Background The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. Methods We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. Results Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). Conclusions Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.)

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Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes

The red blood cell distribution width (RDW) is a simple and inexpensive parameter, which reflects the degree of heterogeneity of erythrocyte volume (conventionally known as anisocytosis), and is traditionally used in laboratory hematology for differential diagnosis of anemias. Nonetheless, recent evidence attests that anisocytosis is commonplace in human disorders such as cardiovascular disease, venous thromboembolism, cancer, diabetes, community-acquired pneumonia, chronic obstructive pulmonary disease, liver and kidney failure, as well as in other acute or chronic conditions. Despite some demographic and analytical issues related to the routine assessment that may impair its clinical usefulness, an increased RDW has a high negative predictive value for diagnosing a variety of disorders, but also conveys important information for short- and long-term prognosis. Even more importantly, the value of RDW is now being regarded as a strong and independent risk factor for death in the general population. Although it has not been definitely established whether an increased value of RDW is a risk factor or should only be considered an epiphenomenon of an underlying biological and metabolic imbalance, it seems reasonable to suggest that the assessment of this parameter should be broadened far beyond the differential diagnosis of anemias. An increased RDW mirrors a profound deregulation of erythrocyte homeostasis involving both impaired erythropoiesis and abnormal red blood cell survival, which may be attributed to a variety of underlying metabolic abnormalities such as shortening of telomere length, oxidative stress, inflammation, poor nutritional status, dyslipidemia, hypertension, erythrocyte fragmentation and alteration of erythropoietin function. As such, the aim of this article is to provide general information about RDW and its routine assessment, to review the most relevant implications in health and disease and give some insights about its potential clinical applications.

Red blood cell distribution width: A simple parameter with multiple clinical applications

As people age, their tissues accumulate an increasing number of somatic mutations. Although most of these mutations are of little or no functional consequence, a mutation may arise that confers a fitness advantage on a cell. When this process happens in the hematopoietic system, a substantial proportion of circulating blood cells may derive from a single mutated stem cell. This outgrowth, called "clonal hematopoiesis," is highly prevalent in the elderly population. Here we discuss recent advances in our knowledge of clonal hematopoiesis, its relationship to malignancies, its link to nonmalignant diseases of aging, and its potential impact on immune function. Clonal hematopoiesis provides a glimpse into the process of mutation and selection that likely occurs in all somatic tissues.

Clonal hematopoiesis in human aging and disease

THE red cell distribution width (RDW) is a quantitative measure of variability in the size of circulating erythrocytes with higher values reflecting greater heterogeneity in cell sizes. Although RDW is routinely reported to physicians in clinical practice as part of the automated complete blood count (CBC), it is currently mainly used as an auxiliary index in the differential diagnosis of microcytic anemia. Iron deficiency anemia is associated with a high RDW, whereas thalassemia syndromes produce red blood cells (RBCs) of more homogenous size.

A few studies recently showed that higher RDW, even within the normal reference range, was strongly associated with increased risk of death and cardiovascular disease (CVD) events in middle-aged and older adults (1–7). Although the exact mechanisms are unclear, this association is provocative because it is independent of numerous factors, including nutritional status, anemia, inflammation, and age-associated diseases (5). Furthermore, RDW significantly improved mortality risk prediction beyond established risk factors, as assessed by several indices of model calibration and discrimination (5). Given that higher RDW is associated with advancing age and higher disease burden (5), it is possible that RDW is a novel biomarker that reflects multiple physiological impairments related to aging.

Of the previous studies that examined RDW and mortality, all but one were performed in patients with clinically significant CVD. Whether RDW is prognostic in more representative community-based populations requires further investigation. The aim of the current study was to quantify the association of RDW with total and cause-specific mortality in seven population-based studies of older adults with varied health and demographic compositions. Specifically, we characterized the dose–response relationship and assessed its consistency across the studies as well as in major subgroups of older adults.

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Red Cell Distribution Width and Mortality in Older Adults: A Meta-analysis

Validation and potential mechanisms of red cell distribution width as a prognostic marker in heart failure.

BACKGROUND
Red blood cell distribution width (RDW), a component of an electronic complete blood count, is a measure of heterogeneity in the size of circulating erythrocytes. In patients with symptomatic cardiovascular disease (CVD), RDW is associated with mortality. However, it has not been demonstrated that RDW is a predictor of mortality independent of nutritional deficiencies or in the general population.


METHODS
Red blood cell distribution width was measured in a national sample of 8175 community-dwelling adults 45 years or older who participated in the 1988-1994 National Health and Nutrition Examination Survey; mortality follow-up occurred through December 31, 2000. Deaths from all causes, CVD, cancer, and other causes were examined as a function of RDW.


RESULTS
Higher RDW values were strongly associated with an increased risk of death. Compared with the lowest quintile of RDW, the following were adjusted hazard ratios (HRs) for all-cause mortality (and 95% confidence intervals [CIs]): second quintile, HR, 1.1 (95% CI, 0.9-1.3); third quintile, HR, 1.2 (95% CI, 1.0-1.4); fourth quintile, HR, 1.4 (95% CI, 1.2-1.8); and fifth quintile, HR, 2.1 (95% CI, 1.7-2.6). For every 1% increment in RDW, all-cause mortality risk increased by 22% (HR, 1.22; 95% CI, 1.15-1.30; P < .001). Even when analyses were restricted to nonanemic participants or to those in the reference range of RDW (11%-15%) without iron, folate, or vitamin B(12) deficiency, RDW remained strongly associated with mortality. The prognostic effect of RDW was observed in both middle-aged and older adults for multiple causes of death.


CONCLUSION
Red blood cell distribution width is a widely available test that is a strong predictor of mortality in the general population of adults 45 years or older.

Ershler

Papers

Red Blood Cell Distribution Width and the Risk of Death in Middle-aged and Older Adults.