Article
作者: Harper, Ursula ; Salmon, Eloise ; Tu, Tiffany ; Sood, Amika ; Bierzynska, Agnieszka ; Adeyemo, Adebowale ; Hunley, Tracy ; Ochoa, Alejandro ; Kallash, Mahmoud ; Chandrasekharappa, Settara ; Kiryluk, Krzysztof ; Dharnidharka, Vikas ; Solarin, Adaobi ; Sanna-Cherchi, Simone ; Esezobor, Christopher ; Gharavi, Ali ; Dabrik, Ashley ; Weng, Patricia ; Rheault, Michelle ; Koziell, Ania ; Chan, Cliburn ; Lane, Brandon ; Seifert, Michael E ; Sinha, Aditi ; Chambers, Eileen ; Bagga, Arvind ; Wu, Guanghong ; Guay-Woodford, Lisa ; Sethna, Christine ; Gibson, Keisha ; Thalgahagoda, Shenal ; Pruette, Cozumel ; Amaral, Sandra ; Saleem, Moin ; Hooper, David ; Verghese, Priya ; Jackson, Annette ; Rotimi, Charles ; Welsh, Gavin ; Webb, Nicholas ; Kretzler, Matthias ; Srivastava, Tarak ; Chryst-Stangl, Megan ; Greenbaum, Larry ; Abeyagunawardena, Asiri ; Selewski, David ; Gbadegesin, Rasheed ; Donovan, Frank
INTRODUCTION:Nephrotic syndrome (NS), a common glomerular disease in children, is classified based on response to corticosteroid therapy as either steroid-sensitive nephrotic syndrome (SSNS), or steroid-resistant nephrotic syndrome (SRNS). However, there are no current reliable predictors of therapy response at initial clinical presentation.
METHODS:To evaluate predictors, we conducted genome-wide association studies, developed polygenic risk scores (PRS) for therapy response and analyzed classical HLA alleles in 1,997 children (994 discovery and 1,003 replication/validation cohorts) previously unstudied children with NS and 3,558 ancestry-matched control individuals.
RESULTS:A significant association with HLA loci defined by variants in HLA-DQB1, HLA-DRB1, and HLA-DQA1 were found for SSNS (but not SRNS), along with a second immune-related SSNS locus: CLEC16A. A PRS that discriminates between SSNS and SRNS was validated in two independent cohorts. The HLA haplotype HLA- DRB1∗07:01∼DQA1∗02:01∼DQB1∗02:02 was associated with about four times the risk of developing SSNS. A model incorporating HLA haplotype, PRS score, and age at disease onset was the best predictor of steroid responsiveness with an area under the curve of 0.68-0.70 and an overall classification accuracy of SSNS versus SRNS of 67-71%.
CONCLUSIONS:Our findings confirm that SSNS, unlike SRNS, is an immune-mediated HLA-associated disorder. The PRS for therapy response and HLA haplotype can serve as biomarkers, provide a foundation for more accurate diagnoses and tailored individualized treatment.