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Genomic Mismatch at LIMS1 Locus and Kidney Allograft Rejection
Nicholas J Steers1, Yifu Li1, Zahida Drace1
1From the Department of Medicine, Division of Nephrology (N.J.S., Y.L., J.A.D., C.F., L.L., K.X., Y.-J.N., Y.D.N., J.Y.Z., R.S., O.B., D.B., N.O., F.O., S.G., K.M., J.W., S.M., J.R., D.J.C., J.B., A.G.G., K.K.), the Department of Surgery (L.E.R.), and the Department of Pathology and Cell Biology (E.-R.M.V., G.V., V.D.), Vagelos College of Physicians and Surgeons, and the Departments of Epidemiology (S.M.) and Biostatistics (I.I.-L.), Mailman School of Public Health, Columbia University, New York; Immunogenetics and Biology of Transplantation, Città della Salute e della Scienza, University Hospital of Turin, and Medical Genetics, Department of Medical Sciences, University of Turin, Turin (Z.D., S.D., A.A.), and the Division of Nephrology, Azienda Ospedaliera Spedali Civili of Brescia, Montichiari Hospital, University of Brescia, Brescia (F.S.) - all in Italy; the Department of Pathology, M.D. Anderson Cancer Center, Houston (F.Z.J.); the Division of Genetics and Genomics, Boston Children's Hospital, and the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston (M.R.); the Department of Pediatrics, Division of Pediatric Nephrology, University of Michigan School of Medicine, Ann Arbor (C.E.G., M.G.S.); the Department of Medicine, Renal, Electrolyte, and Hypertension Division, University of Pennsylvania, Philadelphia (Y.-A.K., K.S.); the Division of Nephrology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey (Y.C.); the Nephrology Research Group, Queen's University of Belfast, Belfast, United Kingdom (A.E.C., A.P.M., A.J.M.); and the Department of Internal Medicine, Division of Nephrology (S.J.L.B., M.H.B.), and the Department of Epidemiology, Unit of Genetic Epidemiology and Bioinformatics (H.S.), University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
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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