Paediatrics- Scholarly Publications
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Browsing Paediatrics- Scholarly Publications by Author "Abeyagunawardena, A."
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- ItemOpen AccessGenetic Testing for Steroid-Resistant-Nephrotic Syndrome in an Outbred Population(Frontiers, 2018) Varner, J.; Chryst-Stangl, M.; Esezobor, C.; Solarin, A.; Wu, G.; Lane, B.; Hall, G.; Abeyagunawardena, A.; Matory, A.; Hunley, T.; Lin, J.; Howell, D.; Gbadegesin, R.Background: Steroid-resistant nephrotic syndrome (SRNS) is a leading cause of end-stage kidney disease in children and young adults. Despite advances in genomic science that have led to the discovery of >50 monogenic causes of SRNS, there are no clear guidelines for genetic testing in clinical practice. Methods: Using high throughput sequencing, we evaluated 492 individuals from 181 families for mutations in 40 known SRNS genes. Causative mutations were defined as missense, truncating, and obligatory splice site variants with a minor allele frequency <1% in controls. Non-synonymous variants were considered pathogenic if determined to be deleterious by at least two in silico models. We further evaluated for differences in age at disease onset, family history of SRNS or chronic kidney disease, race, sex, renal biopsy findings, and extra-renal manifestations in subgroups with and without disease causing variants. Results: We identified causative variants in 40 of 181 families (22.1%) with SRNS. Variants in INF2, COL4A3, and WT1 were the most common, accounting for over half of all causative variants. Causative variants were identified in 34 of 86 families (39.5%) with familial disease and 6 of 95 individuals (6.3%) with sporadic disease (2 p < 0.00001). Family history was the only significant clinical predictor of genetic SRNS. Conclusion: We identified causative mutations in almost 40% of all families with hereditary SRNS and 6% of individuals with sporadic disease, making family history the single most important clinical predictors of monogenic SRNS. We recommend genetic testing in all patients with SRNS and a positive family history, but only selective testing in those with sporadic disease.
- ItemOpen AccessHLA-DQA1 and APOL1 as Risk Loci for Childhood-Onset Steroid-Sensitive and Steroid-Resistant Nephrotic Syndrome.(Elsevier Inc, 2018) Adeyemo, A.; Esezobor, C.; Solarin, A.; Abeyagunawardena, A.; Kari, J.; El Desoky, S.; Greenbaum, L.; Kallash, M.; Silva, C.; Young, A.; Hunley, T.; de Jesus-Gonzalez, N.; Srivastava, T.; Gbadegesin, R.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 HLADQA1 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 HLADQA1 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, HLADQB1* 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.