Design and Implementation of The International Genetics and Translational Research in Transplantation Network (iGeneTRAiN). In press Transplantation October 1st 2015
This paper describes in detail the iGeneTRAiN initial 22 genetic studies comprising over 28,000 transplant recipients or donors, which have existing genome-wide genotype data (this number has now grown to nearly 30 studies with over 32,000 and it is still growing). The paper, with input from over 120 iGeneTRAiN co-authors, describes the genetic and phenotypic data available in these comprising heart, kidney, liver, and lung transplant studies. It also formally demonstrates the significant statistical power in iGeneTRAiN to detect main effect genetic association signals across these studies for graft survival, acute rejection, new onset of diabetes after transplantation (NODAT), and for delayed graft function.
Concept and design of a genome-wide association genotyping array tailored for transplantation-specific studies.Yun Rose Li et al. In press Genome Medicine October 1st 2015.
This paper describes in detail the ‘Tx GWAS array’ (Axiom, Affymetrix), a unique genome-wide genotyping tool to facilitate genomic research studies in transplant-related studies. The Tx GWAS array containing approximately 782,000 markers is designed using the most recent human genomic reference datasets, and includes customized content for known and potentially relevant metabolic and pharmacological gene regions relevant to transplantation. This paper formally assesses the performance of the Tx GWAS array on benchmarked reference samples from HapMap/1000 Genomes Project (1KGP). It shows low Mendelian error and high concordance rates. It also demonstrates much higher capture of high priority content such as killer cell immunoglobulin-like receptor (KIR) region versus conventional platforms, and shows the very dense content in the MHC/HLA regions. The imputation pipeline is also described. We have now generated an imputation pipeline comprising the 1KGPv3 and The Genome of The Netherlands (Go-NL)v5 using IMPUTE2 and SHAPEIT which allows approximately 88 million sites across the human genome to be inferred (approximately 15 million of which are typically used for conventional GWAS analyses). We have also constructed a loss-of-function (LoF) pipeline based on the imputed data with the directly and imputed genotypes, and with deep characterization of rich expression resources, which allows deep characterization of LoFs across the phased chromosomes.
Genome-wide association studies (GWAS) published to date
Only three Transplantation GWA studies, shown below, have been published to date, and the numbers of subjects are very modest by standard GWAS efforts. Hopefully the number of studies, and aggregation of total patients within these studies, will increase dramatically over the next 12 months with iGeneTRAiN and other efforts.
A genome-wide association study of recipient genotype and medium-term kidney allograft function.
O’Brien RP, Phelan PJ, Conroy J, O’Kelly P, Green A, Keogan M, O’Neill D, Jennings S, Traynor C, Casey J, McCormack M, Conroy R, Chubb A, Ennis S, Shields DC, Cavalleri GL, Conlon PJ.
Clinical Transplantation.2013 May-Jun;27(3):379-87. doi: 10.1111/ctr.12093.
Genetics of new-onset diabetes after transplantation.
McCaughan JA, McKnight AJ, Maxwell AP.
Journal of the American Society of Nephrology.2014 May;25(5):1037-49. doi: 10.1681/ASN.2013040383.
Clinical and Genetic Factors Associated with Cutaneous Squamous Cell Carcinoma in Kidney and Heart Transplant Recipients.
Sanders ML, Karnes JH, Denny JC, Roden DM, Ikizler TA, Birdwell KA.
Transplantation Direct.2015 May;1(4). doi: 10.1097/TXD.0000000000000521.
Recent genetic/biomarker publications from iGeneTRAiN members
Urine Metabolite Profiles Predictive of Human Kidney Allograft Status.
Suhre K, Schwartz JE, Sharma VK, Chen Q, Lee JR, Muthukumar T, Dadhania DM, Ding R, Ikle DN, Bridges ND, Williams NM, Kastenmüller G, Karoly ED, Mohney RP, Abecassis M, Friedewald J, Knechtle SJ, Becker YT, Samstein B, Shaked A, Gross SS, Suthanthiran M.
Journal of the American Society of Nephrology.2015 Jun 5. pii: ASN.2015010107.
Dosing equation for tacrolimus using genetic variants and clinical factors.
Passey C, Birnbaum AK, Brundage RC, Oetting WS, Israni AK, Jacobson PA.
British Journal of Clinical Pharmacology.2011 Dec;72(6):948-57. doi: 10.1111/j.1365-2125.2011.04039.x.
Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection.
De Vlaminck I, Valantine HA, Snyder TM, Strehl C, Cohen G, Luikart H, Neff NF, Okamoto J, Bernstein D, Weisshaar D, Quake SR, Khush KK.
Sci Transl Med. 2014 Jun 18;6(241):241ra77. doi: 10.1126/scitranslmed.3007803.
Identification of common blood gene signatures for the diagnosis of renal and cardiac acute allograft rejection.
Li L, Khush K, Hsieh SC, Ying L, Luikart H, Sigdel T, Roedder S, Yang A, Valantine H, Sarwal MM.
PLoS One. 2013 Dec 16;8(12):e82153. doi: 10.1371/journal.pone.0082153. eCollection 2013.
Temporal response of the human virome to immunosuppression and antiviral therapy.
De Vlaminck I, Khush KK, Strehl C, Kohli B, Luikart H, Neff NF, Okamoto J, Snyder TM, Cornfield DN, Nicolls MR, Weill D, Bernstein D, Valantine HA, Quake SR.
Cell. 2013 Nov 21;155(5):1178-87. doi: 10.1016/j.cell.2013.10.034.
Urinary-cell mRNA profile and acute cellular rejection in kidney allografts.
Suthanthiran M, Schwartz JE, Ding R, Abecassis M, Dadhania D, Samstein B, Knechtle SJ, Friedewald J, Becker YT, Sharma VK, Williams NM, Chang CS, Hoang C, Muthukumar T, August P, Keslar KS, Fairchild RL, Hricik DE, Heeger PS, Han L, Liu J, Riggs M, Ikle DN, Bridges ND, Shaked A. Clinical Trials in Organ Transplantation 04 (CTOT-04).
New England Journal of Medicine.2013 Jul 4;369(1):20-31. doi: 10.1056/NEJMoa1215555.
Recent Transplantation Genomic Reviews/Commentaries
Transplantation genetics: current status and prospects.
B Almoguera, A Shaked, BJ Keating.
American Journal of Transplantation. April 14, 2014.
Transplant rejection and risk: in search of the genetic dark matter.
Oetting WS, Jacobson PA, Israni AK.
Journal of Gastrointestinal Liver Disease. 2013 Jun;22(2):125-6.
TMaking the genomic leap in HCT: application of second-generation sequencing to clinical advances in hematopoietic cell transplantation.
Li YR, Levine JE, Hakonarson H, Keating BJ.
European Journal of Human Genetics. 2014 Jun;22(6):715-23. doi: 10.1038/ejhg.2013.247