Medical and Graduate Student Preceptorship for Tiffany Phanhdone

The specific aim of this preceptorship is to investigate the genetic basis of SRC. Under the supervision and guidance of Dr. John Varga along with Dr. Benjamin Korman and Mary Carns, M.S., Ms. Phanhdone's responsibilities will be to have a key role in carrying out this research project. In these activities, she will be continually supervised, assisted and instructed by Dr. Varga, Dr. Korman, and their colleagues with expertise in genetics, clinical research, and biostatistics. It is well documented that different mutations in the same gene or same pathway lead to different phenotypic manifestations in diseases with similar features. It has been previously studied that atypical hemolytic uremic syndrome (aHUS) is due to genetic mutations in the complement system. aHUS is a thrombo-microangiopathy triggered by endothelial cell injury. Although the exact pathogenesis of SRC is unknown, patients with acute SRC also show thrombotic microangiopathy that is strikingly similar to aHUS. Since there seems to be overlap between aHUS and SRC, a genetic component is suspected in SRC. Given that roughly 15% of SSc patients also exhibit hypocomplementemia, we suggest that a subset of SSc patients may carry mutations in the same genes or pathways and therefore develop SRC which is phenotypically similar to aHUS. Dr. Eli Roberson and his colleagues at Washington University in Saint Louis have renowned expertise in complement pathway genetics and performed the seminal work leading to the recognition that these genes play a key role in susceptibility to aHUS and related conditions and we will continue to interact closely with them. Previous studies have shown an association between ARA and SRC. As a result, the purpose of this study is to compare the frequency of about 200 candidate genetic variants in two groups, ARA positive patients with SRC (case) and ARA positive patients without SRC (controls), to see if any of them are over-represented in those with SRC. We will analyze genetic material as well as demographic, clinical, and laboratory data, in order to find any specific genetic variants that make scleroderma patients more susceptible to developing SRC and evaluate the role of any epigenetic factors. Given the relative rarity of SRC, we envision this endeavor as one involving up to a dozen collaborating institutions throughout the United States. We have already held exploratory conversations with several colleagues who have expressed a high degree of enthusiasm for the project and indicated the availability of appropriate clinical material for the research to go forward. One of the valuable benefits of my proposed research will be the ability to communicate with and coordinate the efforts of a large and multi-institutional team of rheumatology investigators; these skills will be valuable to my growth as a physician scientist. With specific genetic information, it could be possible to find out if newly diagnosed scleroderma patients will eventually go into renal crisis. If specific genes can be detected in ARA positive patients, the potential SRC in scleroderma patients can be closely monitored and effectively well managed before life-threatening conditions ensue.