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| 外周白细胞分类计数与类风湿关节炎相关性的孟德尔随机化研究 |
| A Mendelian randomization study of the correlation between the peripheral leukocyte differential count and rheumatoid arthritis |
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| DOI：10.3969/j.issn.1006-7108.2025.09.005 |
| 中文关键词: 类风湿关节炎 外周白细胞分类计数 孟德尔随机化 |
| 英文关键词:rheumatoid arthritis peripheral leukocyte differential count Mendelian randomization |
| 基金项目:河南省2023年科技发展计划（232102310202） |
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| 中文摘要: |
| 目的 探讨外周白细胞分类计数与类风湿关节炎（rheumatoid arthritis, RA）发病风险的双向遗传关联，阐明白细胞亚群在RA病理生理中的作用机制。方法 基于两样本和多因素孟德尔随机化（Mendelian randomization, MR）方法，分析中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞、淋巴细胞和单核细胞计数对血清学阳性/阴性RA发病风险的影响及反向因果关联。数据源自国际血细胞联盟（n=563 946）和芬兰生物银行（n=377 277）的欧洲人群全基因组关联研究（GWAS）。采用逆方差加权法（inverse variance weighting，IVW）、MR-Egger和MR-PRESSO 3种方法进行因果关联分析，并行敏感性分析。结果 外周嗜酸性粒细胞计数升高与血清学阳性RA的风险增高相关，IVW、MR-Egger和MR-PRESSO的OR值（95 %CI）分别为1.309（1.144 ~ 1.497），1.495（1.153 ~ 1.938），1.121（1.025 ~ 1.226），P均＜0.05；外周嗜酸性粒细胞计数升高和血清学阴性RA的风险增高亦存在相关性，OR值（95 %CI）分别为1.202（1.071 ~ 1.349），1.289（1.031 ~ 1.612），1.142（1.032 ~ 1.264）, P均＜0.05。外周单核细胞计数升高与血清学阳性RA的风险增高存在相关性，OR值（95 %CI）分别为1.108（1.016 ~ 1.209），1.105（1.032 ~ 1.183）1.108（1.016 ~ 1.209），1.076（0.935 ~ 1.237），1.105（1.032 ~ 1.183），P均＜0.05。多因素分析显示，嗜酸性粒细胞和单核细胞在影响RA风险时可能共享基因层面的位点或机制。此外，血清学阳性RA可反向上调外周中性粒细胞、嗜酸性粒细胞、嗜碱性粒细胞和单核细胞计数（P＜0.05）。灵敏度分析未发现异质性和水平多效性。结论 外周白细胞计数与RA间在基因水平上存在双向关联，特别是嗜酸性粒细胞在RA的发生和发展中发挥重要作用。这有助于深化对RA发病机制的认识，为RA预防和控制提供理论依据。 |
| 英文摘要: |
| Objective To explore the bidirectional association between peripheral leukocyte differential count and the risk of rheumatoid arthritis (RA), and to gain an in-depth understanding of the role of leukocytes in the pathogenesis and pathophysiologic process of RA at genetic level. Methods Based on a two-sample and multifactorial Mendelian randomization (MR) approach, the effects of peripheral neutrophil, eosinophil, basophil, lymphocyte, and monocyte counts on the risk of developing serology-positive RA and serology-negative RA were investigated, as well as the inverse effect of RA on peripheral leukocyte differential counts. Data were obtained from the genome-wide association studies (GWAS) of the International Blood Cell Consortium (Blood Cell Consortium) and FinnGen Consortium, involving approximately 560,000 and 370,000 subjects of European ancestry, respectively. Causal association analysis was performed using three methods: inverse variance weighting (IVW), MR-Egger, and MR-PRESSO, and sensitivity analysis was performed. Results Elevated peripheral eosinophil counts were correlated with increased risk of serology-positive RA, with ORs (95% CIs) of 1.309 (1.144 ~ 1.497), 1.495 (1.153 ~ 1.938), and 1.121 (1.025-1.226) for IVW, MR-Egger, and MR-PRESSO, respectively, and all P < 0.05. Elevated peripheral eosinophil counts and increased risk of serology-negative RA were also correlated with OR (95% CI) of 1.202 (1.071-1.349), 1.289 (1.031-1.612), and 1.142 (1.032- 1.264), respectively, all with P < 0.05. The correlation between elevated peripheral monocyte counts and increased risk of serology-positive RA were correlated with increased risk of RA with OR (95% CI) of 1.108 (1.016 -1.209), 1.105 (1.032- 1.183) 1.108 (1.016 - 1.209), 1.076 (0.935 - 1.237), and 1.105 (1.032-1.183), with all P < 0.05. Multifactorial analyses revealed that eosinophils and monocytes shared gene-level loci or mechanisms in influencing RA risk. In addition, serology-positive RA significantly increased the levels of peripheral neutrophil, eosinophil, basophil, and monocyte counts (P < 0.05). Sensitivity analysis did not reveal heterogeneity or horizontal pleiotropy. Conclusion There is a bidirectional association between peripheral leukocyte count and RA at the genetic level, especially eosinophils play an important role in the onset and development of RA. This helps to deepen the understanding of RA pathogenesis and provides a theoretical basis for RA prevention and control. |
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