基于孟德尔随机化探索全身骨密度对椎间盘退变的年龄特异性影响  

Age-dependent effects of total body bone mineral density on intervertebral disc degeneration based on Mendelian randomization

作　　者：石明亮 陈清 谢栋 牛保成 吴昊 赵琦 杨立利 SHI Ming-liang;CHEN Qing;XIE Dong;NIU Bao-cheng;WU Hao;ZHAO Qi;YANG Li-li(Spine Center,Department of Orthopaedics,Shanghai Changzheng Hospital,Second Affiliated Hospital of Naval Medical University,Shanghai 200003,China;Department of Orthopaedics,No.905 Hospital of PLA Navy,Shanghai 200052,China)

机构地区：[1]海军军医大学第二附属医院(上海长征医院)脊柱外科,上海200003 [2]中国人民解放军海军第九〇五医院骨科,200052

出　　处：《中华骨质疏松和骨矿盐疾病杂志》2024年第4期326-335,共10页Chinese Journal Of Osteoporosis And Bone Mineral Research

基　　金：国家自然科学基金(82372431);上海市卫健委“卫生健康领军人才”计划(2022LJ007);上海市科委“科技创新行动计划”自然科学基金(22ZR1476700);上海市2023年度创新医疗器械应用示范项目(23SHS05700-06);上海市长宁区第五轮创新团队;上海长征医院“揭榜挂帅”培育项目(2023YJBF-PY10)。

摘　　要：目的使用孟德尔随机化方法,探索遗传预测的全身骨密度对椎间盘退变的年龄特异性影响,以及是否可能作为肥胖影响椎间盘退变的中介因素之一。方法从芬兰数据库和骨质疏松联盟中获取了椎间盘退变以及5个年龄层全身骨密度的全基因组关联研究数据。此外,考虑了与肥胖等相关的9个变量。为确保研究的可靠性,本研究采用了严格的分析框架,包括双向、多变量和两步孟德尔随机化分析。结果遗传预测的30岁以上个体全身骨密度与椎间盘退变发生具有提示性关联(0.01<P<0.05),其中46~60岁全身骨密度升高与椎间盘退变发生显著相关[逆方差加权(inverse variance weighting,IVW),OR=1.124,95%CI:1.063~1.1893,P=4.47E-05],并在多变量模型中仍保持显著性。在两步孟德尔随机化框架中,遗传预测的全身无脂肪质量(IVW,β=0.141,95%CI:0.033~0.249,P=1.023E-02)和躯干无脂肪质量(IVW,β=0.129,95%CI:0.024~0.234,P=1.575E-02)与46~60岁全身骨密度显著相关;遗传预测的肥胖相关性状均与椎间盘退变显著相关。未观察到循环瘦素水平或脂联素与全身骨密度或椎间盘退变有关(P>0.05)。结论遗传预测的46~60岁人群全身骨密度升高将增加椎间盘退变的发生风险,并且可能作为与无脂肪质量相关的肥胖影响椎间盘退变的中介因素之一。Objective To employ Mendelian randomization(MR)to investigate the impact of total body bone mineral density(BMD)on intervertebral disc degeneration(IVDD)across various age groups,and to explore whether BMD serves as a mediator in the relationship between obesity and IVDD.Methods Extensive data were extracted from the FinnGen database and the GEFOS,encompassing genome-wide association studies on IVDD and total body BMD(TB-BMD)across five age groups.The analysis also encompassed nine traits linked to obesity and adipokines.To enhance the robustness of the study,a stringent analytical framework that incorporated bidirectional,multivariate,and two-step MR methodologies was implemented.Results Genetically predicted elevated TB-BMD in individuals over 30 years old exhibited suggestive associations with the risk of IVDD(0.01<P<0.05).Genetically predicted TB-BMD(age 46-60)was significantly associated with IVDD risk[inverse variance weighting(IVW),OR=1.124,95%CI:1.063-1.1893,P=4.47E-05],and remained significant in the multivariable model.In a two-step MR framework,genetically predicted whole-body fat-free mass(IVW,β=0.141,95%CI:0.033-0.249,P=1.023E-02)and trunk fat-free mass(IVW,β=0.129,95%CI:0.024-0.234,P=1.575E-02)were significantly associated with TB-BMD.Moreover,all genetically predicted obesity-related traits displayed significant associations with the risk of IVDD.Notably,circulating leptin levels and lipocalin did not exhibit associations with TB-BMD or IVDD.Conclusion Genetic predicted higher TB-BMD(age 46-60)increases the risk of IVDD and may serve as one of the mediators of obesity associated with fat-free mass affecting IVDD.

关 键 词：全身骨密度 椎间盘退变 孟德尔随机化 

分 类 号：R681.53[医药卫生—骨科学]