Discovery of genetic factors associated with graft loss and patient survival can generate fundamental insights into the biological and immunological factors underpinning posttransplant diseases and graft survival. Although barriers exist for harmonizing retrospective and prospective transplant study designs beyond single-site independent studies, international guidelines and hard outcomes allow for standardization of phenotypes, such as graft and patient survival, AR, NODAT, and DGF. In addition, where feasible, participating studies will share genotype and phenotype information between centers to fully maximize power to detect novel biological findings with the greater goal of conferring clinical impact. The collapsing of phenotypes across solid-organ types may not be ideal for organ-specific phenotypes such as kidney DGF, for other phenotypes, in particular NODAT and pharmacogenomic-related phenotypes, aggregation will collectively improve statistical power. The current absence of adequately powered data sets makes our consortium a unique force for GWAS efforts in Tx. The data sets in iGeneTRAiN constitute the largest genomic and phenotypic Tx data sets aggregated to date, with genomewide genotyping and phenotypes collected for more than 27500 subjects (with >11300 D-R pairs) recruited from 1993 to 2014.
The results from iGeneTRAiN will create clinical knowledge and applications in a number of specific areas: (1) Knowledge gained from genomewide as well as MHC/KIR variants, which may be highly penetrant, will facilitate novel insight into the biology of genomic incompatibility of D-R pairings. This may inform better patient care through improved risk assessment and monitoring of higher risk HLA D-R pairs, and/or more tailored IST. (2) More appropriate D-R matching before Tx may be possible based on MHC/HLA and KIR genotype combinations, or LoF compatibility in D-R pairs (eg, where 0 gene copies exist, ie, hdCNV, in the recipient and 1 or 2 gene copies exist in the respective donor), especially in the living donor transplant setting where multiple potential donors may exist. Consortia such as The Electronic Medical Records and Genomics (eMERGE) Network have very effective models for the development of genotype/phenotype algorithms from electronic medical records. The eMERGE is currently implementing dissemination of clinical genomic tests into electronic medical records and returning results back to physicians and patients in a clinical care setting,51 and initial efforts in clinically guided genotyping of tacrolimus has now begun in one of the eMERGE/iGeneTRAiN sites.15 (3) Genomic signals associated with clinical outcomes have been shown to be “druggable” through repositioning of existing drugs, or through targeting of defined small molecules known to interact with genes of interest.52,53 Results from iGeneTRAiN GWAS thus offers the potential for facilitating identification of new therapeutics for use after Tx. (4) Genetic loci associated with response to immunosuppressive agents (eg, calcineurin inhibitors, mycophenolate or thymoglobulin) may also enable personalized medicine through means, such as genotype guided dosing of ISTs or identification of genetic variants associated with idiosyncratic (eg, hypersensitivity) drug reactions.
The potential limitations of our study are also common to many GWAS efforts, including complex phenotypes with nongenetic confounders as well as limited power to identify novel loci and variants which may have modest effect sizes. We aim to overcome these issues by setting up large, well-powered studies with manually curated and harmonized phenotypes. Nongenetic factors such as cold ischemic time and use of immunosuppressive drugs heavily influence clinical outcomes, and we will use all available modelling techniques to account for these covariates where available. However, evidence from many phenotypes has taught us that genetic polymorphisms with even modest independent effect sizes can uncover key biological mechanisms in solid organ Tx outcomes.
The iGeneTRAiN aggregation of existing GWAS efforts is essential to amass and harmonize large numbers of highly curated genotype and phenotype data sets,54 which can then be transitioned to deep sequencing studies to gain nucleotide resolution coverage of regions of interest. Such large initial numbers are crucial for accrual of transplant outcome events to inform the sequencing studies for refinement of putative causal signals, which we believe will ultimately advance the field.
The concept of the iGeneTRAiN network structure as a model in Tx research is extremely powerful on a number of fronts. First, the ability to harmonize cohorts within the same solid-organ studies affords the ability to perform replication look-ups of putative genetic associations in independent cohorts, which is an absolute requirement for any large-scale genomic study. There are minimal transplant genomic studies in existence to date for such replication efforts. The ability to discover cross-organ as well as organ-specific associations using such large sample sizes is a unique strength of iGeneTRAiN. We wish to encourage other studies to join this consortium and use genome-wide genotyping arrays with well-phenotyped samples, which can be harmonized with the networks data sets. More appropriately phenotyped studies will increase the statistical power through meta-analysis to discover new loci underpinning phenotypes such as NODAT, immunosuppression-related outcomes, DGF and rejection. A major focus of the consortium is in-depth analyses of HLA and KIR polymorphisms with a range of transplant outcomes. A number of the iGeneTRAiN studies including A-WISH, CTOT-3, Deterioration of Kidney Allograft Function Genomics/Gen03, genomics of chronic renal allograft rejection have also performed functional biomarker studies using micro RNA, messenger RNA, proteomics, and/or metabolomics as follow-up surveillance studies to detect rejection and other complications of Tx.
In conclusion, iGeneTRAiN is a large consortium of solid-organ transplant studies that aims to lead genomic investigations into clinical outcomes after organ Tx. Our consortium seeks to significantly advance our understanding of the genetic architecture of transplant-related outcomes and in doing so, improve outcomes for these high-risk patients. The GWAS analyses will include recipient-only analyses, D-R mismatches with focus on LoF variants and nonsynonymous single-nucleotide polymorphisms, and interaction analyses between D-R pairs. Findings from this consortium are expected to provide unique insights into genomic incompatibility of D-R pairs, and fundamental incremental improvements in knowledge of the biology underpinning rejection and complications of Tx, with the ultimate goal of novel therapeutic targets, informing personalized prescribing of immunosuppressive therapies, and prolonging graft and patient survival.
The authors thank the patients and their families for their participation in the genotyping studies. The authors are also very thankful for the contributions of the all of the study coordinators and clinicians from the respective studies that made collection of these DNA samples and phenotyping possible.
APPENDIX
The International Genetics & Translational Research in Transplantation Network (iGeneTRAiN):
Brendan J. Keating, DPhil, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA, Department of Pediatrics, Perleman School of Medicine, University of Pennsylvania, Philadelphia, PA, and The Children's Hospital of Philadelphia, Philadelphia, PA; Jessica van Setten, PhD, Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands; Pamala A. Jacobson, PharmD, FCCP, College of Pharmacy, University of Minnesota, Minneapolis, MN; Michael V. Holmes, MD, PhD, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA; Shefali S. Verma, MSc, Center for SystemsGenomics, The Pennsylvania State University, University Park, PA; Hareesh R. Chandrupatla, MSc, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA and The Children's Hospital of Philadelphia, Philadelphia, PA; Nikhil Nair, BSc, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA and The Children's Hospital of Philadelphia, Philadelphia, PA; Hui Gao, PhD, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA and The Children's Hospital of Philadelphia, Philadelphia, PA; Yun R. Li, PhD, The Children's Hospital of Philadelphia, Philadelphia, PA and Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Bao-Li Chang, PhD, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA and The Children's Hospital of Philadelphia, Philadelphia, PA; Chanel Wong, BSc, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA and The Children's Hospital of Philadelphia, Philadelphia, PA; Randy Phillips, MD, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA; Brian S. Cole, PhD, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA and Department of Biostatistics and Epidemiology, Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, PA; Eyas Mukhtar, BSc, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA and The Children's Hospital of Philadelphia, Philadelphia, PA; Weijia Zhang, PhD, Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY; Hongzhi Cao, PhD, BGI-Shenzhen, Shenzhen, China and Department of Biology, University of Copenhagen,Copenhagen, Denmark; Maede Mohebnasab, MD, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA; Cuiping Hou, MSc, The Children's Hospital of Philadelphia, Philadelphia, PA; Takesha Lee, BSc, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA and The Children's Hospital of Philadelphia, Philadelphia, PA; Laura Steel, BSc, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA and The Children's Hospital of Philadelphia, Philadelphia, PA; Oren Shaked, MD, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA; James Garifallou, BSc, The Children's Hospital of Philadelphia, Philadelphia, PA; Michael B. Miller, PhD, Department of Psychology, University of Minnesota, Minneapolis, MN; Konrad J. Karczewski, PhD, Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA and Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA; Abdullah Akdere, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA; Ana Gonzalez, BSc, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA; Kelsey M. Lloyd, BA, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA; Daniel McGinn, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA; Zach Michaud, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA; Abigail Colasacco, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA; Monkol Lek, PhD, Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA and PrograminMedical and PopulationGenetics, Broad Institute of Harvard and MIT, Cambridge, MA; Yao Fu, BSc, Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT; and Mayur Pawashe, BSc, Molecular Biophysics and Biochemistry Department, Yale University, New Haven, CT; Toumy Guettouche, PhD, The Children's Hospital of Philadelphia, Philadelphia, PA; Aubree Himes, BSc, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA and The Children's Hospital of Philadelphia, Philadelphia, PA; Leat Perez, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA; Weihua Guan, PhD, Division of Biostatistics, University of Minnesota, Minneapolis, MN; Baolin Wu, PhD, Division of Biostatistics, University of Minnesota, Minneapolis, MN; David Schladt, MS, Minneapolis Medical Research Foundation, Hennepin County Medical Center, Minneapolis, MN; Madhav Menon, MD, Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY; Zhongyang Zhang, PhD, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY; Vinicius Tragante, PhD, Division of Heart and Lungs, Department of Cardiology, University, Medical Center Utrecht, Utrecht, The Netherlands; Nicolaas de Jonge, MD PhD, Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands; Henny G. Otten, PhD, Department of Immunology, University Medical Center, Utrecht, the Netherlands; Roel A. de Weger, PhD, Department of Pathology, University Medical Center, Utrecht, The Netherlands; Ed A. van de Graaf, MD, PhD, Department of Pulmonary Disease, University Medical Center Utrecht, The Netherlands; Carla C. Baan, PhD, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands; Olivier C. Manintveld, MD, PhD, Department of Cardiology, Erasmus University Medical Center, Rotterdam, The Netherlands; Iwijn De Vlaminck, PhD, Department of Bioengineering and Applied Physics, Stanford University, Stanford, CA and Howard Hughes Medical Institute, Stanford, CA; Brian D. Piening, PhD, Howard Hughes Medical Institute, Stanford, CA and Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA; Calvin Strehl, BSc, Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA; Mary Shaw, RN, BBA, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA; Harold Snieder, PhD, Department of Epidemiology, Unit of Genetic Epidemiology and Bioinformatics, University of Groningen, University Medical Center Groningen, The Netherlands; Goran B. Klintmalm, MD, PhD, FACS, Baylor Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX; Jacqueline G. O'Leary, MD, MPH, Division of Hepatology, Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas, TX; Sandra Amaral, MD, MHS, Division of Nephrology, The Children's Hospital of Philadelphia, Philadelphia, PA and Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA; Samuel Goldfarb, MD, Division of PulmonaryMedicine, The Children's Hospital of Philadelphia, Philadelphia, PA; Elizabeth Rand, MD, Division of Gastroenterology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Joseph W. Rossano, MD, MS, FAAP, FAAC, Division of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA; Utkarsh Kohli, MD¸ Division of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, PA; Peter Heeger, MD, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY and Department of Medicine, Icahn School of Medicine at Mount Sinai, NY; Eli Stahl, PhD, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY; Jason D. Christie, MD, MSCE, Division of Pulmonary, Allergy & Critical Care, University of Pennsylvania, Philadelphia, PA; Maria Hernandez Fuentes, PhD, Division of Transplantation Immunology and Mucosal Biology, Guy’s Hospital & King’s College London, United Kingdom; John E. Levine, MD, MS, Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI; Richard Aplenc, MD, PhD, Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA; Eric E. Schadt, PhD, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY; Barbara E. Stranger PhD, Section of Genetic Medicine, University of Chicago, Chicago, IL; Jolanda Kluin, MD, PhD, Department of Cardiothoracic Surgery, University Medical Center Utrecht, The Netherlands; Luciano Potena MD, PhD, Heart Failure and Heart Transplant Unit, Cardiovascular Department, University of Bologna, Italy; Andreas Zuckermann, MD, Department of Cardiac Surgery, Medical University of Vienna, Austria; Kiran Khush, MD, MAS, Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA; Alhusain J. Alzahrani, PhD, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia; Fahad A. Al-Muhanna, MD, College of Medicine, University of Dammam, Dammam, Kingdom of Saudi Arabia; Amein K. Al-Ali, PhD, College of Medicine, University of Dammam, Dammam, Kingdom of Saudi Arabia; Rudaynah Al-Ali, MBBS, Department of Internal Medicine, King Fahd Hospital of the University, University of Dammam, Dammam, Kingdom of Saudi Arabia; Abdullah M. Al-Rubaish, MD, College of Medicine, University of Dammam, Dammam, Kingdom of Saudi Arabia; Samir Al-Mueilo, MBBS, College of Medicine, University of Dammam, Dammam, Kingdom of Saudi Arabia; Edna M. Byrne, PhD, The University of Queensland, St. Lucia, Brisbane, Australia; David Miller, PhD, Queensland Centre for Medical Genomics, IMB, University of Queensland, Queensland, Australia and Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Stephen I. Alexander, MB, BS, MPH, Centre for Kidney Research, The Children's Hospital at Westmead, University of Sydney, NSW, Australia; Suna Onengut-Gumuscu, PhD; Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, VA; Stephen S. Rich, PhD, Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, VA; Manikkam Suthanthiran, MD, Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medical College, New York, NY; Helio Tedesco, MD, Division of Nephrology, Hospital do Rim e Hipertensão, São Paulo, Brazil; Chee L. Saw, PhD, HCLD, HLA Laboratory, Hematology Division, McGill University Health Centre, Montreal, Canada; Jiannis Ragoussis, PhD, McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada; Abdallah G. Kfoury, MD, Intermountain Heart Institute, Murray, UT; Benjamin Horne, MPH, PhD, Intermountain Heart Institute, Murray, UT; John Carlquist, PhD, Intermountain Heart Institute, Murray, UT; Mark B. Gerstein, PhD, The University of Queensland, St. Lucia, Brisbane, Australia and Intermountain Heart Institute, Murray, UT; Roman Reindl-Schwaighofer, MD, Division of Nephrology Dialysis, Department of Internal Medicine III, University of Vienna, Austria; Rainer Oberbauer, MD, Division of Nephrology Dialysis, Department of Internal Medicine III, University of Vienna, Austria; Cisca Wijmenga, PhD, University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands; Scott Palmer, MD, MHS, Department of Medicine, Duke University School of Medicine, Durham, NC; Alexandre C. Pereira, MD, PhD, Laboratory of Genetics & Molecular Cardiology, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil; Javier Segovia, MD, PhD, Heart Transplant Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda,Madrid, Spain; Luis A. Alonso-Pulpon, MD, PhD, Heart Transplant Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda,Madrid, Spain; Manuel Comez-Bueno, MD, Heart Transplant Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda,Madrid, Spain; Carlos Vilches, MD, Department of Immunology, Hospital Universitario Puerta de Hierro Majadahonda,Madrid, Spain; Natalia Jaramillo, MD, Heart Transplant Unit, Department of Cardiology, Hospital Universitario Puerta de HierroMajadahonda, Madrid, Spain; Martin H. de Borst, MD, PhD, Division of Nephrology, Department of Internal Medicine, University Medical Center, University of Groningen, Groningen, The Netherlands; Maarten Naesens, MD, PhD, Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium; Ke Hao, PhD, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, NY; Daniel G. MacArthur, PhD, Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA; Suganthi Balasubramanian, PhD, Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT and Molecular Biophysics and Biochemistry Department, Yale University, New Haven, CT; Peter J. Conlon, MD, Department of Transplantation and Renal Medicine, Beaumont Hospital, Dublin, Ireland; Graham M. Lord, MD, PhD, Division of Transplantation Immunology and Mucosal Biology, Guy’s Hospital & King’s College London, United Kingdom; Marylyn D. Ritchie, PhD, Center for Systems Genomics, The Pennsylvania State University, University Park, PA; Michael Snyder, PhD, Department of Genetics, Stanford University School of Medicine, Stanford, CA and Stanford Cardiovascular Insti tute, Stanford University School of Medicine, Stanford, CA; Kim M. Olthoff, MD, FACS, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA; Jason H. Moore, PhD, Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, VA; Effie W. Petersdorf, MD, Division of Medical Oncology, Fred Hutchinson Cancer Research Center, University of Washington, School of Medicine Seattle, WA; Malek Kamoun, MD, PhD, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Jun Wang, PhD, BGI-Shenzhen, Shenzhen, China; Dimitri S. Monos, PhD, The Children's Hospital of Philadelphia, Philadelphia, PA and Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Paul I.W de Bakker, PhD, Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands and Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands; Hakon Hakonarson, MD, PhD, The Children's Hospital of Philadelphia, Philadelphia, PA; Barbara Murphy, MD, Division of Nephrology and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY; Matthew B. Lankree, MD, PhD, Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Pablo Garcia-Pavia, MD, PhD, Heart Transplant Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain; William S. Oetting, PhD, Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN; Kelly A. Birdwell, MD, MSCI, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; Stephan J. L Bakker, MD, PhD, Division of Nephrology, Department of Internal Medicine, University Medical Center, University of Groningen, Groningen, The Netherlands; Ajay K. Israni, MD, Hennepin County Medical Center, University of Minnesota, Minneapolis, MN; Abraham Shaked, MD PhD, Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, PA; Folkert W. Asselbergs, MD, PhD, Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands, Institute of Cardiovascular Science, University College London, London, United Kingdom, and Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
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