Association of Clonal Hematopoiesis of Indeterminate Potential With Inflammatory Gene Expression in Patients With Severe Degenerative Aortic Valve Stenosis or Chronic Postischemic Heart Failure

JAMA Cardiol. 2020 Oct 1;5(10):1170-1175. doi: 10.1001/jamacardio.2020.2468.


Importance: Cytokine release syndrome is a complication of coronavirus disease 2019. Clinically, advanced age and cardiovascular comorbidities are the most important risk factors.

Objective: To determine whether clonal hematopoiesis of indeterminate potential (CHIP), an age-associated condition with excess cardiovascular risk defined as the presence of an expanded, mutated somatic blood cell clone in persons without other hematological abnormalities, may be associated with an inflammatory gene expression sensitizing monocytes to aggravated immune responses.

Design, setting, and participants: This hypothesis-generating diagnostic study examined a cohort of patients with severe degenerative aortic valve stenosis or chronic postinfarction heart failure, as well as age-matched healthy control participants. Single-cell RNA sequencing and analyses of circulating peripheral monocytes was done between 2017 and 2019 to assess the transcriptome of circulating monocytes.

Exposures: Severe degenerative aortic valve stenosis or chronic postinfarction heart failure.

Main outcomes and measures: CHIP-driver sequence variations in monocytes with a proinflammatory signature of genes involved in cytokine release syndrome.

Results: The study included 8 patients with severe degenerative aortic valve stenosis, 6 with chronic postinfarction heart failure, and 3 healthy control participants. Their mean age was 75.7 (range, 54-89) years, and 6 were women. Mean CHIP-driver gene variant allele frequency was 4.2% (range, 2.5%-6.9%) for DNMT3A and 14.3% (range, 2.6%-37.4%) for TET2. Participants with DNMT3A or TET2 CHIP-driver sequence variations displayed increased expression of interleukin 1β (no CHIP-driver sequence variations, 1.6217 normalized Unique Molecular Identifiers [nUMI]; DNMT3A, 5.3956 nUMI; P < .001; TET2, 10.8216 nUMI; P < .001), the interleukin 6 receptor (no CHIP-driver sequence variations, 0.5386 nUMI; DNMT3A, 0.9162 nUMI; P < .001;TET2, 0.5738 nUMI; P < .001), as well as the NLRP3 inflammasome complex (no CHIP-driver sequence variations, 0.4797 nUMI; DNMT3A, 0.9961 nUMI; P < .001; TET2, 1.2189 nUMI; P < .001), plus upregulation of CD163 (no CHIP-driver sequence variations, 0.5239 nUMI; DNMT3A, 1.4722 nUMI; P < .001; TET2, 1.0684 nUMI; P < .001), a cellular receptor capable of mediating infection, macrophage activation syndrome, and other genes involved in cytokine response syndrome. Gene ontology term analyses of regulated genes revealed that the most significantly upregulated genes encode for leukocyte-activation and interleukin-signaling pathways in monocytes of individuals with DNMT3A (myeloid leukocyte activation: log[Q value], -50.1986; log P value, -54.5177; regulation of cytokine production: log[Q value], -21.0264; log P value, -24.1993; signaling by interleukins: log[Q value], -18.0710: log P value, -21.1597) or TET2 CHIP-driver sequence variations (immune response: log[Q value], -36.3673; log P value, -40.6864; regulation of cytokine production: log[Q value], -13.1733; log P value, -16.3463; signaling by interleukins: log[Q value], -12.6547: log P value, -15.7977).

Conclusions and relevance: Monocytes of individuals who carry CHIP-driver sequence variations and have cardiovascular disease appear to be primed for excessive inflammatory responses. Further studies are warranted to address potential adverse outcomes of coronavirus disease 2019 in patients with CHIP-driver sequence variations.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Aortic Valve Stenosis / complications*
  • COVID-19 / complications
  • Case-Control Studies
  • Clonal Hematopoiesis / genetics*
  • Cytokine Release Syndrome / genetics
  • Cytokines / metabolism
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA Methyltransferase 3A
  • DNA-Binding Proteins / genetics
  • Dioxygenases
  • Female
  • Gene Expression*
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Heart Failure / complications*
  • Heterozygote
  • Humans
  • Male
  • Middle Aged
  • Monocytes
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Proto-Oncogene Proteins / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, Interleukin-6 / metabolism
  • Transcriptome


  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD163 antigen
  • Cytokines
  • DNA-Binding Proteins
  • DNMT3A protein, human
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Proto-Oncogene Proteins
  • Receptors, Cell Surface
  • Receptors, Interleukin-6
  • Dioxygenases
  • TET2 protein, human
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A