This study first reveals that four consecutive missense SNPs in the LILRB3 gene (LILRB3-4SNPs) are significantly associated with kidney transplant failure in African Americans and demonstrates their synergistic acceleration of disease progression with APOL1 risk alleles. This genetic variant correlates with multiple immune-related disease susceptibilities and shows enhanced inflammation and ferroptosis in monocytes through multi-omics analysis.
Literature Overview
The article 'LILRB3 genetic variation is associated with kidney transplant failure in African American recipients', published in Nature Medicine, reviews LILRB3 genetic variants' association with graft dysfunction in African American transplant recipients. The research confirms the variant's high prevalence in African populations through multiple transplant cohorts and large biobanks, demonstrating its significant impact on graft survival and renal function decline.
Background Knowledge
African American kidney transplant recipients exhibit significantly higher graft failure rates compared to other populations, which is genetically determined. LILRB3, an immunoglobulin-like receptor family member, regulates immune cell function by binding SHP-1/2 to suppress TLR-induced inflammatory responses under normal conditions. The four consecutive missense SNPs (LILRB3-4SNPs) identified in this study locate near ITIM motifs, potentially disrupting SHP-1/2 binding and triggering immune activation and ferroptosis. Ferroptosis is an iron-dependent non-apoptotic cell death mechanism closely related to chronic kidney disease progression. The study further uncovers synergistic effects between this variant and APOL1 G1/G2 alleles, suggesting composite genetic risks in kidney disease progression. While previous studies investigated HLA and non-HLA region SNPs related to transplant failure, this study systematically demonstrates LILRB3's unique role in African Americans through RNA sequencing combined with multi-omics analysis. The findings provide new directions for genetic screening-based transplant prognosis evaluation and targeted interventions.
Research Methods and Experiments
The research team utilized pre-transplant blood RNA sequencing data from the GoCAR cohort (n=170) combined with SNP arrays and targeted DNA sequencing to identify allele expression fractions (AEF) associated with graft failure. They further validated findings across multiple transplant cohorts (SIRPA, CTOT19, VericiDx) and large biobanks (BioMe and All-of-Us). Multi-omics analysis included RNA sequencing, serum mass spectrometry, single-cell sequencing, and in vitro functional experiments.
Key Conclusions and Perspectives
Research Significance and Prospects
This study identifies a novel LILRB3 genetic variant specific to African Americans, providing a potential genetic biomarker for kidney transplant prognosis and intervention strategies. Future research should focus on mechanistic verification of the variant's binding capacity with SHP-1/2 and modeling its immune and ferroptotic phenotypes in animal models. The findings suggest ferroptosis inhibitors may represent potential therapeutic options for kidney transplant recipients carrying this variant.
Conclusion
Through comprehensive genomic and multi-omics analysis, this study systematically demonstrates that four consecutive missense SNPs in the LILRB3 gene (LILRB3-4SNPs) strongly correlate with transplant failure and renal function decline in African American kidney transplant recipients. The variant not only shows high prevalence in African populations but also synergizes with APOL1 alleles to accelerate end-stage renal disease progression. Mechanistically, the variant may enhance TLR-stimulated inflammatory and ferroptotic responses by weakening LILRB3-SHP-2 interactions. These findings establish a theoretical foundation for implementing genetic screening and targeted interventions in African American populations and suggest new directions for developing regulatory pathway therapeutics targeting ferroptosis-related mechanisms.
