Abstract 607: Clonal hematopoiesis alters blood cell counts in the UK Biobank

Abstract

Abstract Clonal hematopoiesis (CH) is an age-related accumulation of detectable somatic mutations in circulating leukocytes that is associated with diverse outcomes including hematologic cancer, solid tumors, cardiovascular disease, neurodegenerative disorders and overall mortality. The biological mechanisms by which CH is associated with disease is poorly understood, with hypotheses suggesting CH is a potential marker of genomic maintenance capacity or a potential marker of immune system imbalance. The most common age-related chromosomal alteration observed in men with CH is mosaic loss of the Y chromosome (mLOY). The relative high frequency of mLOY makes mLOY an attractive marker for investigating disease-related mechanisms associated with CH. In particular, leukocyte counts are associated with hematologic cancer, cardiovascular disease and mortality in men and may, in part, mediate some of the observed associations between CH and disease. We investigated mLOY in a large collection of 223,182 men from the UK Biobank to study potential impacts of mLOY on blood cell count indices. We used existing UK Biobank array intensity data from the male-specific region of the Y chromosome to detect deviations in the median log2 R ratio (mLRR) that signifies the presence of mLOY. In total, 3,789 men had evidence for mLOY, and of these 596 men had evidence for mLOY affecting high cellular proportions (approximately 24% of cells). Age and smoking adjusted models indicated leukocyte count is, on average, elevated by 5.82% (95% CI=4.82-6.83, P-value=5.38×10−30) in men with mLOY and by 11.95% (95% CI=9.47-14.44, P-value=1.99×10−21) in men with high levels of mLOY. Analysis of leukocyte proportions indicated the association between mLOY and leukocyte count was restricted to myeloid progenitor cells, with significant elevations observed in neutrophil and monocyte counts (P-values=1.06×10−25 and 4.89×10−56, respectively). Neutrophil count was most highly altered with average changes in cell count of 8.69% (95% CI=7.60-9.77) in men with mLOY and 14.70% (95% CI=12.04-17.37, P-value=2.32×10−156) in men with high levels of mLOY. Sensitivity analyses in never smokers observed similar elevations in leukocyte, neutrophil and monocyte count in men with mLOY, suggesting our findings were not a result of residual confounding by smoking. Furthermore, elevations in platelet count and reductions in erythrocyte count in men with mLOY provide additional evidence myeloid progenitor cells are impacted by mLOY. We found no evidence suggesting lymphocytes are impacted by mLOY. Together, these observations indicate that men with mLOY have substantial deviations in blood cell counts, particularly in neutrophil count. In this way, alterations in leukocyte counts may be one mechanism by which CH contributes to disease. Citation Format: Mitchell J. Machiela, Weiyin Zhou, Erikka Loftfield, Meredith Yeager, Neal D. Freedman, Stephen J. Chanock. Clonal hematopoiesis alters blood cell counts in the UK Biobank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 607.