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Virtual Workshop: Measures of Somatic Mutation-related Clonal Hematopoiesis in Humans: Enhancing Contributions to Clinical, Epidemiologic, and Genetic Aging Studies

Dates:

March 24, 2021: 11am-4pm, ET

March 25, 2021: 11am-2:45pm, ET

Sponsored by: NIA's Division of Geriatrics and Clinical Gerontology and Division of Aging Biology

The overall purpose of this workshop is to gain knowledge on the prevalence of clonal expansion of hematopoietic cells associated with somatic mutations as a function of age in humans and the evolution of technologies to analyze these mutations in human specimens. The term “clonal hematopoiesis of indeterminate potential” (CHIP) has been applied to a subset of such clones in which known genetic drivers of hematologic malignancies are found. However, mutations in many other genes are associated with clonal expansion in the absence of CHIP. Both these types of clonal hematopoiesis (CH) have been associated with increased mortality risk and cardiovascular disease risk in addition to risk of hematologic malignancies. With the rapid development of genomic technologies, a variety of options are available to assess these types of clonal hematopoiesis in human population studies focusing on exceptional longevity and age-related diseases and clinical trials testing interventions for health and life span. This will provide opportunities to assess the clinical significance of differing mutations occurring in differing blood cell types for a variety of age-related outcomes, and to assess physiologic factors, environmental exposures, and germline genetic risk factors for the development of clonal hematopoiesis.  

This 2-day workshop will include three different sessions focused on clonal hematopoiesis/somatic mutations and aging phenotypes in human cohorts, novel technologies that could potentially be used in clinical specimens and the implementation of these technologies in longevity studies and translational (intervention) studies for biomarker discovery and therapeutic targets. The final session will discuss opportunities to address research issues such as: 

  • Selection of sequencing technique(s) in differing types of studies.  
  • Relationship of differing CH mutations to associated aging physiologic and clinical phenomena at differing ages 
  • Potential differential effects of CH in differing blood cell subpopulations on aging changes. 
  • Relationship of risk of CH somatic mutations to differing human germline variants, particularly those influencing aging changes.  
  • Relationship of modifiable risk factors to development of CH mutations and rate of expansion of CH clones with age.  
  • Improving the evidentiary basis regarding options for health care of persons with CHIP
  • Analysis of data from planned, current, or completed trials on age-related outcomes to clarify the potential benefits and harms of using CHIP assessment to influence treatment decisions, by assessing the relationship of CHIP to treatment effect.

    Registration Information

    Register for the workshop

    Workshop Program

    View the agenda, abstracts, and speakers in the CHIP Workshop program

    Agenda 

    Day 1

    11:00am-11:10am: Welcome and Introductions

    11:10am-11:20am: Workshop Goals (Dr. Evan Hadley, Director, Division of Geriatrics and Clinical Gerontology, National Institute on Aging)

    11:20am-11:50am: Keynote Presentation: Somatic Mutations, CHIP, and Aging (Dr. Ken Walsh, University of Virginia)

    11:50am-1:15pm: Session 1: CH Mutations and Association to Aging Phenotypes

    • Age Related Clonal Hematopoiesis and Adverse Effects (Dr. Siddhartha Jaiswal, Stanford University)
    • Influences on CH Outcomes: Time and Mutation Type (Dr. Margaret Goodell, Baylor College of Medicine)
    • CVD and CHIP (Dr. Pradeep Natarajan, Massachusetts General Hospital)
    • Q&A and Discussion

    1:15pm-2:00pm: Lunch Break

    2:00pm-4:00pm: Session 2: Sequencing Technologies and Clinical Specimens

    • Error-Corrected Sequencing to Characterize Clonal Hematopoiesis in Humans from Birth to Death (Dr. Todd Druley, Washington University)
    • Computational Framework to Identify Mosaic/Somatic Chromosomal Alterations from Genetic Data (Dr. Giulio Genovese, Broad Institute of Harvard and MIT)
    • Single-cell Whole Genome Sequencing and the Pathogenic Mechanisms of Somatic Mutations in Aging (Dr. Jan Vijg, Albert Einstein College of Medicine)
    • Mapping the Prevalence of Clonal Hematopoiesis in Cell-free DNA using Ultra-deep Sequencing (Dr. Oliver Venn, GRAIL, Inc.)
    • Q&A and Discussion

    Day 2

    11:00am-11:10am: Welcome and Introductions

    11:10am-1:20pm: Session 3: Clinical Applications of CHIP Analyses in Longevity Studies and Translational Geroscience

    • Prognostic Relevance of CHIP (Dr. Jaroslaw Maciejewski, Cleveland Clinic)
    • Dynamic Clonal Hematopoiesis and Functional T-cell Immunity in a Supercentenarian (Dr. Erik B. van den Akker, Leiden University Medical Centre)
    • Age ExWAS and CHIP (Dr. Alan Shuldiner, Regeneron Pharmaceuticals)

    Break (10 minutes)

    • Interplay between Inherited Germline Genetic Factors and Acquired Somatic Mutations and Contribution to Age-related Diseases (Dr. Alexander Bick, Vanderbilt University)
    • Rhesus Macaques as Natural and Engineered Models for Clonal Hematopoiesis of Aging (Dr. Cynthia Dunbar, National Heart, Lung, and Blood Institute, National Institutes of Health)
    • Mice as a Model to Study Mechanisms of Age-related Clonal Expansion (Dr. Anastasia V. Shindyapina, Brigham and Women’s Hospital, Harvard Medical School)

    1:20pm-2:00pm: Lunch Break

    2:00pm-2:45pm: Wrap Up Discussion & Recommendations to NIA

    The following topics need to be addressed by the speakers in their talks and overall discussions to identify opportunities and address current research issues/bottlenecks

    • Selection of sequencing technique(s) in differing types of studies.
    • Relationship of differing CH mutations to associated aging physiologic and clinical phenomena at differing ages.
    • Potential differential effects of CH in differing blood cell subpopulations on aging changes.
    • Relationship of risk of CH somatic mutations to differing human germline variants.
    • Relationship of modifiable risk factors to development of CH mutations and rate of expansion of CH clones with age.
    • Improving the evidentiary basis regarding options for health care of persons with CHIP.
    • Opportunities to analyze data from planned, current, or completed trials on age-related outcomes to clarify the potential benefits and harms of using CHIP assessment to influence treatment decisions, by assessing the relationship of CHIP to treatment effect.

    Contact Information

    Please contact Kathleen Mercure, MHSA [c] for questions you may have about the workshop.