Search

To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR) =1.90) and TNFSF15 (rs6478109, P=2.54E-8, OR=0.72) regions achieved genome-wide significance and were replicated in Korean, South Asian and African populations. Trans-ethnic meta-analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1-KIRREL2 (P meta =6.71E-28, OR=1.88) and TNFSF15 (P meta =5.40E-11, OR=1.33) loci. Analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele specific expression with significantly lower expression of the transcript derived from the risk haplotype (Wilcox test p=9.3E-4). Because rare pathogenic variants in NPHS1 cause congenital nephrotic syndrome of the Finnish type (CNSF), the present study provides further evidence that variation along the allele frequency spectrum in the same gene can cause or contribute to both a rare monogenic disease (CNSF) and a more complex, polygenic disease (SSNS)., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Few data exist for the genetic variants underlying the risk for steroid-sensitive nephrotic syndrome (SSNS) in children. The objectives of this study were to evaluate HLA-DQA1 and APOL1 variants as risk factors for SSNS in African American children and use classic HLA antigen types and amino acid inference to refine the HLA-DQA1 association., Study Design: Case-control study., Setting & Participants: African American children with SSNS or steroid-resistant nephrotic syndrome (SRNS) were enrolled from Duke University and centers participating in the Midwest Pediatric Nephrology Consortium., Factor: Genetic variants in HLA-DQA1 (C34Y [rs1129740]; F41S [rs1071630]) and APOL1 high-risk alleles., Outcomes: SSNS and SRNS., Measurements: Direct sequencing for the HLA-DQA1 and APOL1 variants in 115 African American children (65 with SSNS and 50 with SRNS). Imputation of classic HLA alleles and amino acids was done in 363 South Asian children., Results: The 2 HLA-DQA1 variants were significantly associated with SSNS in African American children (C34Y: P=5.7 × 10 -11 ; OR, 3.53; 95% CI, 2.33-5.42; F41S: P=1.2 × 10 -13 ; OR, 4.08; 95% CI, 2.70-6.28), but not with SRNS (C34Y: P=0.6; F41S: P=0.2). APOL1 high-risk variants were not associated with SSNS (P=0.5) but showed significant associations with SRNS (P=1.04 × 10 -7 ; OR, 4.17; 95% CI, 2.23-7.64). HLA-DQA1*0201, HLA-DQB1*0201, and HLA-DRB1*0701 were the classic HLA alleles with the most significant associations with SSNS risk. The most significantly associated amino acid positions were HLA-DQα1 56 and 76 (both P=2.8 × 10 -7 ). Conditional analysis revealed that these variants most likely account for the observed association., Limitations: Modest sample size and limited statistical power to detect small to moderate effect sizes. Children studied may not be representative of all African American children in the United States., Conclusions: HLA-DQA1 is a risk locus for SSNS, but not SRNS, in African American children, consistent with its role in SSNS risk in children of European, Asian, and African ancestries. There is little evidence of a significant role for the APOL1 high-risk alleles in childhood SSNS in African American children. Refinement of the HLA-DQA1 association identified the critical classic HLA antigen types and amino acids of the HLA-DQ α1 molecule., (Copyright © 2017 National Kidney Foundation, Inc. All rights reserved.)

Background: The clinical course of steroid-sensitive nephrotic syndrome (SSNS) among Nigerian children has rarely been reported; this makes prognostication difficult., Objectives: The objective was to determine the frequency of relapses including frequent relapses (FR) and steroid-dependence (SD) in a cohort of Nigerian children with SSNS. A secondary objective was to identify clinical and demographic factors associated with relapse in these children., Methods: Medical records of children with SSNS in a Tertiary Hospital in Nigeria were reviewed. Children with onset of nephrotic syndrome (NS) at age <1-year, follow-up period <12 months and secondary causes of NS were excluded. The relapse status of each child was determined in the 1st and 2nd year after diagnosis and the proportions with no relapse, FR and SD were calculated., Results: Fifty children (68% males; median [range] age at onset of NS 4.8 [1.1-14.9] years) were followed-up for 31.1 (12.1-79.8) months. In the 1st and 2nd year of follow-up, 23 (46%) and 24 (70.6%) children experienced relapse, respectively. In the 1st-year, 0% and 10% had FR and SD while in the 2nd year 2.9% and 11.8% had FR and SD, respectively. Age at onset of NS, gender, time to first remission, serum creatinine or presence of hypertension or microscopic hematuria was not associated with 1st or 2nd year relapse., Conclusion: About half and two-thirds of children with NS in our center experience relapse in the 1st and 2nd year of follow-up, respectively; much fewer proportions experienced FR and SD in these periods. None of the commonly reported demographic and clinical factors was associated with NS relapse.