PT - JOURNAL ARTICLE AU - Laurent Mesnard AU - Thangamani Muthukumar AU - Maren Burbach AU - Carol Li AU - Huimin Shang AU - Darshana Dadhania AU - John R Lee AU - Vijay K Sharma AU - Jenny Xiang AU - John J. Friedewald AU - Michael M. Abecassis AU - Manikkam Suthanthiran AU - Fabien Campagne TI - Exome Sequencing, Histoincompatibility and Long-Term Kidney Allograft Function AID - 10.1101/015651 DP - 2015 Jan 01 TA - bioRxiv PG - 015651 4099 - http://biorxiv.org/content/early/2015/02/26/015651.short 4100 - http://biorxiv.org/content/early/2015/02/26/015651.full AB - BACKGROUND Kidney transplantation is the treatment of choice for most patients with end-stage renal disease and existing data suggest that post transplant graft function is a predictor of kidney graft failure.METHODS Exome sequencing of DNA from kidney graft recipients and their donors was used to determine recipient and donor mismatches at the amino acid level. The number of mismatches that are more likely to induce an immune response in the recipient was computationally estimated and designated the allogenomics mismatch score. The relationship between the allogenomics score and post transplant kidney allograft function was examined using linear regression.RESULTS A significant inverse correlation between the allogenomics mismatch score and kidney graft function at 36 months post transplantation was observed in a discovery cohort of kidney recipient-donor pairs (r2>=0.57, P<0.05, the score vs. level of serum creatinine or estimated glomerular filtration rate). This relationship was confirmed in an independent validation cohort of kidney recipient-donor pairs. We observed that the strength of the correlation increased with time post-transplantation. This inverse correlation remained after excluding HLA loci from the calculation of the score. Exome sequencing yielded allogenomics scores with stronger correlations with graft function than simulations of genotyping assays which measure common polymorphisms only.CONCLUSIONS The allogenomics mismatch score, derived by exome sequencing of recipient-donor pairs, facilitates quantification of histoincompatibility between the organ donor and recipient impacting long-term post transplant graft function. The allogenomics mismatch score, by serving as a prognostic biomarker, may help identify patients at risk for graft failure.Impact statement Prediction of post transplant kidney graft function with the allogenomics mismatch score to quantify histoincompatibilty between the kidney recipient-donor pair.Major subject areas, keywords, and research organism(s) Genomics, kidney transplantation, organ transplantation, immunology, Human Leukocyte Antigen, long-term graft function.