血细胞生成很复杂，部分是基因决定的，受后天因素影响。然而，在衰老的背景下，这些因素如何相互作用有很少的数据可用，而衰老与骨髓增殖偏向、克隆性造血（CH）和髓系癌症的发生率增加有关。我们调查了2996名来自魁北克、55至101岁的相关和无关女性的遗传和后天因素，以了解血细胞特征可变性的基础。我们进行了全基因组关联研究，评估了慢性疾病的影响，并进行了CH驱动基因和X染色体失活（XCI）为基础的克隆性分析。使用广义线性混合模型进行了多变量分析。我们记录了年龄与中性粒细胞和单核细胞计数的增加以及淋巴细胞计数的减少相关。中性粒细胞计数受到GSDMA和PSMD3-CSF3区域的变异影响，但此关联随着年龄的增长而减少。同时，年龄较大的有心脏代谢病同时存在的个体中，中性粒细胞计数显著增加（4.1 x 109/L vs 3.83 x 109/L，p值<0.001）。这些年龄相关疾病也与其他来源于髓系的细胞增加有关。CH或XCI克隆性均未与中性粒细胞计数相关。总之，我们展示了中性粒细胞计数受遗传影响，但随着个体衰老，这种贡献减少，向后天因素转移。衰老与骨髓增殖偏向相关，这种偏向在心脏代谢病的存在下更明显，但不是CH的存在。这些发现支持细胞外因素可能通过低级炎症来促进骨髓发生偏移。 版权所有©2023年美国血液学会。

Blood cell production is complex, partly genetically determined and influenced by acquired factors. However, there is a paucity of data on how these factors interplay in the context of aging, which is associated with a myeloid proliferation bias, clonal hematopoiesis (CH) and an increased incidence of myeloid cancers. We investigated hereditary and acquired factors underlying blood cell trait variability in a cohort of 2996 related and unrelated women from Quebec aged 55 to 101 years. We performed a genome-wide association study, evaluated the impact of chronic diseases and performed targeted deep sequencing of CH driver genes and X-chromosome inactivation (XCI)-based clonality analyses. Multivariable analyses were conducted using generalized linear mixed models. We document that aging is associated with increasing neutrophil and monocyte counts and decreasing lymphocyte counts. Neutrophil counts were influenced by variants in the region of GSDMA and PSMD3-CSF3 but this association decreased with age. In parallel, aging individuals with cardiometabolic comorbidities exhibited significantly higher neutrophil counts (4.1x109/L vs 3.83x109/L, p-value <0.001). These age-related diseases were also associated with an increase in other myeloid-derived cells. Neither CH or XCI clonality correlated with neutrophil counts. In conclusion, we show that neutrophils counts are genetically influenced, but as individuals age this contribution decreases in favor of acquired factors. Aging is associated with a myeloid proliferation bias which is greater in the presence of cardiometabolic comorbidities but not of CH. These findings support that cell-extrinsic factors may contribute to the myeloid shift possibly through low-grade inflammation.Copyright © 2023 American Society of Hematology.