Association of Total and Differential Leukocyte Counts With Cardiovascular Disease and Mortality in the UK Biobank

Welsh, Claire; Welsh, Paul; Mark, Patrick B.; Celis‐Morales, Carlos; Lewsey, James; Gray, Stuart R.; Lyall, Donald M.; Iliodromiti, Stamatina; Gill, Jason M.R.; Pell, Jill P.; Jhund, Pardeep S.; Sattar, Naveed

doi:10.1161/atvbaha.118.310945

Cited by 80 publications

(76 citation statements)

References 39 publications

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“…Several previous studies have reported that WCC was associated with mortality even after adjusting for smoking 1 5 7–12. This is not fully consistent with our analysis in healthy population.…”

Section: Discussioncontrasting

confidence: 68%

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White cell counts in relation to mortality in a general population of cohort study in the Netherlands: a mediating effect or not?

Abete

Lassale

et al. 2019

BMJ Open

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BackgroundWhite cell count (WCC) is a clinical marker of inflammation. Data are limited regarding the association of total and differential WCC with risk of mortality, and its role related with smoking and body mass index (BMI).MethodsA total of 14 433 participants (4150 men; 10 283 women; average age 47.3±11.8 years) from the Dutch European Prospective Investigation into Cancer and Nutrition-Netherlands cohort were included. The associations between prediagnostic total WCC and its subtypes and risk of all-cause, cancer and cardiovascular disease (CVD) mortality were assessed. The role of WCC related with smoking and BMI on mortality was further explored. Multivariate Cox regression models were performed to estimate the HR and 95% CI.ResultsAfter an average follow-up of 15.8 years, a total of 936 death cases were identified (466 cancer; 179 CVD; 291 other causes). Statistically significant graded associations between total WCC, and counts of lymphocytes, monocytes, neutrophils and eosinophils and risk of total mortality were observed. These associations were more apparent in current smokers. Strong associations for all-cause mortality or cancer mortality were observed in subjects with BMI ≥25 kg/m2, ever smoking and elevated WCC (HR 3.92, 95% CI 2.76 to 5.57; HR 3.93, 95% CI 2.30 to 6.72). WCC partly mediated the associations between smoking or BMI and all-cause mortality.ConclusionsPrediagnostic WCC and its subtypes are associated with all-cause, cancer and CVD mortality risk. It may play a partially mediate role on the association between smoking or obesity and mortality.

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Section: Discussioncontrasting

confidence: 68%

“…A few studies have shown that WCC or subtype is an independent predictor of mortality after controlling for potential confounding, for example, smoking 1 5 7–12. This conclusion, however, might conflict with the fact that the WCC is influenced by many factors, such as infection, inflammation, smoking and obesity.…”

Section: Introductionmentioning

confidence: 99%

White cell counts in relation to mortality in a general population of cohort study in the Netherlands: a mediating effect or not?

Abete

Lassale

et al. 2019

BMJ Open

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“…[16][17][18][30][31][32] Higher neutrophil counts are associated with cardiovascular disease in men. 15 TA B L E 2 Estimated changes from baseline in the circulating numbers of total leukocytes, platelets, and erythrocytes as well as the absolute and relative counts of the leukocyte subtypes for testosterone dose groups in the 5aR trial .004…”

Section: Discussionmentioning

confidence: 99%

“…14 However, there are no randomized trial data on the effects of exogenous testosterone on circulating leukocytes and platelets. Because of the known association of increased leukocyte [15][16][17][18] and platelet counts [19][20][21] with cardiovascular and thromboembolic risk, these findings, if confirmed in human studies, could affect the safety of testosterone treatment. These findings could also provide important clues to the site of testosterone's action in the bone marrow.…”

Section: Suppression Of Endogenous Testosterone Secretion Throughmentioning

confidence: 93%

Differential effects of testosterone on circulating neutrophils, monocytes, and platelets in men: Findings from two trials

et al. 2020

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Background Testosterone treatment increases erythrocytes in men, but its effects on leukocyte and platelet counts are unknown and could affect its safety. Objective To determine whether testosterone affects circulating leukocytes and platelets in men. Methods Secondary analyses of two randomized testosterone trials were performed: the 5α‐reductase (5aR) and OPTIMEN trials. In 5aR trial, 102 healthy men, 21‐50 years (mean age 38), received a long‐acting GnRH agonist, and 50, 125, 300, or 600 mg/week testosterone enanthate (TE) plus placebo or 2.5 mg/day dutasteride for 20 weeks. In OPTIMEN, 78 functionally limited men, ≥65 years (mean age 72) with protein intake ≤ 0.83 g kg−1 day−1, were randomized to controlled diets with 0.8 g kg−1 day−1 protein or 1.3 g kg−1 day−1 protein plus placebo or TE (100 mg/week) for 6 months. Changes from baseline in total and differential leukocyte count, and platelet count were evaluated. Results In 5aR, testosterone administration was associated with increases in total leukocyte (estimated change from baseline 40, 490, 1230, and 1280 cells/µL, P < .001), neutrophil (65.1, 436.1, 1177.2, and 1192.2 cells/µL, P < .001), monocyte (−20.2, 24.5, 90.6, and 143.9 cells/µL, P < .001), platelet (−7.3, 8.4, 8.7, and 8.9 × 103 cells/µL, P = .033), and erythrocyte counts. Testosterone did not affect absolute lymphocyte count. Similar increase in total leukocyte count was observed with testosterone treatment in OPTIMEN (change 0.77 × 103 cells/µL, P vs placebo = 0.004). Conclusions Testosterone administration in men differentially increases neutrophil and monocyte counts. These findings, together with its erythropoietic effects, suggest that testosterone promotes the differentiation of hematopoietic progenitors into the myeloid lineage. These findings have potential mechanistic, therapeutic, and safety implications.

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“…Therefore, it has been generally considered that a biomarker, or a panel of biomarkers, reflecting the inflammatory and prothrombotic actions in the arterial wall, would be a highly valuable complement to the lipid biomarkers. A broad number of blood‐based biomarkers have been investigated, and not unexpectedly, several have shown an association with CVD and the risk of acute atherothrombotic events . These range from white blood cell counts (leucocytes, neutrophils) to soluble markers such as chemokines (MCP‐1), cytokines (IL‐6, IL‐18), acute‐phase proteins (CRP, serum amyloid A) and autoantibodies against specific molecular epitopes in LDL particles, such as phosphatidylcholine and apo‐B‐100 peptide sequences.…”

Section: Biomarkers For Cvd and Atherosclerosis: Current State And Nementioning

confidence: 99%

Exploring the role of extracellular matrix proteins to develop biomarkers of plaque vulnerability and outcome

et al. 2020

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Cardiovascular disease (CVD) is the most common cause of death in industrialized countries. One underlying cause is atherosclerosis, which is a systemic disease characterized by plaques of retained lipids, inflammatory cells, apoptotic cells, calcium and extracellular matrix (ECM) proteins in the arterial wall. The biologic composition of an atherosclerotic plaque determines whether the plaque is more or less vulnerable, that is prone to rupture or erosion. Here, the ECM and tissue repair play an important role in plaque stability, vulnerability and progression. This review will focus on ECM remodelling in atherosclerotic plaques, with focus on how ECM biomarkers might predict plaque vulnerability and outcome.

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Association of Total and Differential Leukocyte Counts With Cardiovascular Disease and Mortality in the UK Biobank

Abstract: Among circulating leukocyte subpopulations, neutrophil count in men was most consistently associated with fatal and nonfatal CVD. Further studies of interventions that lower circulating neutrophils, such as canakinumab, are required to investigate causality.

Cited by 80 publications

References 39 publications

White cell counts in relation to mortality in a general population of cohort study in the Netherlands: a mediating effect or not?

White cell counts in relation to mortality in a general population of cohort study in the Netherlands: a mediating effect or not?

Differential effects of testosterone on circulating neutrophils, monocytes, and platelets in men: Findings from two trials

Exploring the role of extracellular matrix proteins to develop biomarkers of plaque vulnerability and outcome

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