LILRB3 genetic variation is associated with kidney transplant failure in African American recipients.

African American (AA) kidney transplant recipients exhibit a higher rate of graft loss compared with other racial and ethnic populations, highlighting the need to identify causative factors. Here, in the Genomics of Chronic Allograft Rejection cohort, pretransplant blood RNA sequencing revealed a cluster of four consecutive missense single-nucelotide polymorphisms (SNPs), within the leukocyte immunoglobulin-like receptor B3 (LILRB3) gene, strongly associated with death-censored graft loss. This SNP cluster (named LILRB3-4SNPs) encodes missense mutations at amino acids 617-618 proximal to a SHP1/2 phosphatase-binding immunoreceptor tyrosine-based inhibitory motif. The LILRB3-4SNPs cluster is specifically enriched within AA individuals and exhibited a strong association with death-censored graft loss and estimated glomerular filtration rate decline in the AA participants from multiple transplant cohorts. In two large Biobanks (BioMe and All-of-Us), the LILRB3-4SNPs cluster was associated with the early onset of end-stage renal disease and acted synergistically with the apolipoprotein L1 (APOL1) G1/G2 allele to accelerate disease progression. The SNPs were also linked to multiple immune-related diseases in AA individuals. Last, on multiomics analysis of blood and biopsies, recipients with LILRB3-4SNPs showed enhanced inflammation and monocyte ferroptosis. While larger and prospective studies are needed, our data provide insights on the genetic variation underlying kidney transplant outcomes.