Feeding the Fire: CHIP and Inflammation

Clonal hematopoiesis of indeterminate potential (CHIP), known as a “premalignant” state in the blood critical to the development of blood cancer, increases in frequency with age and also has been associated with a higher risk for developing coronary heart disease. In a presentation at the 2017 ASH Annual Meeting, Elina K. Cook, MD, PhD-c, from the Department of Pathology and Molecular Medicine at Queen’s University in Kingston, Ontario, shared results from an analysis of sequencing data from more than 300 older adults. The study established that CHIP is associated with increased risk for other cardiometabolic diseases exacerbated by inflammation, including cardiopulmonary disease.

Based on previous research about comorbidities associated with CHIP in inflammatory disease, Dr. Cook and colleagues hypothesized that CHIP clones, stratified by mutation type, may be linked to unique, inflammatory diseases of aging. “Specifically, mutated TET2 clones may be more likely to emerge in, or to condition, a pro-inflammatory disease environment (e.g., one containing increased interleukin [IL]-6),” the authors explained.

The researchers analyzed leukocyte genomic DNA from 348 healthy adults older than 65 years (mean age = 80.4 years) who were enrolled at two centers in Toronto. Samples were sequenced for 48 commonly mutated myeloid genes and correlated with blood lab results and data on 28 comorbidities.

CHIP was detected in 28 percent of participants. This proportion increased with age, from less than 13 percent among those less than 70 years to 29 percent among those greater than 85 years.

Patients with CHIP were more than four times as likely as those without CHIP to have higher monocyte counts and three times more likely to have valvular heart disease, compared with patients without CHIP. Odds ratios for each were:

  • higher monocyte count: 4.1 (95% CI 1.2-13.9; p=0.021)
  • valvular heart disease: 2.9 (95% CI 1.4-6.6; p=0.007)
  • chronic asymptomatic/symptomatic cardiopulmonary disease: 2.8 (95% CI 1.4-5.5; p=0.003)
  • Eastern Cooperative Oncology Group performance status score: 1.6 (95% CI 1.1-2.3; p=0.013)
  • Charlson Comorbidity Index: 1.2 (95% CI 1.0-1.4; p=0.031)

Together, these translated to lower predicted rates of 10-year survival and “support previous associations between cardiovascular disease, CHIP, and mutant monocytes/macrophages,” the researchers noted.

TET2 and DNMT3A were the most commonly mutated genes among this patient group, and when the investigators compared those mutations with CHIP, they found that those with CHIP and DNMT3A mutations (D-CHIP) were more likely to have comorbid diseases such as gastroesophageal reflux diseases. Those in the group with TET2 mutations (T-CHIP) were more likely to have cardiopulmonary disease.

“We reported novel connections of comorbidities with CHIP and found specific comorbidities associated with either or both T-CHIP and D-CHIP subtypes,” the researchers wrote. “Moreover, for the first time in humans, we find higher serum levels of certain pro-inflammatory drivers in each CHIP subtype.”

In those with T-CHIP, serum levels of the pro-inflammatory IL-6 were elevated, compared with D-CHIP (p=0.013), while those with D-CHIP had elevated serum Eotaxin-1/CCL11, an eosinophil chemo-attractor (p=0.028). These markers remained elevated in their respective subgroups, even after the investigators removed certain comorbidities as potential confounders.

“In the clinical realm, knowing one’s CHIP subtype (e.g., T-CHIP) may enable personalized monitoring for specific diseases and preventative, proactive approaches,” the authors concluded. “Ultimately, this may lead to therapeutic avenues that target mutant clones and their specific inflammatory environments to reduce the burden of CHIP and associated comorbidities.”

“CHIP is more prevalent than previously reported, possibly due to our aged cohort,” the authors observed, noting a possible limitation of the study.

The authors report no financial conflicts.


Reference

Cook EK, Izukawa TR, Young S, et al. Feeding the fire: the comorbid and inflammatory backdrop of clonal hematopoiesis of indeterminate potential (CHIP) by mutation subtype. Abstract #426. Presented at the 2017 American Society of Hematology Annual Meeting, December 10, 2017; Atlanta, GA.

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