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.)

ABO-incompatible living donor kidney transplantation in Portugal

“…However, recent findings opened up a new prospect in this field; the genomic collision may be a relevant underlying mechanism to consider in such cases. 15 Infection rate was 42% in the present study. Hwang et al also reported high rate of infection complications in ABOi kidney transplantation recipients (66%).…”

Proteomics Reveals Extracellular Matrix Injury in the Glomeruli and Tubulointerstitium of Kidney Allografts with Early Antibody-Mediated Rejection

“…22 Both IFNɣ and TNFα accentuate antibody-mediated injury in AMR. [23][24][25] Moreover, tubular proteins can be targeted by non-HLA antibodies, 22,26 which reinforces the rationale for studying AMR in the tubulointerstitium.…”

Natural Autoantibodies in Chronic Pulmonary Diseases

“…We also found an anti-LIM zinc finger domain containing 1 (LMS1) autoAb among INSIP-associated natural autoAbs. Recently, a genomic mismatch in the LIMS1 gene was identified as a cause of previously unpredictable rejection [44]. In this previous study, production of IgG2-and IgG3-types of anti-LIMS autoAbs was associated with allograft rejection.…”

“…LOXL2 [42,43], LIMS1 [44], NINJ2 [41], HVCN1 [45,46], TMEM79 [47], VSTM2A [48], FNDC4 [49] Interestingly, especially among antigens recognized by INSIP patient sera, there are many extracellular or membrane proteins, which are accessible by antibodies even under normal conditions. This suggests that the antigen-antibody interactions may be implicated in the pathogenesis or clinical course of disease.…”