Dissecting Causes and Consequences of Clonal Hematopoiesis

Age is the dominant risk factor for most chronic diseases; yet mechanisms by which aging confers risk are largely unknown. One unifying feature of aging diseases as diverse as cardiovascular disease and cancer is the acquisition of somatic mutations in hematopoietic stem cells (frequently in DNMT3A, TET2, JAK2), termed Clonal Hematopoiesis of Indeterminate Potential (CHIP). We recently demonstrated that CHIP is virtually absent in adults under 40, but found in >10% of adults over 70. CHIP confers a 10-fold increased risk of blood cancers, 2-fold increased risk of heart attack and 1.5-fold increased risk of death, with greater risk conferred by CHIP with greater clonal expansion.

It is presently unknown why only some humans develop CHIP, why only some CHIP clones expand, and why only some CHIP carriers develop clinical events. I hypothesize that germline and somatic genetic variation explains this biological and clinical heterogeneity. Establishing mechanisms for CHIP acquisition, clonal expansion and CHIP-associated disease, will highlight therapeutic targets for the prevention of CHIP, clonal expansion and disease outcomes, for which no therapies currently exist.

In recent work, I analyzed >100,000 genomes from the NHLBI TOPMed project to detect CHIP. I performed a genome-wide association study that identified three CHIP associated loci and defined specific mechanisms that confer CHIP risk at these loci. I am currently building on these efforts leading CHIP research efforts within TOPMed, the UK Biobank and the VA Million Veteran Program to characterize the causes and consequences of clonal hematopoiesis.


Understanding the determinants of genetic penetrance

During my PhD work with Drs. Christine and Jonathan Seidman, I made foundational observations that mendelian genetic mutations have significantly decreased penetrance in the general population than in family studies. This finding has considerable importance for genomic medicine as ~3% of individuals in the general population carry a mutation that causes familial cardiomyopathy, hypercholesterolemia, diabetes, aortopathy or cancer syndromes but only a small subset will develop disease. My work in this area was recognized by Forbes Magazine which included me in the 2015 Forbes 30 Under 30 in healthcare list.

In ongoing work, I am quantifying how several factors contribution to penetrance including: (1) environmental exposures, (2) epistatic gene x gene interactions and (3) common genetic background as quantified by polygenic risk scores. My preliminary studies have identified specific examples of all three of these mechanisms affecting cardiometabolic disease penetrance. Ultimately, a greater understanding of factors that contribute to penetrance will enable improved risk prediction and the identification of therapeutic targets that might modify disease risk.


Implementing genomic medicine

Translating research advances to patient care is a natural outgrowth of my two areas of scientific interest described above. I am interested in understanding how we can use genome-first approaches to identify patients with undiagnosed, but actionable, mendelian diseases such as familial hypercholesterolemia or cardiomyopathy. I am also interested in advancing the use of polygenic risk scores in clinical settings. I have helped launch the MGH Preventative Genomics Clinic in September 2019, embedding this vision of genome-first medicine in the context of the MGH primary care practices. Ongoing active research activities in this area entail establishing best practices for genomic medicine clinics and understanding downstream consequences on patient and population health outcomes of genomic medicine.