中国组织工程研究

中国组织工程研究 ›› 2024, Vol. 28 ›› Issue (35): 5688-5694.doi: 10.12307/2024.825

• 组织工程相关大数据分析 Big data analysis in tissue engineering • 上一篇    下一篇

基于孟德尔随机化分析躯干及下肢脂肪量与椎间盘退变的因果关系

杨敬言1，马  涉1，黄仁俊1，王超逸1，赵余炀1，于  栋2   

  1. 1北京中医药大学第三临床医学院，北京市  100029；2北京中医药大学第三附属医院，北京市  100029
  • 收稿日期:2023-12-04 接受日期:2024-01-04 出版日期:2024-12-18 发布日期:2024-03-15
  • 通讯作者: 于栋，博士，主任医师，硕士生导师，北京中医药大学第三附属医院脊柱科，北京市 100029
  • 作者简介:杨敬言，男，1999年生，山西省太原市人，汉族，北京中医药大学在读硕士，主要从事中医骨伤科学方面的研究。
  • 基金资助:
    北京中医药大学第三附属医院2022年度“中医骨伤治疗与运动康复智能化”教育部工程研究中心培育项目(BZYSY-2022-GCYJZXQX-08)，项目负责人：于栋

Causal relationship between trunk and lower limb fat mass and intervertebral disc degeneration based on a Mendelian randomization analysis

Yang Jingyan1, Ma She1, Huang Renjun1, Wang Chaoyi1, Zhao Yuyang1, Yu Dong2   

  1. 1The Third Clinical School of Beijing University of Chinese Medicine, Beijing 100029, China; 2The Third Clinical Hospital of Beijing University of Chinese Medicine, Beijing 100029, China
  • Received:2023-12-04 Accepted:2024-01-04 Online:2024-12-18 Published:2024-03-15
  • Supported by:
    2022 Cultivation Project of the Ministry of Education Engineering Research Center for “Intelligent Treatment of Traditional Chinese Medicine Orthopaedic Injury and Sports Rehabilitation,” The Third Affiliated Hospital of Beijing University of Chinese Medicine, No. BZYSY-2022-GCYJZXQX-08 (to YD)

PDF

7

摘要：


文题释义：

孟德尔随机化：是一种以遗传变异为工具变量，遵循孟德尔定律，即相应的等位基因在胚胎形成时期随机分配且固定的原则，排除混杂因素对结果的影响，加强了因果推断证据强度的研究方法。
椎间盘退变：椎间盘是一种由髓核、纤维环、终板软骨构成的组织，位于两个相邻椎体间，连接上下椎体。致病因素长期的影响下可能导致椎间盘水分丢失、结构破坏及承载能力下降，从而出现退行性变。


背景：近期观察性研究发现局部脂肪量对于椎间盘退变评估有重要意义，而肥胖长期被认为是椎间盘退变的危险因素之一，作为肥胖核心因素的脂肪量在既往研究中与椎间盘退变的因果关系尚不明确。

目的：探讨不同分布的脂肪量与椎间盘退变的因果关系，以帮助增加对椎间盘退变发病机制的认知及制定预防、治疗及预后的策略。
方法：从公开发表的IEU Open GWAS中以强相关性及满足连锁不平衡为条件提取躯干及下肢脂肪量的遗传位点作为工具变量，结合FinnGen最新第9版数据库中选取椎间盘退变作为结局进行孟德尔随机化分析，通过逆方差加权法、MR-Egger回归、简单中位数法、加权中位数法和加权中值法等回归模型的OR值和95%CI评估躯干及下肢脂肪量与椎间盘退变间的因果关系。使用Cochran’s Q检验评估遗传工具变量的异质性，使用MR-Egger截距检验评估多效性，使用留一法评估作为工具变量的单核苷酸多态性对暴露和结局因果关系影响的敏感性。

结果与结论：①逆方差加权法检测结果显示，躯干脂肪量与椎间盘退变发病风险呈正向因果关联(OR=1.25，95%CI：1.15-1.35，P < 0.001)，双下肢脂肪量与椎间盘退变发病风险呈反向因果关联(OR=0.7，95%CI：0.63-0.78，P < 0.001；OR=0.69，95%CI：0.62-0.76，P < 0.001)；②MR-Egger截距分析未检测到潜在的水平多效性；③MR-PRESSO未检测到偏倚单核苷酸多态性，异质性检验存在，留一法敏感性分析提示分析结果可靠；④上述结果证实，躯干脂肪量与椎间盘退变有正向因果关系，随着躯干脂肪量增加，椎间盘退变的风险升高；双下肢脂肪量与椎间盘退变有反向因果关系，即随着双下肢脂肪量增加，椎间盘退变风险降低；脂肪的含量及分布会影响椎间盘退变的发病风险，应给予更多的关注。

https://orcid.org/0009-0004-4123-2841(杨敬言)

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

关键词: 全基因组关联研究, 孟德尔随机化, 椎间盘退变, 脂肪量, 逆方差加权法, 敏感性分析, 单核苷酸多态性, 因果关系

Abstract: BACKGROUND: It has been found in recent observational studies that assessing localized fat mass is crucial in the evaluation of disc degeneration. Although obesity has been recognized as a risk factor for disc degeneration, the causal relationship between fat mass, which is a key factor in obesity, and intervertebral disc degeneration has been unclear in previous studies.
OBJECTIVE: To investigate the causal risk factors of intervertebral disc degeneration associated with different distributions of fat mass, thereby enhancing the understanding of the pathogenesis of intervertebral disc degeneration and contributing to the development of preventive, therapeutic, and prognostic strategies.
METHODS: Genetic markers associated with trunk and lower limb fat mass were extracted as instrumental variables from the publicly available IEU Open GWAS under the conditions of strong correlation and fulfillment of linkage disequilibrium. These markers were combined with the Mendelian randomization analysis to investigate the relationship between body fat and intervertebral disc degeneration. We used the latest version 9 database of FinnGen and assessed the results using several regression models, including inverse variance weighting, MR-Egger regression, simple mode, weighted mode, and weighted median estimator. We also assessed the heterogeneity of the genetic markers using Cochran’s Q test, and multiplicity was assessed using the MR-Egger intercept test. Additionally, we used the leave-one-out method to determine the sensitivity of individual genetic markers to the causal effect of the exposure and outcome. The results were presented as odds ratios (OR) and 95% confidence intervals (CI).
RESULTS AND CONCLUSION: The results from the inverse variance weighting method revealed that there was a positive causal relationship between trunk fat mass and the risk of developing intervertebral disc degeneration (OR=1.25, 95% CI: 1.15-1.35, P < 0.001). Additionally, there was an inverse causal relationship between bilateral lower limb fat mass and the risk of developing intervertebral disc degeneration (OR=0.7, 95% CI: 0.63-0.78, P < 0.001; OR=0.69, 95% CI: 0.62-0.76, P < 0.001). Furthermore, the MR-Egger intercept analysis did not detect any potential horizontal pleiotropy. No bias single nucleotide polymorphisms were detected, while heterogeneity tests were present, and the leave-one-out sensitivity analysis suggested reliable results. The results above demonstrate a positive causal relationship between trunk fat mass and intervertebral disc degeneration. As trunk fat mass increases, the risk of intervertebral disc degeneration rises. With an increase in both lower limb fat mass, the risk of intervertebral disc degeneration decreases. Fat content and distribution affects the risk of developing intervertebral disc degeneration and should be given more attention.

Key words: genome-wide association study, Mendelian randomization, intervertebral disc degeneration, fat mass, inverse variance weighting method, sensitivity analysis, single nucleotide polymorphism, causality

中图分类号: