This study, through multi-omics analysis, first identifies the LILRB3-4SNPs variant in the LILRB3 gene as strongly associated with graft failure and kidney disease progression in African American transplant recipients. By enhancing inflammatory responses and monocyte ferroptosis, this variant provides a novel genetic target for clinical intervention.
Literature Overview
This article titled 'LILRB3 genetic variation is associated with kidney transplant failure in African American recipients', published in Nature Medicine, reviews the identification of four consecutive missense SNPs (LILRB3-4SNPs) in the LILRB3 gene through RNA sequencing, whole-exome sequencing, and multi-omics analysis. These variants show significant correlations with graft loss and renal function decline in African American kidney transplant recipients. Located near the ITIM domain, the variant may affect LILRB3 binding to SHP-1/2 phosphatases, thereby regulating inflammation and ferroptosis. The study further validates associations between this variant and risks of early end-stage renal disease (ESRD) and immune-related diseases in multiple independent cohorts.
Background Knowledge
LILRB3 (Leukocyte Immunoglobulin-Like Receptor B3) belongs to the immunoglobulin-like receptor family, primarily expressed in myeloid cells. It negatively regulates immune responses by binding and inhibiting SHP-1/2 phosphatases via its ITIM domain. Previous studies suggest roles in autoimmune and tumor immunity, but its function in kidney transplantation remains unclear. African Americans exhibit higher graft loss rates post-transplant, yet underlying genetic factors remain undefined. This study identifies LILRB3-4SNPs as an African American-specific variant through analysis of multiple transplant cohorts and biobanks. The variant may exacerbate transplant failure via enhanced inflammation and ferroptosis mechanisms, showing synergistic effects with APOL1 G1/G2 alleles to accelerate kidney disease progression. This discovery provides novel genetic biomarkers for personalized treatment of African American kidney disease patients.
Research Methods and Experiments
The research team conducted pre-transplant blood RNA sequencing in the GoCAR cohort to identify SNP clusters associated with graft loss. Using targeted DNA sequencing and whole-exome sequencing (WES), they confirmed the variant's enrichment in African Americans. Subsequent association analyses were performed across multiple transplant cohorts (SIRPA, CTOT19, VericiDx) and biobanks (BioMe, All-of-Us). Molecular mechanisms were elucidated through scRNA-seq, protein interaction modeling, and functional experiments including THP-1 cell overexpression and ferroptosis detection.
Key Conclusions and Perspectives
Research Significance and Prospects
This study establishes the first genetic link between LILRB3 variants and kidney transplant failure with systemic inflammation/ferroptosis mechanisms. It provides a genetic explanation for transplant failure disparities in African Americans and suggests ferroptosis inhibitors as potential therapeutic strategies. Future work should validate clinical impacts in larger prospective cohorts and develop animal models to investigate in vivo functions, laying foundations for precision medicine.
Conclusion
Through multi-cohort analysis and functional experiments, this study reveals the LILRB3-4SNPs four-SNP variant as a critical genetic risk factor in African Americans. It shows strong associations with transplant failure, eGFR decline, and accelerated ESRD progression, potentially through weakened LILRB3-SHP-1/2 binding that enhances inflammation and monocyte ferroptosis. The findings offer novel insights into genetic mechanisms underlying transplant failure in African Americans and suggest that targeting ferroptosis could improve clinical outcomes. Further molecular mechanism studies and functional validation in animal models are required to establish a basis for precision medicine interventions.
