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 Y. Na, 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

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

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
StatePublished - 16 May 2019
Externally publishedYes

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