Pediatric transplant patients are treated with standardized regimens since few clinical or demographic risk factors have been identified that can predict a child's chance of developing major post-transplant complications. An individualized treatment regimen could potentially diminish the chances of acute or chronic rejection, drug toxicity and infection. The ability to predict the likelihood of a clinical event would allow clinicians to preemptively use an immunosuppressive regimen that would optimize outcomes for the pediatric transplant recipient. We hypothesize that recipient genetic variations will be important independent risk factors for post-transplant outcomes. In this project we address how three genetically determined variables influence cardiac transplant outcome in a large cohort of 750 pediatric patients from 6 institutions nationwide. They are a) HLA incompatibility, b) mediators of inflammation and c) drug disposition and metabolism. Using a new algorithm (HLAMatchmaker) that determines HLA compatibility at the structural level we will assess the HLA compatibility between patient and donor. Polymorphisms of genes that control cytokine production, inflammatory molecules and growth factors involved in tissue inflammation and repair will be tested and correlated with various clinical outcomes. The effect of genetic makeup on drug disposition and metabolism that impact drug efficacy and toxicity will also be evaluated. We hypothesize that the level of HLA incompatibility controls the immune response to the heart allograft and that this response may be altered (enhanced or diminished) by other genetic factors tested: cytokine and effector molecule polymorphisms and pharmacogenomics.
Our specific aims are: 1) To determine how the HLAMatchmaker algorithm can be applied to predict outcome following pediatric heart transplantation; 2) To assess if polymorphisms in candidate genes alter the frequency and severity of acute and chronic rejection; 3) To determine the effects of pharmacogenomic factors on drug efficacy, toxicity and drug dosage requirement; and 4) To identify independent genetic predictors of acute and chronic rejection for pediatric cardiac transplantation and to determine whether racial disparities in outcome can be explained on the basis of genetic variation. This unique study is conducted on heart transplant patients entered in the Pediatric Heart Transplant Study where detailed outcome measures are available for statistical modeling of the impact of genetic polymorphisms on various clinical outcomes. Our goal is to develop a better understanding of the risk factors that can predict clinical outcomes and avoid complications associated with excessive immunosuppression. This information can be used in future clinical trials for individualizing immunosuppression based on genetic profiling.
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