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 Rohanizadegan; Christopher 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

doi:10.1056/NEJMoa1803731

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 journal › Article › peer-review

48 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 language	English (US)
Pages (from-to)	1918-1928
Number of pages	11
Journal	New England Journal of Medicine
Volume	380
Issue number	20
DOIs	https://doi.org/10.1056/NEJMoa1803731
State	Published - May 16 2019
Externally published	Yes

ASJC Scopus subject areas

Medicine(all)

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10.1056/NEJMoa1803731

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Steers, N. J., Li, Y., Drace, Z., D'Addario, J. A., Fischman, C., Liu, L., Xu, K., Na, Y. J. Y., Neugut, 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

Steers, NJ, Li, Y, Drace, Z, D'Addario, JA, Fischman, C, Liu, L, Xu, K, Na, YJY, Neugut, D, Zhang, JY, Sterken, R, Balderes, O, Bradbury, D, Ozturk, N, Ozay, F, Goswami, S, Mehl, K, Wold, J, Jelloul, FZ, Rohanizadegan, M, Gillies, CE, Vasilescu, ERM, Vlad, G, Ko, YA, Mohan, S, Radhakrishnan, J, Cohen, DJ, Ratner, LE, Scolari, F, Susztak, K, Sampson, MG, Deaglio, S, Caliskan, Y, Barasch, J, Courtney, AE, Maxwell, AP, McKnight, AJ, Ionita-Laza, I, Bakker, SJL, Snieder, H, De Borst, MH, D'Agati, V, Amoroso, A, Gharavi, AG & Kiryluk, K 2019, 'Genomic mismatch at LIMS1 locus and kidney allograft rejection', New England Journal of Medicine, vol. 380, no. 20, pp. 1918-1928. https://doi.org/10.1056/NEJMoa1803731

@article{61f6c0fbd5aa4989a4b7bbebcd2b3ee7,

title = "Genomic mismatch at LIMS1 locus and kidney allograft rejection",

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.).",

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

note = "Funding Information: Supported by the Columbia University Transplant Center, a New York Presbyterian Hospital Translational Pilot Grant funded by the New York State Empire Clinical Research Investigator Program, a Columbia University Precision Medicine Pilot Award funded by the Dean of the College of Physicians and Surgeons, and the Columbia Clinical and Translational Science Award Precision Medicine Pilot Program funded by a grant (UL1TR001873) from the NIH National Center for Advancing Translational Sciences and by grants (T35-DK093430, to Ms. Fischman; and T32-DK108741 Supplement, to Ms. Neugut) from the National Institute of Diabetes and Digestive and Kidney Diseases. Replication studies in the Torino cohort were supported by a Department of Excellence Grant 2018–2022 funded by the Italian Ministry of Education to the Department of Medical Sciences of the University of Turin. The Columbia Center for Translational Immunology Flow Cytometry Core is supported in part by a grant (S10RR027050) from the NIH Office of the Director, and the Confocal and Specialized Microscopy Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University is supported by a grant (P30CA013696) from the NIH National Cancer Institute. Funding Information: Supported by the Columbia University Transplant Center, a New York Presbyterian Hospital Translational Pilot Grant funded by the New York State Empire Clinical Research Investigator Program, a Columbia University Precision Medicine Pilot Award funded by the Dean of the College of Physicians and Surgeons, and the Columbia Clinical and Translational Science Award Precision Medicine Pilot Program funded by a grant (UL1TR001873) from the NIH National Center for Advancing Translational Sciences and by grants (T35-DK093430, to Ms. Fischman; and T32-DK108741 Supplement, to Ms. Neugut) from the National Institute of Diabetes and Digestive and Kidney Diseases. Replication studies in the Torino cohort were supported by a Department of Excellence Grant 2018-2022 funded by the Italian Ministry of Education to the Department of Medical Sciences of the University of Turin. The Columbia Center for Translational Immunology Flow Cytometry Core is supported in part by a grant (S10RR027050) from the NIH Office of the Director, and the Confocal and Specialized Microscopy Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University is supported by a grant (P30CA013696) from the NIH National Cancer Institute. Publisher Copyright: Copyright {\textcopyright} 2019 Massachusetts Medical Society.",

year = "2019",

month = may,

day = "16",

doi = "10.1056/NEJMoa1803731",

language = "English (US)",

volume = "380",

pages = "1918--1928",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "20",

}

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 - Funding Information: Supported by the Columbia University Transplant Center, a New York Presbyterian Hospital Translational Pilot Grant funded by the New York State Empire Clinical Research Investigator Program, a Columbia University Precision Medicine Pilot Award funded by the Dean of the College of Physicians and Surgeons, and the Columbia Clinical and Translational Science Award Precision Medicine Pilot Program funded by a grant (UL1TR001873) from the NIH National Center for Advancing Translational Sciences and by grants (T35-DK093430, to Ms. Fischman; and T32-DK108741 Supplement, to Ms. Neugut) from the National Institute of Diabetes and Digestive and Kidney Diseases. Replication studies in the Torino cohort were supported by a Department of Excellence Grant 2018–2022 funded by the Italian Ministry of Education to the Department of Medical Sciences of the University of Turin. The Columbia Center for Translational Immunology Flow Cytometry Core is supported in part by a grant (S10RR027050) from the NIH Office of the Director, and the Confocal and Specialized Microscopy Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University is supported by a grant (P30CA013696) from the NIH National Cancer Institute. Funding Information: Supported by the Columbia University Transplant Center, a New York Presbyterian Hospital Translational Pilot Grant funded by the New York State Empire Clinical Research Investigator Program, a Columbia University Precision Medicine Pilot Award funded by the Dean of the College of Physicians and Surgeons, and the Columbia Clinical and Translational Science Award Precision Medicine Pilot Program funded by a grant (UL1TR001873) from the NIH National Center for Advancing Translational Sciences and by grants (T35-DK093430, to Ms. Fischman; and T32-DK108741 Supplement, to Ms. Neugut) from the National Institute of Diabetes and Digestive and Kidney Diseases. Replication studies in the Torino cohort were supported by a Department of Excellence Grant 2018-2022 funded by the Italian Ministry of Education to the Department of Medical Sciences of the University of Turin. The Columbia Center for Translational Immunology Flow Cytometry Core is supported in part by a grant (S10RR027050) from the NIH Office of the Director, and the Confocal and Specialized Microscopy Shared Resource of the Herbert Irving Comprehensive Cancer Center at Columbia University is supported by a grant (P30CA013696) from the NIH National Cancer Institute. 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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JO - New England Journal of Medicine

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Genomic mismatch at LIMS1 locus and kidney allograft rejection

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