Genetic Predisposition for Thrombotic Microangiopathy
PrincipaI Investigator: Sonata Jodele, MD
Key Personnel: Ralph Gruppo, MD, Jaroslaw Meller
Our project will examine genetic factors that predispose bone marrow transplant (BMT) patients to a severe transplant complication called thrombotic microangiopathy (TMA).TMA is a systemic blood vessel injury that occurs from an uncontrolled inflammatory response. The complement system is our immune defense mechanism that protects us from infection and is controlled by complement genes. Persons who have abnormal complement genes are likely to develop over activation of this immune system leading to TMA. TMA occurs in about 30% of BMT patients resulting in death in severe cases. We showed that patients with certain complement gene variants develop TMA. We noted that severe TMA resulting in death most often occurs in African American patients and those patients have multiple complement gene variants, usually 3-7, that were not seen in Caucasian patients- an entirely NOVEL finding.
This project will allow us to better understand how TMA occurs and who is at risk for this severe complication. To learn this, we will expand our preliminary data by examining complement genes in an additional 40 African American patients. This strong discovery cohort with increased representation of African American subjects will allow us to make a robust hypothesis regarding complement activation, genetic variation and the mechanism of TMA, together with the impact of race in this disease. We will also examine complement genes in healthy Caucasian and African American children for better understanding of occurrence of these complement gene variants in the African American population. Gene variants associated with severe TMA will be first analyzed by computer simulation (in silico modeling) to identify the significance of these genetic changes and to plan animal and laboratory models for future research. This study will allow us to better understand TMA as a disease and to propose novel preventative and therapeutic strategies. Targeted complement gene testing along with our expert consultation will be made available to other institutions.