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Children's Hospital researchers identify genetic mutation that may predict organ rejection

Using a novel combination of cutting-edge technologies to scan the human genome, researchers at Children's Hospital of Pittsburgh of UPMC have identified a genetic mutation that identifies transplant recipients who experience rejection.

Known as a single nucleotide polymorphism (SNP), the genetic mutation validates the effectiveness of the system the researchers developed to search the human genome, according to principal investigator Rakesh Sindhi, MD, director of Pediatric Transplant Research in the Hillman Center for Pediatric Transplantation at Children's Hospital. They studied DNA samples from 80 children who received liver transplants and their parents.

"To identify mutations that mark a disease, from the millions of known mutations in the human genome, one needs to study hundreds, even thousands of patients with that disease. As a result, large-scale scanning of known mutations has not been applied to rarer diseases, such as those that affect children. However, by combining multiple layers of genetic information, with information from the cell types and processes affected by these genes, we can now study less common diseases using smaller numbers of subjects," Dr. Sindhi said. "Such mutations are likely to become the basis of a genomic fingerprint, which will allow us to predict who will experience rejection beforehand, and to personalize antirejection medication. The novel combination of techniques used in this study is a major methodological advance toward developing personalized diagnostics for transplant recipients, which will improve outcomes and quality of life."

Results of the study are published in the September issue of Gastroenterology, the official publication of the American Gastroenterological Association.

The approach used by Dr. Sindhi and colleagues involves powerful new tools known as microarrays. Over 500,000 known mutations spanning the entire genome are evaluated in one type of microarray. The substructure of gene products known as ribonucleic acid, or RNA, is evaluated for all known genes in another type of microarray. The mutation associated with rejection was first identified by comparing known mutations in children who received liver transplantation or were given a particular antirejection regimen, with those from their biological parents. Therefore, this study also provides evidence for the inherited basis of rejection and rejection-free outcomes on a given anti-rejection regimen.

Studying antirejection medications is important because, while they make transplantation possible, they also can have side effects such as infections and cancers, some of which can be life-threatening.

"By establishing a genomic fingerprint for rejection, and applying personalized antirejection strategies before the transplant even occurs, we are hopeful we can reduce rejection rates and drug-induced side effects for children with liver transplants, from 50 percent to 20 percent or less," Dr. Sindhi said.


Contact: Marc Lukasiak
Children's Hospital of Pittsburgh

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