外周血白细胞计数与胰腺癌风险因果关联的孟德尔随机化研究

Peripheral white blood cell counts and pancreatic cancer risk: a Mendelian randomization study

摘要:

背景与目的 胰腺癌预后极差，普通人群缺乏有效筛查手段。循环白细胞作为可及的免疫炎症指标，其与胰腺癌发病风险的因果关系尚不明确。本研究基于孟德尔随机化（MR）方法，系统评估外周血白细胞绝对计数及其亚型与胰腺癌风险之间的潜在因果关联。方法 采用双样本MR设计。暴露数据来源于Blood Cell Consortium的白细胞总数及5种主要亚型GWAS汇总数据，结局数据来源于FinnGen第12轮胰腺癌GWAS（欧洲人群），并在东亚人群GWAS数据中进行验证。以逆方差加权法（IVW）为主要分析方法，并结合多变量MR、反向MR及多种敏感性分析评估结果的稳健性。结果 单变量MR分析显示，遗传预测的嗜酸性粒细胞计数升高与胰腺癌风险降低相关（IVW：OR=0.886，95% CI=0.793~0.990，P=0.033），且在多种方法中方向一致。多变量MR分析表明，在控制其他白细胞亚型后，该保护效应仍然存在（OR=0.848，95% CI=0.723~0.995，P=0.043）。反向MR未发现胰腺癌对白细胞性状的因果作用。东亚人群验证结果与欧洲人群方向一致。其余白细胞性状未见稳定关联。结论 较高的遗传预测嗜酸性粒细胞水平可能与较低胰腺癌发病风险相关。该结果为胰腺癌免疫病因学提供支持，但尚不足以直接用于临床筛查或干预决策。

Abstract:

Background and Aims Pancreatic cancer has an extremely poor prognosis, and effective screening strategies for the general population are lacking. Circulating white blood cells are accessible immunoinflammatory markers, but their causal relationship with pancreatic cancer risk remains unclear. This study aimed to systematically evaluate the potential causal associations between peripheral white blood cell counts and pancreatic cancer risk using Mendelian randomization (MR).Methods A two-sample MR design was applied. GWAS summary statistics for total white blood cell count and five major subtypes were obtained from the Blood Cell Consortium. Pancreatic cancer outcome data were derived from FinnGen release 12 (European population), with additional validation using East Asian GWAS datasets. The inverse-variance weighted (IVW) method was used as the primary analysis, complemented by multivariable MR, reverse MR, and multiple sensitivity analyses.Results Univariable MR analysis showed that genetically predicted higher eosinophil count was associated with a lower risk of pancreatic cancer (IVW: OR=0.886, 95% CI=0.793-0.990, P=0.033), with consistent direction across methods. Multivariable MR confirmed that this protective association persisted after adjusting for other leukocyte subtypes (OR=0.848, 95% CI=0.723-0.995, P=0.043). Reverse MR provided no evidence for a causal effect of pancreatic cancer on white blood cell traits. The East Asian validation analysis showed a consistent direction of effect. No robust associations were observed for other leukocyte traits.Conclusion Genetically predicted higher eosinophil levels may be associated with a reduced risk of pancreatic cancer. These findings provide supportive evidence for the immunoetiology of pancreatic cancer, but are not yet sufficient for direct clinical application.