Genome-wide non-HLA donor-recipient genetic differences influence renal allograft survival via early allograft fibrosis
Autor: | Zhongyang Zhang, Chengguo Wei, Ajay K. Israni, Eli A. Stahl, Weiqing Huang, Madhav C. Menon, Khadija Banu, Bao-Li Loza, Zeguo Sun, Ivy A. Rosales, Brendan J. Keating, Qisheng Lin, Barbara Murphy, Felipe Garzon, Weijia Zhang, Zhengzi Yi, Robert B. Colvin, Ke Hao |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Graft Rejection medicine.medical_treatment 030232 urology & nephrology Single-nucleotide polymorphism Human leukocyte antigen Kidney Article 03 medical and health sciences 0302 clinical medicine Fibrosis HLA Antigens Medicine Humans Kidney transplantation Subclinical infection business.industry Proportional hazards model Alloimmunity Graft Survival Immunosuppression medicine.disease Allografts Kidney Transplantation 030104 developmental biology Nephrology Immunology business |
Zdroj: | Kidney Int |
Popis: | 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. |
Databáze: | OpenAIRE |
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