Genomic Mismatch at LIMS1 Locus and Kidney Allograft Rejection

被引：73

作者：

Steers, N. J. ^{[1
]}

Li, Y. ^{[1
]}

Drace, Z. ^{[6
,7
]}

D'Addario, J. A. ^{[1
]}

Fischman, C. ^{[1
]}

Liu, L. ^{[1
]}

Xu, K. ^{[1
]}

Na, Y. -J ^{[1
]}

Neugut, Y. D. ^{[1
]}

Zhang, J. Y. ^{[1
]}

Sterken, R. ^{[1
]}

Balderes, O. ^{[1
]}

Bradbury, D. ^{[1
]}

Ozturk, N. ^{[1
]}

Ozay, F. ^{[1
]}

Goswami, S. ^{[1
]}

Mehl, K. ^{[1
]}

Wold, J. ^{[1
]}

Jelloul, F. Z. ^{[9
]}

Rohanizadegan, M. ^{[10
,11
]}

Gillies, C. E. ^{[12
]}

Vasilescu, E. -R. M. ^{[3
]}

Vlad, G. ^{[3
]}

Ko, Y-A ^{[13
]}

Mohan, S. ^{[1
,4
]}

Radhakrishnan, J. ^{[1
]}

Cohen, D. J. ^{[1
]}

Ratner, L. E. ^{[2
]}

Scolari, F. ^{[8
]}

Susztak, K. ^{[13
]}

Sampson, M. G. ^{[12
]}

Deaglio, S. ^{[6
,7
]}

Caliskan, Y. ^{[14
]}

Barasch, J. ^{[1
]}

Courtney, A. E. ^{[15
]}

Maxwell, A. P. ^{[15
]}

McKnight, A. J. ^{[15
]}

Ionita-Laza, I. ^{[5
]}

Bakker, S. J. L. ^{[16
]}

Snieder, H. ^{[17
]}

de Borst, M. H. ^{[16
]}

D'Agati, V. ^{[3
]}

Amoroso, A. ^{[6
,7
]}

Gharavi, A. G. ^{[1
]}

Kiryluk, K. ^{[1
]}

机构：

[1] Vagelos Coll Phys & Surg, Dept Med, Div Nephrol, New York, NY USA

[2] Vagelos Coll Phys & Surg, Dept Surg, New York, NY USA

[3] Vagelos Coll Phys & Surg, Dept Pathol & Cell Biol, New York, NY USA

[4] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA

[5] Columbia Univ, Mailman Sch Publ Hlth, Dept Biostat, New York, NY USA

[6] Univ Hosp Turin, Citta Salute & Sci, Immunogenet & Biol Transplantat, Turin, Italy

[7] Univ Turin, Dept Med Sci, Med Genet, Turin, Italy

[8] Univ Brescia, Azienda Osped Spedali Civili Brescia, Montichiari Hosp, Div Nephrol, Brescia, Italy

[9] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[10] Boston Childrens Hosp, Div Genet & Genom, Boston, MA USA

[11] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[12] Univ Michigan, Sch Med, Dept Pediat, Div Pediat Nephrol, Ann Arbor, MI 48109 USA

[13] Univ Penn, Dept Med, Renal Elect & Hypertens Div, Philadelphia, PA 19104 USA

[14] Istanbul Univ, Istanbul Fac Med, Div Nephrol, Istanbul, Turkey

[15] Queens Univ Belfast, Nephrol Res Grp, Belfast, Antrim, North Ireland

[16] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Div Nephrol, Groningen, Netherlands

[17] Univ Groningen, Univ Med Ctr Groningen, Unit Genet Epidemiol & Bioinformat, Dept Epidemiol, Groningen, Netherlands

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2019年 / 380卷 / 20期

关键词：

ANTIBODY-MEDIATED REJECTION; DONOR-SPECIFIC ANTIBODIES; NON-HLA ANTIBODIES; WIDE ASSOCIATION; LEUKOCYTE ANTIGEN; H-Y; TRANSPLANTATION; RESPONSES; DELETION; IMMUNITY;

D O I：

10.1056/NEJMoa1803731

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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=9.8x10(-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=6.5x10(-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=4.7x10(-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.

引用

页码：1918 / 1928

页数：11

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