PMID- 32454123 OWN - NLM STAT- MEDLINE DCOM- 20210621 LR - 20210903 IS - 1523-1755 (Electronic) IS - 0085-2538 (Print) IS - 0085-2538 (Linking) VI - 98 IP - 3 DP - 2020 Sep TI - Genome-wide non-HLA donor-recipient genetic differences influence renal allograft survival via early allograft fibrosis. PG - 758-768 LID - S0085-2538(20)30540-8 [pii] LID - 10.1016/j.kint.2020.04.039 [doi] AB - Donor-recipient (D-R) differences at human leukocyte antigen (HLA) loci are currently incorporated into organ sharing, allocation and immunosuppression decisions. However, while acute rejection episodes have substantially diminished, progressive histologic damage occurs in allografts and improved long-term survival remains an unrealized goal among kidney recipients. Here we tested the hypothesis that non-HLA dependent, genome-wide D-R genetic differences could contribute to unchecked alloimmunity with histologic and functional consequences, culminating in long-term allograft failure. Genome-wide single nucleotide polymorphism (SNP) array data, excluding the HLA region, was utilized from 385 transplants to study the role of D-R differences upon serial histology and allograft survival. ADMIXTURE analysis was performed to quantitatively estimate ancestry in each D-R pair and PLINK was used to estimate the proportion of genome-shared identity-by-descent (pIBD) between D-R pairs. Subsequently, quantitative measures of recipient ancestry based on non-HLA SNPs was associated with death-censored allograft survival in adjusted Cox models. In D-R pairs of similar ancestry, pIBD was significantly associated with allograft survival independent of HLA mismatches in 224 transplants. Surprisingly, pIBD and recipient ancestry were not associated with clinical or subclinical rejection at any time post-transplant. Significantly, in multivariable analysis, pIBD inversely correlated with vascular intimal fibrosis in 160 biopsies obtained less than one year which in turn was significantly associated with allograft survival. Thus, our novel data show that non-HLA D-R differences associate with early vascular intimal fibrosis and allograft survival. CI - Copyright (c) 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved. FAU - Zhang, Zhongyang AU - Zhang Z AD - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. FAU - Menon, Madhav C AU - Menon MC AD - Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Recanati Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. FAU - Zhang, Weijia AU - Zhang W AD - Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA. FAU - Stahl, Eli AU - Stahl E AD - Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA. FAU - Loza, Bao-Li AU - Loza BL AD - Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA. FAU - Rosales, Ivy A AU - Rosales IA AD - Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. FAU - Yi, Zhengzi AU - Yi Z AD - Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA. FAU - Banu, Khadija AU - Banu K AD - Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA. FAU - Garzon, Felipe AU - Garzon F AD - Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA. FAU - Sun, Zeguo AU - Sun Z AD - Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA. FAU - Wei, Chengguo AU - Wei C AD - Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA. FAU - Huang, Weiqing AU - Huang W AD - Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA. FAU - Lin, Qisheng AU - Lin Q AD - Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA. FAU - Israni, Ajay AU - Israni A AD - Nephrology, Medicine, Hennepin Healthcare System, University of Minnesota, Minneapolis, Minnesota, USA. FAU - Keating, Brendan J AU - Keating BJ AD - Penn Transplant Institute, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA. FAU - Colvin, Robert B AU - Colvin RB AD - Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. FAU - Hao, Ke AU - Hao K AD - Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA; Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address: ke.hao@mssm.edu. FAU - Murphy, Barbara AU - Murphy B AD - Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA. Electronic address: barbara.murphy@mssm.edu. LA - eng GR - R01 DK122164/DK/NIDDK NIH HHS/United States GR - U01 AI063594/AI/NIAID NIH HHS/United States GR - U01 AI070107/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200523 PL - United States TA - Kidney Int JT - Kidney international JID - 0323470 RN - 0 (HLA Antigens) SB - IM MH - Allografts MH - Fibrosis MH - Graft Rejection/genetics MH - Graft Survival/genetics MH - HLA Antigens/genetics MH - Humans MH - Kidney MH - *Kidney Transplantation/adverse effects PMC - PMC7483801 MID - NIHMS1605465 OTO - NOTNLM OT - allograft survival OT - genetic ancestry OT - identity by descent OT - kidney transplantation EDAT- 2020/05/27 06:00 MHDA- 2021/06/22 06:00 PMCR- 2021/09/01 CRDT- 2020/05/27 06:00 PHST- 2019/06/12 00:00 [received] PHST- 2020/03/22 00:00 [revised] PHST- 2020/04/02 00:00 [accepted] PHST- 2020/05/27 06:00 [pubmed] PHST- 2021/06/22 06:00 [medline] PHST- 2020/05/27 06:00 [entrez] PHST- 2021/09/01 00:00 [pmc-release] AID - S0085-2538(20)30540-8 [pii] AID - 10.1016/j.kint.2020.04.039 [doi] PST - ppublish SO - Kidney Int. 2020 Sep;98(3):758-768. doi: 10.1016/j.kint.2020.04.039. Epub 2020 May 23.