背景:观察性研究表明白细胞(WBC)亚型与2型糖尿病(T2D)风险之间存在关联。然而,目前尚不清楚这种关系是否是因果关系。我们使用孟德尔随机化(MR)来研究WBC亚型对T2D和血糖性状的因果效应。
方法:中性粒细胞的汇总数据,淋巴细胞,单核细胞,嗜酸性粒细胞,和嗜碱性粒细胞计数从最近的全基因组关联研究中提取(n=173,480)。DIAGRAM和MAGIC联盟提供了有关T2D和血糖特征的汇总数据,包括空腹血糖(FG)(n=133,010),糖化血红蛋白(HbA1c)(n=46,368),和稳态模型评估-估计的胰岛素抵抗(HOMA-IR)(n=37,037)。一系列MR分析(单变量MR,多变量MR,和反向MR)用于研究不同WBC亚型与T2D和血糖性状的因果关系。
结果:使用逆方差加权方法,我们发现遗传确定的中性粒细胞增加一个标准偏差[奇数比(OR):1.086,95%置信区间(CI):0.877-1.345],淋巴细胞[0.878(0.766-1.006)],单核细胞[1.010(0.906-1.127)],嗜酸性粒细胞[0.995(0.867-1.142)],嗜碱性粒细胞[0.960(0.763-1.207)]与T2D风险无因果关系。这些发现与三种多效性稳健方法(MR-Egger,加权中位数,和基于模式的估计器)和多变量MR分析。反向MR分析没有提供T2D对WBC亚型的反向因果关系的证据。WBC亚型对FG的零因果效应,HbA1c,和HOMA-IR也被鉴定。
结论:WBC在胰岛素抵抗和T2D的发展中没有因果关系。观察到的这些因素之间的关联可以通过残余混杂来解释。
BACKGROUND: Observational studies have demonstrated an association between white blood cells (WBC) subtypes and type 2 diabetes (T2D) risk. However, it is unknown whether this relationship is causal. We used Mendelian randomization (MR) to investigate the causal effect of WBC subtypes on T2D and glycemic traits.
METHODS: The summary data for neutrophil, lymphocyte, monocyte, eosinophil, and basophil counts were extracted from a recent genome-wide association
study (n = 173,480). The DIAGRAM and MAGIC consortia offered summary data pertaining to T2D and glycemic characteristics, including fasting glucose (FG) (n = 133,010), glycosylated hemoglobin (HbA1c) (n = 46,368), and homeostatic model assessment-estimated insulin resistance (HOMA-IR) (n = 37,037). A series of MR analyses (univariable MR, multivariable MR, and reverse MR) were used to investigate the causal association of different WBC subtypes with T2D and glycemic traits.
RESULTS: Using the inverse-variance weighted method, we found one standard deviation increases in genetically determined neutrophil [odd ratio (OR): 1.086, 95% confidence interval (CI): 0.877-1.345], lymphocyte [0.878 (0.766-1.006)], monocyte [1.010 (0.906-1.127)], eosinophil [0.995 (0.867-1.142)], and basophil [0.960 (0.763-1.207)] were not causally associated with T2D risk. These findings were consistent with the results of three pleiotropy robust methods (MR-Egger, weighted median, and mode-based estimator) and multivariable MR analyses. Reverse MR analysis provided no evidence for the reverse causation of T2D on WBC subtypes. The null causal effects of WBC subtypes on FG, HbA1c, and HOMA-IR were also identified.
CONCLUSIONS: WBCs play no causal role in the development of insulin resistance and T2D. The observed association between these factors may be explained by residual confounding.