Biography:
I am a fellow in adult Rheumatology and Immunology at Vanderbilt University Medical Center. I completed my medical school and graduate school studies at the University of North Carolina at Chapel Hill and came to Vanderbilt for internship, residency, and now fellowship. My research aims to examine the role of somatic mutations auto-inflammatory diseases.
Each person is born with an average of 40 new genetic variants that neither of parents had. With each year of life, their blood stem cells (the cells that produce the immune system) accumulate about 20 more mutations, termed “somatic mutations”. By the time a person is middle-aged, the new variants that they were born with make up only a small fraction of their novel genetic variants. It has been recently discovered that somatic mutations in ~70 genes can cause the blood stem cells harboring those mutations to proliferate in a condition called “clonal hematopoiesis” (CH). CH has been found to predispose people to various auto-inflammatory conditions such as VEXAS, giant cell arteritis, and gout, though many with CH do not develop these inflammatory conditions. Using large biobanks, I will examine whether there is a “second hit” in another gene that causes people with CH to develop these or other inflammatory conditions.
Research Summary:
We think of genetic mutations as something we inherit. But scientists have long known mutations can arise in the bone marrow of adults in a process called somatic mutation. In 2014 scientists found that somatic mutation in 74 genes predisposed patients to leukemia, heart disease and death. In 2020, scientists found that somatic mutation in one other gene, UBA1, can cause severe inflammation throughout the whole body and named the disease VEXAS.
VEXAS has become well known in the medical community. There are four other genes where somatic mutations have rarely been found to cause inflammation, but they are not as well known. I propose to computationally search through three large biobanks (Vanderbilt BioVU, NIH AllOfUs, and the UKBioBank) for somatic mutations in these less well-known genes. Because there are over one million individuals in these biobanks, I can detect rare mutations. It will be valuable to know if such somatic mutations exist. Beyond that, though, I will examine the diagnoses, lab values, and medications of people found to carry these to see if they cause any disease.
There are three auto-inflammatory diseases known to be associated with somatic mutations in the original 74 genes. But it not known whether these diseases might also be associated with somatic mutations in other genes. Flipping the previous study on its head, for my second study, I will identify patients int the biobanks who have one of three diseases (VEXAS, giant cell arteritis, and gout) and examine their whole genomes for undiscovered somatic mutations. Results from this study may help us understand why some people develop these diseases and why some people respond differently to treatments.
