Department of Epidemiology, Zhejiang Chinese Medical University School of Public Health, Hangzhou, 310053, China.
Center for General Practice Medicine, Department of General Practice Medicine, Clinical Research Institute, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China.
BMC Med. 2023 Feb 3;21(1):39. doi: 10.1186/s12916-023-02736-7.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that is accompanied by muscle weakness and muscle atrophy, typically resulting in death within 3-5 years from the disease occurrence. Though the cause of ALS remains unclear, increasing evidence has suggested that inflammation is involved in the pathogenesis of ALS. Thus, we performed two-sample Mendelian randomization (MR) analyses to estimate the associations of circulating levels of cytokines and growth factors with the risk of ALS.
Genetic instrumental variables for circulating cytokines and growth factors were identified from a genome-wide association study (GWAS) of 8293 European participants. Summary statistics of ALS were obtained from a GWAS including 20,806 ALS cases and 59,804 controls of European ancestry. We used the inverse-variance weighted (IVW) method as the primary analysis. To test the robustness of our results, we further performed the simple-median method, weighted-median method, MR-Egger regression, and MR pleiotropy residual sum and outlier test. Finally, a reverse MR analysis was performed to assess the possibility of reverse causation between ALS and the cytokines that we identified.
After Bonferroni correction, genetically predicted circulating level of basic fibroblast growth factor (FGF-basic) was suggestively associated with a lower risk of ALS [odds ratio (OR): 0.74, 95% confidence interval (95% CI): 0.60-0.92, P = 0.007]. We also observed suggestive evidence that interferon gamma-induced protein 10 (IP-10) was associated with a 10% higher risk of ALS (OR: 1.10, 95% CI: 1.03-1.17, P = 0.005) in the primary study. The results of sensitivity analyses were consistent.
Our systematic MR analyses provided suggestive evidence to support causal associations of circulating FGF-basic and IP-10 with the risk of ALS. More studies are warranted to explore how these cytokines may affect the development of ALS.
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，伴有肌肉无力和肌肉萎缩，通常在疾病发生后 3-5 年内导致死亡。虽然 ALS 的病因仍不清楚，但越来越多的证据表明炎症参与了 ALS 的发病机制。因此，我们进行了两样本 Mendelian 随机化（MR）分析，以估计循环细胞因子和生长因子水平与 ALS 风险之间的关联。
从 8293 名欧洲参与者的全基因组关联研究（GWAS）中确定了循环细胞因子和生长因子的遗传工具变量。来自包括 20806 例 ALS 病例和 59804 例欧洲血统对照的 GWAS 的 ALS 汇总统计数据。我们使用逆方差加权（IVW）方法作为主要分析。为了检验结果的稳健性，我们进一步进行了简单中位数法、加权中位数法、MR-Egger 回归和 MR 多效性残差和异常值检验。最后，进行了反向 MR 分析，以评估 ALS 和我们确定的细胞因子之间反向因果关系的可能性。
经 Bonferroni 校正后，遗传预测的基础成纤维细胞生长因子（FGF-basic）循环水平与 ALS 风险降低相关[比值比（OR）：0.74，95%置信区间（95%CI）：0.60-0.92，P=0.007]。我们还观察到提示性证据表明干扰素γ诱导蛋白 10（IP-10）与 ALS 风险增加 10%相关（OR：1.10，95%CI：1.03-1.17，P=0.005）在主要研究中。敏感性分析的结果一致。
我们的系统 MR 分析提供了提示性证据，支持循环 FGF-basic 和 IP-10 与 ALS 风险之间的因果关系。需要进一步研究探索这些细胞因子如何影响 ALS 的发展。
