Genomic Mismatch at LIMS1 Locus and Kidney Allograft Rejection

Nicholas J Steers, Yifu Li, Zahida Drace, Justin A D'Addario, Clara Fischman, Lili Liu, Katherine Xu, Young-Ji Na, Y Dana Neugut, Jun Y Zhang, Roel Sterken, Olivia Balderes, Drew Bradbury, Nilgun Ozturk, Fatih Ozay, Sanya Goswami, Karla Mehl, Jaclyn Wold, Fatima Z Jelloul, Mersedeh RohanizadeganChristopher E Gillies, Elena-Rodica M Vasilescu, George Vlad, Yi-An Ko, Sumit Mohan, Jai Radhakrishnan, David J Cohen, Lloyd E Ratner, Francesco Scolari, Katalin Susztak, Matthew G Sampson, Silvia Deaglio, Yasar Caliskan, Jonathan Barasch, Aisling E Courtney, Alexander P Maxwell, Amy J McKnight, Iuliana Ionita-Laza, Stephan J L Bakker, Harold Snieder, Martin H de Borst, Vivette D'Agati, Antonio Amoroso, Ali G Gharavi, Krzysztof Kiryluk

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Abstract

BACKGROUND: In the context of kidney transplantation, genomic incompatibilities between donor and recipient may lead to allosensitization against new antigens. We hypothesized that recessive inheritance of gene-disrupting variants may represent a risk factor for allograft rejection.

METHODS: We performed a two-stage genetic association study of kidney allograft rejection. In the first stage, we performed a recessive association screen of 50 common gene-intersecting deletion polymorphisms in a cohort of kidney transplant recipients. In the second stage, we replicated our findings in three independent cohorts of donor-recipient pairs. We defined genomic collision as a specific donor-recipient genotype combination in which a recipient who was homozygous for a gene-intersecting deletion received a transplant from a nonhomozygous donor. Identification of alloantibodies was performed with the use of protein arrays, enzyme-linked immunosorbent assays, and Western blot analyses.

RESULTS: In the discovery cohort, which included 705 recipients, we found a significant association with allograft rejection at the LIMS1 locus represented by rs893403 (hazard ratio with the risk genotype vs. nonrisk genotypes, 1.84; 95% confidence interval [CI], 1.35 to 2.50; P = 9.8×10-5). This effect was replicated under the genomic-collision model in three independent cohorts involving a total of 2004 donor-recipient pairs (hazard ratio, 1.55; 95% CI, 1.25 to 1.93; P = 6.5×10-5). In the combined analysis (discovery cohort plus replication cohorts), the risk genotype was associated with a higher risk of rejection than the nonrisk genotype (hazard ratio, 1.63; 95% CI, 1.37 to 1.95; P = 4.7×10-8). We identified a specific antibody response against LIMS1, a kidney-expressed protein encoded within the collision locus. The response involved predominantly IgG2 and IgG3 antibody subclasses.

CONCLUSIONS: We found that the LIMS1 locus appeared to encode a minor histocompatibility antigen. Genomic collision at this locus was associated with rejection of the kidney allograft and with production of anti-LIMS1 IgG2 and IgG3. (Funded by the Columbia University Transplant Center and others.).

Original languageEnglish
Pages (from-to)1918-1928
Number of pages11
JournalNew England Journal of Medicine
Volume380
Issue number20
DOIs
Publication statusPublished - 16 May 2019
Externally publishedYes

Bibliographical note

Copyright © 2019 Massachusetts Medical Society.

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    Steers, N. J., Li, Y., Drace, Z., D'Addario, J. A., Fischman, C., Liu, L., Xu, K., Na, Y-J., Neugut, Y. D., Zhang, J. Y., Sterken, R., Balderes, O., Bradbury, D., Ozturk, N., Ozay, F., Goswami, S., Mehl, K., Wold, J., Jelloul, F. Z., ... Kiryluk, K. (2019). Genomic Mismatch at LIMS1 Locus and Kidney Allograft Rejection. New England Journal of Medicine, 380(20), 1918-1928. https://doi.org/10.1056/NEJMoa1803731