TY - JOUR
T1 - Genomic mismatch at LIMS1 locus and kidney allograft rejection
AU - Steers, Nicholas J.
AU - Li, Yifu
AU - Drace, Zahida
AU - D'Addario, Justin A.
AU - Fischman, Clara
AU - Liu, Lili
AU - Xu, Katherine
AU - Na, Young Ji Y.
AU - Neugut, Dana
AU - Zhang, Jun Y.
AU - Sterken, Roel
AU - Balderes, Olivia
AU - Bradbury, Drew
AU - Ozturk, Nilgun
AU - Ozay, Fatih
AU - Goswami, Sanya
AU - Mehl, Karla
AU - Wold, Jaclyn
AU - Jelloul, Fatima Z.
AU - Rohanizadegan, Mersedeh
AU - Gillies, Christopher E.
AU - Vasilescu, Elena Rodica M.
AU - Vlad, George
AU - Ko, Yi An
AU - Mohan, Sumit
AU - Radhakrishnan, Jai
AU - Cohen, David J.
AU - Ratner, Lloyd E.
AU - Scolari, Francesco
AU - Susztak, Katalin
AU - Sampson, Matthew G.
AU - Deaglio, Silvia
AU - Caliskan, Yasar
AU - Barasch, Jonathan
AU - Courtney, Aisling E.
AU - Maxwell, Alexander P.
AU - McKnight, Amy J.
AU - Ionita-Laza, Iuliana
AU - Bakker, Stephan J.L.
AU - Snieder, Harold
AU - De Borst, Martin H.
AU - D'Agati, Vivette
AU - Amoroso, Antonio
AU - Gharavi, Ali G.
AU - Kiryluk, Krzysztof
N1 - Publisher Copyright:
Copyright © 2019 Massachusetts Medical Society.
PY - 2019/5/16
Y1 - 2019/5/16
N2 - 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.).
AB - 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.).
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U2 - 10.1056/NEJMoa1803731
DO - 10.1056/NEJMoa1803731
M3 - Article
C2 - 31091373
AN - SCOPUS:85065836339
SN - 0028-4793
VL - 380
SP - 1918
EP - 1928
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 20
ER -