Effects of circulating inflammatory proteins on spinal degenerative diseases: Evidence from genetic correlations and Mendelian randomization study

IF 3.4 3区医学 Q1 ORTHOPEDICS JOR Spine Pub Date : 2024-06-17 DOI:10.1002/jsp2.1346

Qingcong Zheng, Rongjie Lin, Du Wang, Chunfu Zheng, Weihong Xu

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Abstract

Background

Numerous investigations have suggested links between circulating inflammatory proteins (CIPs) and spinal degenerative diseases (SDDs), but causality has not been proven. This study used Mendelian randomization (MR) to investigate the causal associations between 91 CIPs and cervical spondylosis (CS), prolapsed disc/slipped disc (PD/SD), spinal canal stenosis (SCS), and spondylolisthesis/spondylolysis.

Methods

Genetic variants data for CIPs and SDDs were obtained from the genome-wide association studies (GWAS) database. We used inverse variance weighted (IVW) as the primary method, analyzing the validity and robustness of the results through pleiotropy and heterogeneity tests and performing reverse MR analysis to test for reverse causality.

Results

The IVW results with Bonferroni correction indicated that beta-nerve growth factor (β-NGF), C-X-C motif chemokine 6 (CXCL6), and interleukin-6 (IL-6) can increase the risk of CS. Fibroblast growth factor 19 (FGF19), sulfotransferase 1A1 (SULT1A1), and tumor necrosis factor-beta (TNF-β) can increase PD/SD risk, whereas urokinase-type plasminogen activator (u-PA) can decrease the risk of PD/SD. FGF19 and TNF can increase SCS risk. STAM binding protein (STAMBP) and T-cell surface glycoprotein CD6 isoform (CD6 isoform) can increase the risk of spondylolisthesis/spondylolysis, whereas monocyte chemoattractant protein 2 (MCP2) and latency-associated peptide transforming growth factor beta 1 (LAP-TGF-β1) can decrease spondylolisthesis/spondylolysis risk.

Conclusions

MR analysis indicated the causal associations between multiple genetically predicted CIPs and the risk of four SDDs (CS, PD/SD, SCS, and spondylolisthesis/spondylolysis). This study provides reliable genetic evidence for in-depth exploration of the involvement of CIPs in the pathogenic mechanism of SDDs and provides novel potential targets for SDDs.

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循环炎症蛋白对脊柱退行性疾病的影响：遗传相关性和孟德尔随机研究的证据。

背景：大量研究表明，循环炎症蛋白（CIPs）与脊柱退行性疾病（SDDs）之间存在联系，但因果关系尚未得到证实。本研究采用孟德尔随机法（MR）调查了91种CIPs与颈椎病（CS）、椎间盘突出/椎间盘脱出（PD/SD）、椎管狭窄（SCS）和脊椎滑脱症/脊椎溶解症之间的因果关系：CIPs 和 SDDs 的遗传变异数据来自全基因组关联研究（GWAS）数据库。我们以反向方差加权（IVW）为主要方法，通过多向性和异质性检验分析结果的有效性和稳健性，并进行反向MR分析以检验反向因果关系：经 Bonferroni 校正的 IVW 结果表明，β-神经生长因子（β-NGF）、C-X-C 矩阵趋化因子 6（CXCL6）和白细胞介素 6（IL-6）可增加 CS 风险。成纤维细胞生长因子 19（FGF19）、磺基转移酶 1A1（SULT1A1）和肿瘤坏死因子-β（TNF-β）可增加 PD/SD 风险，而尿激酶型纤溶酶原激活剂（u-PA）可降低 PD/SD 风险。FGF19和TNF可增加SCS风险。STAM结合蛋白（STAMBP）和T细胞表面糖蛋白CD6同工酶（CD6同工酶）可增加脊柱骨化/椎体溶解风险，而单核细胞趋化蛋白2（MCP2）和潜伏相关肽转化生长因子β1（LAP-TGF-β1）可降低脊柱骨化/椎体溶解风险：磁共振分析表明，多种基因预测的 CIP 与四种 SDD（CS、PD/SD、SCS 和脊柱滑脱症/椎体溶解症）风险之间存在因果关系。这项研究为深入探讨CIPs参与SDDs的致病机制提供了可靠的遗传学证据，并为SDDs提供了新的潜在靶点。

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