Polygenic Risk Scores and HLA Class II Variants are Biomarkers of Corticosteroid Response in Childhood Nephrotic Syndrome

IntroductionNephrotic 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. MethodsWe 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. ResultsA 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%. ConclusionsOur 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. Translational statementTo identify biomarkers of pattern of steroid responsiveness in childhood-onset nephrotic syndrome, we carried out a case-control study that included over 4,000 samples, including 994 patients with NS in the discovery phase and an additional 1,003 cases from two independent replication cohorts. We identified significant risk of steroid-sensitive NS (SSNS) at HLA class II genes and CLEC16A (a gene important in the regulation of T and B lymphocytes). The HLA haplotype DRB1*07:01[~]DQA1*02:01[~]DQB1*02:02 was associated with four-fold increased odds of SSNS. A model incorporating HLA haplotype, polygenic risk score, and age at onset of the disease was the best predictor of steroid responsiveness providing useful delineation of steroid sensitivity from steroid resistance. In conclusion, age at onset of disease, HLA class II variants and polygenic risk scores are useful biomarkers of corticosteroid response in childhood NS and may serve as useful clinical decision support tools to guide treatment. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=170 SRC="FIGDIR/small/25332825v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@486d1dorg.highwire.dtl.DTLVardef@f3b418org.highwire.dtl.DTLVardef@1b4b5fforg.highwire.dtl.DTLVardef@1187f60_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG