HLA-DQA1 and APOL1 as Risk Loci for Childhood-Onset Steroid-Sensitive and Steroid-Resistant Nephrotic Syndrome

• Type of Material: Article
• Authors: Adebowale Adeyemo, National Human Genome Research Institute; Christopher Esezobor, Lagos University Teaching Hospital; Adaobi Solarin, Lagos State University Teaching Hospital; Asiri Abeyagunawardena, University of Peradeniya; Jameela A. Kari, King Abdulaziz University; Sherif El Desoky, King Abdulaziz University; Larry Greenbaum, Emory University; Margret Kamel, Emory University; Mahmoud Kallash, SUNY Buffalo; Cynthia Silva, Connecticut Children's Hospital; Alex Young, Duke University; Tracey E. Hunley, Vanderbilt University; Nilka de Jesus-Gonzalez, University of Puerto Rico; Tarak Srivastava, Children Mercy Hospital; Rasheed Gbadegesin, Duke University
• Language: English
• Date: 2018-03-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 National Kidney Foundation, Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1053/j.ajkd.2017.10.013
• Title of Journal or Parent Work: American Journal of Kidney Diseases
• ISSN: 0272-6386
• Volume: 71
• Issue: 3
• Start Page: 399
• End Page: 406
• Grant/Funding Information: Dr Gbadegesin received funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) (5R01DK098135 and 5R01DK094987).; We acknowledge support from the Renal Genomics Core (Core B) of the Duke O’Brien Center for Kidney Research supported by theNIDDK/NIH (award P30DK096493).; This study was supported in part by the Doris Duke Charitable Foundation DDCSD award to Dr Gbadegesin.; Dr Adeyemo is supported by the Intramural Research Program of the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by funds from the Office of the Director, NIDDK, and National Human Genome Research Institute at the NIH (Z01HG200362).; Molecular graphics and analyses were performed with the UCSF Chimera package. Chimera is developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by National Institute of General Medical Sciences P41-GM103311).
• Keywords: VARIANTS; Urology & Nephrology; ALLELES; AFRICAN-AMERICANS; Science & Technology; REGION; RENAL-DISEASE; Life Sciences & Biomedicine; ASIANS; NEPHROPATHY; CHILDREN; ASSOCIATION; CHRONIC KIDNEY-DISEASE
• Research Categories: Biology, Genetics; Health Sciences, General

Abstract

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.