05 Oct Genome Wide Testing May Make Transplantation More Personalized
MedicalResearch.com Interview with:
Brendan J. Keating, DPhil
Assistant professor of Transplant Surgery
Medical Research: What is the background for this study? What are the main findings?
Response: Genetic studies in transplantation have been plagued by small samples and very complex phenotypes/outcomes of patients. Transplanted individuals are typically on potent immunosuppression drugs for the rest of their lives, as they have 3.5 million to 10 million variants difference from an unrelated transplanted donor organ. Such populations would certainly benefit from large well-powered genetic studies but only 3 transplant genome-wide genotyping studies comprising a few hundred individuals have been published.
The papers outline the resources in hand for the International Genetics & Translational
Research in Transplantation Network, comprising 22 studies to date (since the publication it has now expanded to 25 studies and > 32,000 subjects with genome-wide genotyping data). We show significant statistical power in iGeneTRAiN to detect main effect association signals across regions such as the MHC region (which harbors the HLA Class I/II regions which are well established to associate with transplantation outcomes). We also show strong genome-wide power to detect transplant outcomes that span all solid organs including graft survival, acute rejection, new onset of diabetes after transplantation (fast becoming the most common comorbidity post-transplantation), and delayed graft function (to date we have looked at this in kidney transplant patients only). We show that iGeneTRAiN is statistically powered to deliver pioneering insights into the genetic architecture of transplant-related outcomes across a range of different solid-organ transplant studies.
The transplant specific GWAS array that we designed (described in depth in the Genome Medicine paper) show that the coverage in key transplant associated regions is much higher than conventional arrays, and we describe the ‘imputation’ pipeline to expand the 780,000 or so variants examined in any given individual to > 15 millions of variants using whole genome sequencing reference datasets.
Medical Research: What should clinicians and patients take away from your report?
Response: While these genome-wide association studies (GWAS) are for research-use only, if fundamental insight are revealed and validated for transplantation complications they can quickly be translated into closer monitoring of at risk patients and/or better matching for transplants where harvesting time constraints are not pressing (i.e. for living donors where time constraints are not as pressing as for deceased donor organ harvesting). It should be noted that a number of the studies involved in iGeneTRAiN are also performing additional ‘omic’ studies (such as metabolomics, proteomics and transcriptomics) on tissues biopsies, urine and sera from these subjects (Suhre et al. Urine Metabolite Profiles Predictive of Human Kidney Allograft Status.J Am Soc Nephrol. PMID: 26047788 and Suthanthiran et al. Urinary-cell mRNA profile and acute cellular rejection in kidney allografts. N Engl J Med. 2013 PMID: 23822777 – note the last author of the latter paper is one of the co-founders of IGeneTRAiN).
Medical Research: What recommendations do you have for future research as a result of this study?
- Immunosuppression and other drugs (Transplant patients have significantly higher rates of de novo hypertension and dyslipidemia which typically requires additional drug regimes).
From large-scale CLIA sequencing studies of approx. 100 important pharmco-genes it is observed that > 95% of individuals have actionable variants which can be used to alter drug dosing or choice of drug. With the recent explosion of direct-to-consumer genomics (some of these research-use only DTC companies have made terrible/false claims – although some of the better ones, in the San Diego and Bay area, are now entering the CLIA space) it is likely that immunosuppression and other drug regimens for transplant patients will be individualized according to such actionable variants.
- Better matching of donors.
There have been two major papers in the last few years in Hematopoietic stem cell transplantation (HSCT) which have showed that donor-recipient genetic incompatibilities can impact signficant complications of transplantation such as graft-versus-host-disease (GvHD): Petersdorf et al. High HLA-DP Expression and Graft-versus-Host Disease. N Engl J Med. 2015 PMID: 26267621 (Effie Petersdorf is a member of iGeneTRAiN leading the HSCT efforts); and McCarroll et al. Donor-recipient mismatch for common gene deletion polymorphisms in graft-versus-host disease. Nature Genetics. 2009 PMID: 19935662). We believe that these are just the tip of the ice-berg for genomic incompatibilities in donor-recipient interactions and the massive scale of genome-wide genotyping data and rich phenotypes from iGeneTRAiN will be a ground-breaking effort in this field.
From: Folkert Asselbergs, MD PhD FESC
Professor of Cardiovascular Genetics at UMC Utrecht
So far, transplantation research was predominantly performed in single
center studies focusing on single organ transplants. Igenetrain has been
founded to facilitate collaboration worldwide and across different
specialities to increase sample size to detect novel pathways responsible
Results of igenetrain will lead to customized therapies in
transplant patients and bring us a step closure to precision medicine
advocated by many. Both physicians and patients will get more information
regarding risk for rejection and potential side-effects of
Igenetrain will improve outcome across solid
organ transplantation and will provide us insights in the mechanisms
underlying rejection. Future studies will need to compare different
therapeutic strategies based on genomic data from both recipient and donor.
Transplantation: Post Author Corrections: September 30, 2015
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Brendan J. Keating, DPhil (2015). Genome Wide Testing May Make Transplantation More Personalized