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Design and Implementation of the International Genetics and Translational Research in Transplantation Network

The International Genetics & Translational Research in Transplantation Network (iGeneTRAiN)

doi: 10.1097/TP.0000000000000913
Original Clinical Science-General
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Background: Genetic association studies of transplantation outcomes have been hampered by small samples and highly complex multifactorial phenotypes, hindering investigations of the genetic architecture of a range of comorbidities which significantly impact graft and recipient life expectancy. We describe here the rationale and design of the International Genetics & Translational Research in Transplantation Network. The network comprises 22 studies to date, including 16494 transplant recipients and 11669 donors, of whom more than 5000 are of non-European ancestry, all of whom have existing genomewide genotype data sets.

Methods: We describe the rich genetic and phenotypic information available in this consortium comprising heart, kidney, liver, and lung transplant cohorts.

Results: We demonstrate significant power in International Genetics & Translational Research in Transplantation Network to detect main effect association signals across regions such as the MHC region as well as genomewide for transplant outcomes that span all solid organs, such as graft survival, acute rejection, new onset of diabetes after transplantation, and for delayed graft function in kidney only.

Conclusions: This consortium is designed and statistically powered to deliver pioneering insights into the genetic architecture of transplant-related outcomes across a range of different solid-organ transplant studies. The study design allows a spectrum of analyses to be performed including recipient-only analyses, donor-recipient HLA mismatches with focus on loss-of-function variants and nonsynonymous single nucleotide polymorphisms.

iGeneTRAiN is a consortium that has genome-wide genotype datasets. These genomic data allows robust statistically analysis of genetic associations that impact graft and patients variables such as, such as: graft survival, acute rejection, new onset of diabetes after transplantation, and delayed graft kidney function.

Received 30 April 2015. Revision received 11 June 2015.

Accepted 4 July 2015.

This project was funded in part by Fundación Mutua Madrileña, Spain. Part of this work is also supported by the Dutch PLN Foundation (www.stichtingpln.nl). Folkert W. Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre and by a Dekker scholarship-Junior Staff Member 2014T001—Netherlands Heart Foundation. Partial funding was also provided by the Deanship of Scientific Research at King Saud University, Riyadh. We also acknowledge funding from the following NIH grants: U01 HG006830; U01-DK062494; UM1AI109565; U01-AI63589 and U19-AI070119.

The authors declare no funding or conflicts of interest.

A.K.I., A.S., and F.W.A. contributed equally to this article.

B.J.K., A.K.I., W.O., P.A.J., A.S., and F.W.A. conceived the study. Y.R.L., J.vS., Y.L., M.V.H., S.S.V., M.L., N.N., H.G., H.C., K.J.K., B.A., H.C., W.G., T.G., D.S.M., T.W., D.G.M.A., M.B.L., H.H., K.B., M.D.R., P.A.J., F.W.A., A.K.I., A.S., and B.J.K. were involved in acquisition of data, analysis, and/or interpretation of data. B.J.K., P.A.J., M.V.H., J.v.S., W.S.O., K.A.B., S.J.L.B., A.K.I., M.B.L., A.S., and F.W.A. were involved in drafting the manuscript and critical revisions. E.M., V.T., L.S., T.L., J.G., B.A., H.C., A.H., J.v.H., A.P., R.U., E.C., A.A.A., F.A.A., A.M.A., B.M., Y.R.L., J.v.S., Y.L., M.V.H., S.S.V., M.L., N.N., H.G., H.C., K.J.K., C.W., M.M., K.M.O., C.W., T.W., M.K., S.B., M.B.L., W.S.O., P.G.P., D.G.M.A., P.A.J., F.W.A., A.K.I., A.S., B.J.K., and all other coauthors were involved in collection of phenotype data and/or critical contributions to the framework of the consortium. All coauthors read and approved the final article, and are accountable for all aspects and integrity of the work.

Correspondence: Brendan J. Keating, D.Phil., Division of Transplantation, 2 Dulles, Hospital of the University of Pennsylvania 3400 Spruce Street, Philadelphia, PA 19104 (bkeating@mail.med.upenn.edu); Ajay Israni, MD, Department of Nephrology, Hennepin Medical Center, 730 S 8th St, Minnesota, MN 55415 (isran001@umn.edu); Abraham Shaked, MD, PhD, Division of Transplantation, 2 Dulles, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104 (Abraham.Shaked@uphs.upenn.edu); Folkert Asselbergs, MD, PhD, Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Room E03.511, P.O. Box 85500, 3508GA Utrecht, the Netherlands (F.W.Asselbergs@umcutrecht.nl).

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