Large HDL particles negatively associate with leukocyte counts independent of cholesterol efflux capacity: A cross sectional study in the populationbased LifeLines DEEP cohort

Background and aims: Leukocytosis, the expansion of white blood cells, is associated with increased cardiovascular risk. Studies in animal models have shown that high-density lipoprotein cholesterol (HDL-c) suppresses
leukocytosis by mediating cholesterol efflux from hematopoietic stem and progenitor cells. HDL-c showed a
moderate negative association with leukocyte numbers in the UK Biobank and Multi-Ethnic Study of Atherosclerosis. Cholesterol efflux capacity of HDL (HDL-CEC) or HDL particle (HDL-P) number have been proposed as improved inverse predictors of CVD compared to plasma HDL-c. In the LifeLines DEEP (LLD) cohort (n = 962), a
sub-cohort representing the prospective population-based LL cohort from the North of The Netherlands, we
tested the hypothesis that HDL-CEC and HDL-P were associated with lower leukocyte counts.
Methods: We carried out multivariable regression and causal mediation analyses (CMA) to test associations between HDL-c, HDL-CEC, or HDL-P and leukocyte counts. We measured HDL-CEC in THP-1 macrophages and
HDL-P and composition using nuclear magnetic resonance.
Results: HDL-c associated negatively with leukocyte counts, as did extra-large and large HDL-P, while HDL-CEC
showed no association. Each one-standard deviation (SD) increase in extra-large HDL-P was associated with
3.0% and 4.8% lower leukocytes and neutrophils, respectively (q < 0.001). In contrast, plasma concentration
of small HDL-P associated positively with leukocyte and neutrophil counts, as did small HDL-P triglycerides
(TG) and total plasma TG. CMA showed that the association between S-HDL-P and leukocytes was mediated by
S-HDL-TG.
Conclusions: The association between HDL-P and leukocyte counts in the general population is dependent on
HDL-P size and composition, but not HDL-CE