Education

PhD, University of California, Berkeley, 1984

Lab information

Kenneth Walsh Lab
The Walsh lab conducts multifaceted studies on how the age-related condition of “clonal hematopoiesis” functions as a causal risk factor for cardio-metabolic diseases. Multiple large exome sequencing studies in humans have shown that aging is associated with the appearance of somatic mutations in the hematopoietic system that provide a competitive growth advantage to the mutant cell and allow for its clonal expansion. While clonal hematopoiesis had long been viewed as a benign feature of the aging process, recent epidemiological studies have shown that it is associated with mortality due in large part to elevated cardiovascular disease risk. However, the descriptive nature of epidemiological studies makes it difficult to assess causality, directionality or mechanism. Using murine genetic models, work from the Walsh lab has provided evidence for a causal connection between clonal hematopoiesis and cardio-metabolic diseases. These studies have also led to the development of a mechanistic framework revealing that cytokine overactivation in immune cells is a major feature of the pathology, and subsequent clinical studies have validated some of these mechanistic details.
Building upon the expertise developed in our “clonal hematopoiesis” studies, we initiated a new direction that examines mosaic loss of the Y chromosome (mLOY) in blood. mLOY is the most common post-zygotic mutation in humans. Epidemiological studies have associated this prevalent form of aneuploidy with all-cause mortality and multiple age-associated diseases. However, it was unknown whether the connection between mLOY and cardiovascular disease is causal, or whether mLOY reflects a biomarker of biological aging (as has been proposed by others). Our recent work has also linked mLOY with cardiovascular disease mortality in the UK Biobank, and it has provided the first mechanistic evidence in support of a causal connection between mLOY and age-associated cardiovascular dysfunction.
The Walsh lab has established a research program to assess the status of clonal hematopoiesis and mLOY in various patient cohorts. These analyses involve collaborations with clinician-scientists from around the world. Collectively, these lines of investigation provide support for the concept that genome instability in the hematopoietic system represents a new causal risk factor and a new mechanism of cardiovascular disease.
https://www.cvrc.virginia.edu/Walsh/index.html

Research focus

Cardiovascular Research

Publications