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<p>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 (<i>LILRB3</i>) gene, strongly associated with death-censored graft loss. This SNP cluster (named <i>LILRB3</i>-4SNPs) encodes missense mutations at amino acids 617–618 proximal to a SHP1/2 phosphatase-binding immunoreceptor tyrosine-based inhibitory motif. The <i>LILRB3</i>-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 <i>LILRB3</i>-4SNPs cluster was associated with the early onset of end-stage renal disease and acted synergistically with the apolipoprotein L1 (<i>APOL1</i>) 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 <i>LILRB3</i>-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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年3月10日

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  • Zeguo Sun,
  • Zhengzi Yi,
  • Chengguo Wei,
  • Wenlin Wang,
  • Tianyuan Ren,
  • Paolo Cravedi,
  • Fasika Tedla,
  • Stephen C. Ward,
  • Evren Azeloglu,
  • Daniel R. Schrider,
  • Yun Li,
  • Atlas Khan,
  • Francesca Zanoni,
  • Jia Fu,
  • Sumaria Ali,
  • Shun Liu,
  • Deguang Liang,
  • Tong Liu,
  • Hong Li,
  • Caixia Xi,
  • Thi Ha Vy,
  • Gohar Mosoyan,
  • Quan Sun,
  • Ashwani Kumar,
  • Zhongyang Zhang,
  • Samira Farouk,
  • Kirk Campell,
  • Jordi Ochando,
  • Kyung Lee,
  • Steve Coca,
  • Jenny Xiang,
  • Patricia Connolly,
  • Lorenzo Gallon,
  • Philip J. O’Connell,
  • Robert Colvin,
  • Madhav C. Menon,
  • Girish Nadkarni,
  • John C. He,
  • Monica Kraft,
  • Xuejun Jiang,
  • Xuewu Zhang,
  • Krzysztof Kiryluk,
  • Aravind Cherukuri,
  • Fadi G. Lakkis,
  • Weiguo Zhang,
  • Shu-hsia Chen,
  • Peter S. Heeger,
  • Weijia Zhang

摘要

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.