0.001)存在因果关系,是2型糖尿病的危险因素;腰臀比与腰椎骨密度(OR=1.0963,P=0.044)的升高可能存在因果联系。表明腰臀比可能间接在糖尿病与骨质疏松之间产生影响。MR-Egger截距测试显示本研究没有水平多效性。留一法检验显示没有单个SNP对整体的结果有较大影响。MR多效性残差和异常值(MR-PRESSO)结果显示未检测到异常的SNP。结论通过MR分析方法得出2型糖尿病与腰椎骨密度升高及脊柱骨折风险增高均存在因果关系,这一悖论的产生可能与中心性肥胖有关。Objective To analyze the causal relationship between type 2 diabetes and lumbar bone mineral density and spinal fractures and to further explore the impact of central obesity on the diabetic bone paradox.Methods A Mendelian randomization(MR)study was implemented.Single nucleotide polymorphisms(SNPs)associated with type 2 diabetes were selected from the data of genome-wide association studies as instrumental variables,with lumbar bone density and spinal fractures as the outcome variables.The inverse variance weighting method,weighted median method,and MR-Egger regression were applied to identify a causal relationship between type 2 diabetes and osteoporosis at the genetic level.Additionally,to analyze the impact of central obesity in the diabetic bone paradox,the waist-to-hip ratio was introduced as a new exposure variable,with type 2 diabetes and lumbar bone density as outcome variables,and the MR method was applied again to uncover the influencing factors.Results The screening criteria were based on the three main assumptions of MR.Finally,62 SNPs for type 2 diabetes and 241 SNPs for waist-to-hip ratio were included in the MR analysis.Using inverse variance weighting as the primary analysis,the causal association effect analysis indicated a causal relationship between type 2 diabetes and increased lumbar bone density(OR=1.0476,P=0.007)and spinal fractures(OR=1.0009,P=0.014).A causal relationship between waist-to-hip ratio and type 2 diabetes(OR=1.6386,P<0.001)was identified,indicating that the waist-to-hip ratio was a risk factor for type 2 diabetes and may have a causal association with increased lumbar bone density(OR=1.0963,P=0.044).This suggests that the waist-to-hip ratio may indirectly affect the relationship between diabetes and osteoporosis.The MR-Egger intercept test showed no horizontal pleiotropy in this study.The leave-one-out analysis indicated that no single SNP had a significant impact on the overall results.Furthermore,the MR-pleiotropy residual sum and outlier(MR-PRESSO)test results did not dete

关 键 词：糖尿病 2型 骨质疏松 腰臀比 悖论 孟德尔随机化研究 

分 类 号：R587.2[医药卫生—内分泌] R580[医药卫生—内科学]