NEW YORK (GenomeWeb) – A team led by Stanford University's Michael Snyder, in collaboration with investigators from the International Genetics & Translational Research in Transplantation Network (iGeneTrain) consortium, has started applying its integrative omics approaches to studies aimed at improving the safety and effectiveness of organ transplantation.
The iGeneTrain effort has been rolling for more than three years, starting from early efforts to bring together solid organ transplant related groups, genotyping data, and phenotypic profiles.
The consortium includes teams studying a wide range of solid organ transplant types, using genomics and multi-omic approaches to consider everything from signatures associated with secondary complications such as skin cancer that have been linked to the immunosuppression required for transplantation, to markers of acute, chronic, or sub-clinical forms of transplant rejection.
Taking this kind of approach is a "no-brainer," Snyder told GenomeWeb, noting that the solid organ transplant field is "ideally suited" to multi-omic analysis. "Obviously donors and recipients can be very different. So to be able to profile [metabolomic and other omic patterns] and understand those differences is a big deal," Snyder said.
He and his colleagues are planning to apply some of the same strategies being used for the "integrative personal omics profile," or iPOP, study, building a multi-omics pipeline specific to organ transplantation problems that is being informed by ongoing discussions and collaboration with investigators such as Brendan Keating, a University of Pennsylvania transplant researcher and leader of the iGeneTrain consortium.
Snyder's team plans to enroll a few hundred heart and kidney transplant patients to study rejection using a combination of RNA sequencing, copy number variant analysis, exome sequencing, peptide arrays, and/or metabolomic profiling on biopsy samples from the recipient, transplant tissue, and blood samples.
"It gets pretty expensive so I don't know if we'll be able to do all of the assays for all of the people, but we will do some assays that are not so expensive, like metabolomics, which we're definitely getting ready to do," Snyder said.
For the first stage of their study, he and his colleagues focused on two heart transplant patients, one with acute transplant rejection and another individual who experienced delayed transplant rejection.
Using samples collected from the two individuals over half a dozen time points, the investigators have obtained preliminary RNA sequencing, peptide, and metabolomic data that seem to fit with what's known about transplant rejection, including rejection-associated shifts in the expression of genes from some immune-related pathways. The RNA-seq data may also hold clues to transcript isoform differences related to immune response and rejection.
"Our immune analyses … I think are going to be extremely informative. You can do stuff at a level that you just couldn't do a few years ago, so I really think we're going to see responses and outcomes much, much better than we've ever been able to," Snyder said. Consequently, he is "very optimistic" about the types of detailed information that might be uncovered using these types of approaches.
Still, Snyder explained, the team does not want to put too much weight in any specific findings from the preliminary research until it has had an opportunity to follow many more transplant recipients. Instead, the early work was mainly done to make sure that the sample materials and methods were working well together.
That group is primarily focused on finding markers associated with transplant rejection, rejection severity, and organ donor-recipient compatibility, he noted, not only in heart transplant cases but also in the context of kidney transplants — ideally following at least 200 cases for each transplant type.
Other members of the iGeneTrain consortium are investigating a broad swath of factors that typically impact organ transplant recipient outcomes. Last year, investigators involved in the consortium published a study in Genome Medicine describing a custom Affymetrix Axiom chip, dubbed the TxArray, that is being employed in at least some of these studies.
At the recent American Society of Human Genetics meeting in Vancouver, Canada, Keating presented data on studies designed to assess microRNA, metabolite, and/or single-cell RNA sequencing patterns in cases of kidney or liver transplant rejection.
At the same conference session, other iGeneTrain members discussed strategies for using TxArray-based genotypes, immune gene profiles, and other genomic features to study transplant phenotypes such as response to immunosuppressive drugs and other potential complications such as delayed graft function, new onset diabetes, or skin cancer after transplantation.