Causal Association of Leukocytes Count and Amyotrophic Lateral Sclerosis: a Mendelian Randomization Study
Causal Association of Leukocytes Count and Amyotrophic Lateral Sclerosis: a Mendelian Randomization Study
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白细胞计数与肌萎缩侧索硬化症的因果关系：孟德尔随机研究
DOI：
10.1007/s12035-020-02053-7
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发表时间：
2020-08-07
影响因子：
5.1
通讯作者：
Shang, Huifang
中科院分区：
文献类型：
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作者：
Li, Chunyu;Yang, Wanchun;Shang, Huifang
临床上已观察到外周免疫与肌萎缩侧索硬化症（ALS）相关，但是否存在因果关系以及作用方向尚存在争议且难以捉摸。本研究的目的是探讨外周免疫细胞特征（包括白细胞总数、单核细胞计数、中性粒细胞计数、嗜酸性粒细胞计数、嗜碱性粒细胞计数和淋巴细胞计数）与 ALS 风险的因果关系。我们进行了两个样本孟德尔随机化分析来估计因果效应。来自人类血细胞特征的全基因组关联研究的显着单核苷酸多态性被用作暴露工具和 ALS 的汇总统计作为结果。通过逆方差加权、MR Egger 回归和加权中位数方法评估因果关系，并通过广泛的敏感性分析进一步验证。我们发现，经过 Bonferroni 校正后，基因决定的白细胞总数增加一个标准差与 ALS 风险降低相关（OR：0.906，95% CI：0.842-0.974，P：0.007），而中性粒细胞计数增加表明与 ALS 风险降低存在关联（OR：0.926，95% CI：0.858-1.000，P： 0.049）。所有敏感性分析的结果都是稳健的。我们的研究揭示了外周白细胞较高的遗传倾向，与 ALS 风险呈反向因果效应，强调了外周免疫在 ALS 发展中的重要作用。
Peripheral immunity has been observed to be associated with amyotrophic lateral sclerosis (ALS) clinically, but whether there exist causal association and the effect direction is controversial and elusive. The objective of this study is to explore the causal relationship of peripheral immune cell traits including total leukocytes count, monocyte count, neutrophil count, eosinophil count, basophil count, and lymphocyte count on ALS risk. We conducted a two-sample Mendelian randomization analysis to estimate the causal effects. Significant single nucleotide polymorphisms from genome-wide association study on human blood cell traits were utilized as exposure instruments and summary statistics of ALS as outcome. The causal relationship was evaluated by inverse variance weighted, MR Egger regression and weighted median methods, and further verified by extensive sensitivity analyses. We found that genetically determined one standard deviation increase in total leukocytes count was associated with lower risk of ALS (OR: 0.906, 95% CI: 0.842–0.974,P: 0.007) after Bonferroni correction, and increased neutrophil count showed suggestive association with reduced ALS risk (OR: 0.926, 95% CI: 0.858–1.000,P: 0.049). The results were robust under all sensitivity analyses. Our study reveals a genetic predisposition to higher peripheral leukocytes with an inverse causal effect on the risk of ALS, highlighting the important role of peripheral immunity in the development of ALS.