Hôpital Maisonneuve-Rosemont Research Center, Montreal, QC, Canada.
Division of Hematology, Hôpital Maisonneuve-Rosemont, Montreal, QC, Canada.
Blood Adv. 2023 Jul 11;7(13):3232-3243. doi: 10.1182/bloodadvances.2022008793.
Blood cell production is a complex process, 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 from 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 the variants in the region of GSDMA and PSMD3-CSF3, but this association decreased with age; in parallel, older individuals with cardiometabolic comorbidities exhibited significantly higher neutrophil counts (4.1 × 109/L vs 3.83 × 109/L; P < .001) than younger individuals. These age-related diseases were also associated with an increase in other myeloid-derived cells. Neither CH nor XCI clonality correlated with neutrophil counts. In conclusion, we show that neutrophil 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.
血细胞生成是一个复杂的过程，部分受遗传因素决定，部分受后天获得性因素影响。然而，关于这些因素在衰老背景下如何相互作用的数据很少，衰老与骨髓增生偏向、克隆性造血（CH）和髓系癌症发病率增加有关。我们在一个由 2996 名来自魁北克的 55 至 101 岁相关和不相关女性组成的队列中研究了血细胞特征变异性的遗传和后天因素。我们进行了全基因组关联研究，评估了慢性疾病的影响，并对 CH 驱动基因和 X 染色体失活（XCI）为基础的克隆性分析进行了靶向深度测序。多变量分析使用广义线性混合模型进行。我们证明，衰老与中性粒细胞和单核细胞计数增加以及淋巴细胞计数减少有关。中性粒细胞计数受 GSDMA 和 PSMD3-CSF3 区域变体的影响，但这种关联随着年龄的增长而减弱；与此同时，患有心血管代谢合并症的老年个体的中性粒细胞计数明显高于年轻个体（4.1×109/L 比 3.83×109/L；P<.001）。这些与年龄相关的疾病也与其他髓系衍生细胞的增加有关。CH 或 XCI 克隆性与中性粒细胞计数均不相关。总之，我们表明中性粒细胞计数受遗传因素影响，但随着个体年龄的增长，这种影响会减少，后天因素的影响会增加。衰老与骨髓增生偏向有关，在存在心血管代谢合并症的情况下，这种偏向更为明显，但与 CH 无关。这些发现支持细胞外因素可能通过低度炎症导致髓系转移。
