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

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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 language	English
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 - 16 May 2019
Externally published	Yes

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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

@article{99365b2de4f340db96f14ef6fae42dd9,

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 = "Publisher Copyright: Copyright {\textcopyright} 2019 Massachusetts Medical Society.",

year = "2019",

month = may,

day = "16",

doi = "10.1056/NEJMoa1803731",

language = "English",

volume = "380",

pages = "1918--1928",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachussetts Medical Society",

number = "20",

}

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

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

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 -

Genomic mismatch at LIMS1 locus and kidney allograft rejection

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