TY - UNPB
T1 - Polygenic Risk Scores and HLA Class II Variants are Biomarkers of Corticosteroid Response in Childhood Nephrotic Syndrome
AU - CureGN Consortium
AU - Tu, Tiffany
AU - Ochoa, Alejandro
AU - Sood, Amika
AU - Drabik, Ashley
AU - Chryst-Stangl, Megan
AU - Lane, Brandon
AU - Wu, Guanghong
AU - Donovan, Frank
AU - Harper, Ursula
AU - Chandrasekharappa, Settara
AU - Esezobor, Christopher
AU - Solarin, Adaobi
AU - Hooper, David
AU - Sethna, Christine
AU - Amaral, Sandra
AU - Kallash, Mahmoud
AU - Rheault, Michelle
AU - Verghese, Priya
AU - Dharnidharka, Vikas
AU - Salmon, Eloise
AU - Weng, Patricia
AU - Srivastava, Tarak
AU - Seifert, Michael E
AU - Pruette, Cozumel
AU - Selewski, David
AU - Gibson, Keisha
AU - Hunley, Tracy
AU - Bierzynska, Agnieszka
AU - Welsh, Gavin
AU - Saleem, Moin
AU - Gbadegesin, Rasheed
PY - 2025/8/7
Y1 - 2025/8/7
N2 - 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 currently no reliable predictors of therapy response at initial clinical presentation.METHODS: We conducted genome-wide association studies, developed polygenic risk scores (PRS) for therapy response and analyzed classical HLA alleles in 1,997 (994 discovery and 1,003 replication/validation cohorts) previously unstudied children with NS and 3,558 ancestry-matched controls.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 ~4 times the risk of developing SSNS. A model incorporating HLA haplotype, PRS score, and age at onset of the disease was the best predictor of steroid responsiveness with an AUC 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 and provide a foundation for more accurate diagnoses and tailored and individualized treatment.
AB - 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 currently no reliable predictors of therapy response at initial clinical presentation.METHODS: We conducted genome-wide association studies, developed polygenic risk scores (PRS) for therapy response and analyzed classical HLA alleles in 1,997 (994 discovery and 1,003 replication/validation cohorts) previously unstudied children with NS and 3,558 ancestry-matched controls.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 ~4 times the risk of developing SSNS. A model incorporating HLA haplotype, PRS score, and age at onset of the disease was the best predictor of steroid responsiveness with an AUC 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 and provide a foundation for more accurate diagnoses and tailored and individualized treatment.
U2 - 10.1101/2025.08.01.25332825
DO - 10.1101/2025.08.01.25332825
M3 - Preprint
C2 - 40970117
BT - Polygenic Risk Scores and HLA Class II Variants are Biomarkers of Corticosteroid Response in Childhood Nephrotic Syndrome
PB - medRxiv
ER -