Sun Zeguo, Yi Zhengzi, Wei Chengguo, Wang Wenlin, Ren Tianyuan, Cravedi Paolo, Tedla Fasika, Ward Stephen C, Azeloglu Evren, Schrider Daniel R, Li Yun, Khan Atlas, Zanoni Francesca, Fu Jia, Ali Sumaria, Liu Shun, Liang Deguang, Liu Tong, Li Hong, Xi Caixia, Vy Thi Ha, Mosoyan Gohar, Sun Quan, Kumar Ashwani, Zhang Zhongyang, Farouk Samira, Campell Kirk, Ochando Jordi, Lee Kyung, Coca Steve, Xiang Jenny, Connolly Patricia, Gallon Lorenzo, O'Connell Philip J, Colvin Robert, Menon Madhav C, Nadkarni Girish, He John C, Kraft Monica, Jiang Xuejun, Zhang Xuewu, Kiryluk Krzysztof, Cherukuri Aravind, Lakkis Fadi G, Zhang Weiguo, Chen Shu-Hsia, Heeger Peter S, Zhang Weijia
Renal Division, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China.
Nat Med. 2025 May;31(5):1677-1687. doi: 10.1038/s41591-025-03568-z. Epub 2025 Mar 10.
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.
与其他种族和族裔人群相比，非裔美国（AA）肾移植受者的移植物丢失率更高，这凸显了识别致病因素的必要性。在此，在慢性移植物排斥基因组队列中，移植前血液RNA测序揭示了白细胞免疫球蛋白样受体B3（LILRB3）基因内四个连续错义单核苷酸多态性（SNP）组成的簇，与死亡审查的移植物丢失密切相关。这个SNP簇（命名为LILRB3 - 4SNPs）在靠近SHP1/2磷酸酶结合免疫受体酪氨酸抑制基序的氨基酸617 - 618处编码错义突变。LILRB3 - 4SNPs簇在AA个体中特异性富集，并且在多个移植队列的AA参与者中与死亡审查的移植物丢失和估计的肾小球滤过率下降密切相关。在两个大型生物样本库（BioMe和全民健康研究）中，LILRB3 - 4SNPs簇与终末期肾病的早期发病相关，并与载脂蛋白L1（APOL1）G1/G2等位基因协同作用以加速疾病进展。这些SNP也与AA个体中的多种免疫相关疾病有关。最后，在对血液和活检组织的多组学分析中，携带LILRB3 - 4SNPs的受者表现出炎症增强和单核细胞铁死亡。虽然需要更大规模的前瞻性研究，但我们的数据为肾移植结果的潜在遗传变异提供了见解。
