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Genomic Mismatch at LIMS1 Locus and Kidney Allograft Rejection.

Steers, Nicholas J; Li, Yifu; Drace, Zahida; D'Addario, Justin A; Fischman, Clara; Liu, Lili; Xu, Katherine; Na, Young-Ji; Neugut, Y Dana; Zhang, Jun Y; Sterken, Roel; Balderes, Olivia; Bradbury, Drew; Ozturk, Nilgun; Ozay, Fatih; Goswami, Sanya; Mehl, Karla; Wold, Jaclyn; Jelloul, Fatima Z; Rohanizadegan, Mersedeh; Gillies, Christopher E; Vasilescu, Elena-Rodica M; Vlad, George; Ko, Yi-An; Mohan, Sumit; Radhakrishnan, Jai; Cohen, David J; Ratner, Lloyd E; Scolari, Francesco; Susztak, Katalin; Sampson, Matthew G; Deaglio, Silvia; Caliskan, Yasar; Barasch, Jonathan; Courtney, Aisling E; Maxwell, Alexander P; McKnight, Amy J; Ionita-Laza, Iuliana; Bakker, Stephan J L; Snieder, Harold; de Borst, Martin H; D'Agati, Vivette; Amoroso, Antonio; Gharavi, Ali G; Kiryluk, Krzysztof.
N Engl J Med; 380(20): 1918-1928, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31091373

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.).
Selo DaSilva