Anemia is a major and currently poorly understood clinical manifestation of hematopoietic aging. Upon aging, hematopoietic clones harboring acquired leukemia-associated mutations expand and become ...detectable, now referred to as clonal hematopoiesis (CH). To investigate the relationship between CH and anemia of the elderly, we explored the landscape and dynamics of CH in older individuals with anemia. From the prospective, population-based Lifelines cohort (n = 167 729), we selected all individuals at least 60 years old who have anemia according to World Health Organization criteria (n = 676) and 1:1 matched control participants. Peripheral blood of 1298 individuals was analyzed for acquired mutations at a variant allele frequency (VAF) of 1% or higher in 27 driver genes. To track clonal evolution over time, we included all available follow-up samples (n = 943). CH was more frequently detected in individuals with anemia (46.6%) compared with control individuals (39.1%; P = .007). Although no differences were observed regarding commonly detected DTA mutations (DNMT3A, TET2, ASXL1) in individuals with anemia compared with control individuals, other mutations were enriched in the anemia cohort, including TP53 and SF3B1. Unlike individuals with nutrient deficiency (P = .84), individuals with anemia of chronic inflammation and unexplained anemia revealed a higher prevalence of CH (P = .035 and P = .017, respectively) compared with their matched control individuals. Follow-up analyses revealed that clones may expand and decline, generally showing only a subtle increase in VAF (mean, 0.56%) over the course of 44 months, irrespective of the presence of anemia. Specific mutations were associated with different growth rates and propensities to acquire an additional hit. In contrast to smaller clones (<5% VAF), which did not affect overall survival, larger clones were associated with increased risk for death.
•Specific mutations, including TP53 and SF3B1, but not DNMT3A, TET2, and ASXL1, were enriched in older individuals with anemia.•In general, clones only confer a limited selective advantage over time, which is differentially affected by specific driver genes.
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Aim
We aimed to analyse the association of clonal haematopoiesis of indeterminate potential (CHIP) with incident heart failure (HF) in a European population cohort.
Methods and results
From the ...prospective Prevention of Renal and Vascular End‐stage Disease (PREVEND) cohort, we included all 374 participants with incident HF and selected 1:1 age‐ and sex‐matched control subjects. Peripheral blood samples of 705 individuals were successfully analysed by error‐corrected next generation sequencing for acquired mutations at a variant allele frequency ≥2% in 27 CHIP driver genes. The median age of the study population was 65 years (interquartile range 58–70) and 35.6% were female. CHIP mutations positively correlated with age, smoking, hypertension and cardiovascular biomarkers including N‐terminal pro‐B‐type natriuretic peptide and mid‐regional pro‐A‐type natriuretic peptide, but the frequency of CHIP was comparable in individuals with incident HF and in control participants (18.4% vs. 17.3%; p = 0.69). In multivariable Cox regression models, CHIP was not significantly associated with incident HF (hazard ratio HR 1.24, 95% confidence interval CI 0.93–1.65; p = 0.144). This association, however, was modified by age (p for CHIP–age interaction = 0.002). Among people younger than 65 years, CHIP mutations were more frequently detected in the case cohort compared to the control cohort (14.2% vs. 5.8%; p = 0.009), and were significantly associated with new‐onset HF (HR 2.07, 95% CI 1.30–3.29; p = 0.002).
Conclusion
Clonal haematopoiesis of indeterminate potential correlates with HF risk factors and biomarkers, and is associated with incident HF in subjects <65 years of age.
Association of clonal haematopoiesis of indeterminate potential (CHIP) with incident heart failure (HF).
Knowledge about evolution of clonal hematopoiesis, which may drive malignant progression, is crucial for clinical decision-making. We investigated the landscape of clonal evolution by error-corrected ...sequencing on 7,045 sequential samples from 3,359 individuals in the prospective population-based Lifelines cohort, with a special focus on cytosis and cytopenia. Spliceosome (SRSF2/U2AF1/SF3B1) and JAK2 mutated clones show highest growth rates over a median 3.6-year period, while clone sizes for DNMT3A and TP53 increase only marginally, independent of cytosis or cytopenia. Nevertheless, large differences are observed between individuals carrying the same mutation, indicative of modulation by non-mutation-related factors. Clonal expansion is not dependent on classical cancer risk factors (e.g., smoking). Risk for incident myeloid malignancy diagnosis is highest for JAK2, spliceosome, or TP53 mutations and absent for DNMT3A, and it is mostly preceded by cytosis or cytopenia. The results provide important insight into high-risk evolutionary patterns to guide monitoring of “CHIP” and “CCUS.”
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•Spliceosome (SF3B1/SRSF2/U2AF1) and JAK2 mutated clones show highest growth rates•DNMT3A and TP53 mutated clones increase only marginally over time•Clonal expansion is independent of general cancer risk factors or cytopenia/cytosis•Spliceosome, TP53, JAK2, and K/NRAS mutations confer highest risk for myeloid cancer
Zeventer et al. report on longitudinal analyses of clonal hematopoiesis in 3,359 community-based individuals. Patterns of clonal evolution reveal large heterogeneity, irrespective of blood count abnormalities. Clonal expansion, patterns of sequential mutation acquisition, and the risk to develop myeloid malignancy are dependent on the specific mutated gene. The results warrant a gene-specific approach in the management of “CHIP” and “CCUS.”
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 has been proposed as improved inverse predictor 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.
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.
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.
The association between HDL-P and leukocyte counts in the general population is dependent on HDL-P size and composition, but not HDL-CEC.
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•High-density lipoprotein cholesterol (HDL-c) negatively associates with leukocyte counts independent of cholesterol efflux capacity of HDL (HDL-CEC).•Extra-large and large HDL particles (HDL-P) negatively associate with leukocyte counts.•The strong positive association between small HDL-P and leukocyte counts is mediated by HDL-triglycerides (TG).•S-HDL-TG showed a strong positive correlation with total plasma TG.
Clonal hematopoiesis (CH), characterized by a fraction of peripheral blood cells carrying an acquired genetic variant, emerges with age. Although in general CH is associated with increased mortality ...and morbidity, no higher risk of death was observed for individuals ≥80 years. Here, we investigated CH in 621 individuals aged ≥80 years from the population-based LifeLines cohort. Sensitive error-corrected sequencing of 27 driver genes at a variant allele frequency ≥1% revealed CH in the majority (62%) of individuals, independent of gender. The observed mutational spectrum was dominated by DNMT3A and TET2 variants, which frequently (29%) displayed multiple mutations per gene. In line with previous results in individuals ≥80 years, the overall presence of CH did not associate with a higher risk of death (hazard ratio, 0.91; 95% confidence interval, 0.70-1.18; P = .48). Being able to assess the causes of death, we observed no difference between individuals with or without CH, except for deaths related to hematological malignancies. Interestingly, comparison of mutational spectra confined to DNMT3A and TET2 vs spectra containing other mutated genes, showed a higher risk of death when mutations other than DNMT3A or TET2 were present (hazard ratio, 1.48; 95% confidence interval, 1.06-2.08; P = .025). Surprisingly, no association of CH with cardiovascular morbidity was found, irrespective of clone size. Further, CH associated with chronic obstructive pulmonary disease. Data on estimated exposure to DNA damaging toxicities (ie, smoking, a history of cancer as a proxy for previous genotoxic therapy, and job-related pesticide exposure) showed an association with spliceosome and ASXL1 variants, but not with DNMT3A and TET2 variants.
•Clonal hematopoiesis is present in 62% of individuals ≥80 years and its prognostic implications are driver gene–specific.•ASXL1 and spliceosome variants are more frequent in individuals with estimated higher exposure to DNA damaging agents.
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Treatment choice according to the individual conditions remains challenging, particularly in older patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). The impact ...of performance status, comorbidities, and physical functioning on survival is not well defined for patients treated with hypomethylating agents. Here we describe the impact of performance status (14% ECOG performance status 2), comorbidity (40% HCT-comorbidity index ≥ 2), and physical functioning (41% short physical performance battery < 9 and 17% ADL index < 6) on overall survival (OS) in 115 older patients (age ≥ 66 years) treated on a clinical trial with a 10-day decitabine schedule. None of the patient-related variables showed a significant association with OS. Multivariable analysis revealed that age > 76 years was significantly associated with reduced OS (HR 1.58; p = 0.043) and female sex was associated with superior OS (HR 0.62; p = 0.06). We further compared the genetic profiles of these subgroups. This revealed comparable mutational profiles in patients younger and older than 76 years, but, interestingly, revealed significantly more prevalent mutated ASXL1, STAG2, and U2AF1 in male compared to female patients. In this cohort of older patients treated with decitabine age and sex, but not comorbidities, physical functioning or cytogenetic risk were associated with overall survival.
Clonal hematopoiesis (CH) is defined by the presence of somatic mutations that may cause clonal expansion of hematopoietic cells. Here, we investigated the association between platelet count ...abnormalities, CH and consequences on overall survival and the development of hematological malignancies. Individuals with thrombocytopenia (n = 631) or thrombocytosis (n = 178) ≥60 years, and their age‐ and sex‐matched controls, were selected within the population‐based Lifelines cohort (n = 167,729). Although the prevalence of CH was not increased in thrombocytopenia cases compared with their controls (37.9% vs 39.3%; P = 0.639), mutations in spliceosome genes (SF3B1, SRSF2, U2AF1) were significantly enriched in thrombocytopenia cases (P = 0.007). Overall, CH in combination with thrombocytopenia did not impact on survival, but thrombocytopenia in combination with multiple mutated genes (hazard ratio HR = 2.08, 95% confidence interval CI, 1.24‐3.50; P = 0.006), mutations in TP53 (HR = 5.83, 95% CI, 2.49‐13.64; P < 0.001) or spliceosome genes (HR = 2.69, 95% CI, 1.29‐5.63; P = 0.009) increased the risk of death. The prevalence of CH in thrombocytosis cases was higher compared with controls (55.8% vs 37.7%; P < 0.001). Especially mutations in JAK2 (P < 0.001) and CALR (P = 0.003) were enriched in individuals with thrombocytosis. The presence of CH in individuals with thrombocytosis did not impact on overall survival. However, during follow‐up of 11 years 23% of the individuals with thrombocytosis and CH were diagnosed with hematological malignancies. From these, 81% were diagnosed with myeloproliferative disease and 76% carried driver mutations JAK2, CALR, or MPL.
Previous studies have shown that skin autofluorescence (SAF), measured with an advanced glycation end product (AGE) reader, estimates the accumulation of AGEs in tissues. SAF is predictive of ...incident type 2 diabetes, cardiovascular disease (CVD), and CV mortality in the general population. Studies in diabetic mice have shown that activation of the receptor for AGEs in hematopoietic progenitor cells increases blood neutrophils and monocytes, impairing atherosclerosis regression. We asked whether SAF is associated with blood neutrophil and monocyte counts in the general population, and whether this was moderated by prediabetes, diabetes, and sex.
We examined the associations between SAF and blood neutrophil/monocyte counts in participants of the Lifelines cohort (n = 58,923: n = 24,382 men, and n = 34,541 women), a prospective population-based cohort from the North of the Netherlands, employing multivariable regression analyses.
SAF positively associated with blood neutrophil and monocyte counts in the whole cohort. The positive association between SAF and monocyte, but not neutrophil, counts was moderated by prediabetes and diabetes. Positive associations between SAF and blood neutrophil and monocyte counts were moderated by male sex. Moreover, three-way interaction analyses revealed that the positive associations between SAF and neutrophil and monocyte counts were moderated by prediabetes, but not diabetes, in male sex.
SAF is positively associated with blood neutrophil and monocyte counts in the general population, especially in men with prediabetes. This may contribute to the increased CV risk in men with prediabetes.
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•Skin autofluorescence (SAF) is positively associated with blood neutrophil and monocyte counts in the Lifelines cohort.•The association between SAF and blood monocyte, but not neutrophil, counts is moderated by prediabetes and diabetes.•The associations between SAF and blood neutrophil and monocyte counts are moderated by male sex.•The associations between SAF and blood neutrophil and monocyte counts are moderated by prediabetes in male sex.
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