HLA-DQA1 and PLCG2 are candidate risk loci for childhood-onset steroid-sensitive nephrotic syndrome

Rasheed A. Gbadegesin, Adebowale Adeyemo, Nicholas J A Webb, Larry A. Greenbaum, Asiri Abeyagunawardena, Shenal Thalgahagoda, Arundhati Kale, Debbie Gipson, Tarak Srivastava, Jen Jar Lin, Deepa Chand, Tracy E. Hunley, Patrick D. Brophy, Arvind Bagga, Aditi Sinha, Michelle N. Rheault, Joanna Ghali, Kathy Nicholls, Elizabeth Abraham, Halima S. JanjuaAbiodun Omoloja, Gina Marie Barletta, Yi Cai, David D. Milford, Catherine O'Brien, Atif Awan, Vladimir Belostotsky, William E. Smoyer, Alison Homstad, Gentzon Hall, Guanghong Wu, Shashi Nagaraj, Delbert Wigfall, John Foreman, Michelle P. Winn

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Abstract

Steroid-sensitive nephrotic syndrome(SSNS) accounts for.80%of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS.We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants thatwere tested (odds ratio, 2.11; 95%confidence interval, 1.56 to 2.86; P=1.6831026 (Fisher exact test). Two of these SNPs-the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1-were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and 589 controls; P=1.42310217). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.82531025). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS.

Original languageEnglish
Pages (from-to)1701-1710
Number of pages10
JournalJournal of the American Society of Nephrology
Volume26
Issue number7
DOIs
Publication statusPublished - 1 Jul 2015
Externally publishedYes

Cite this

Gbadegesin, R. A., Adeyemo, A., Webb, N. J. A., Greenbaum, L. A., Abeyagunawardena, A., Thalgahagoda, S., Kale, A., Gipson, D., Srivastava, T., Lin, J. J., Chand, D., Hunley, T. E., Brophy, P. D., Bagga, A., Sinha, A., Rheault, M. N., Ghali, J., Nicholls, K., Abraham, E., ... Winn, M. P. (2015). HLA-DQA1 and PLCG2 are candidate risk loci for childhood-onset steroid-sensitive nephrotic syndrome. Journal of the American Society of Nephrology, 26(7), 1701-1710. https://doi.org/10.1681/ASN.2014030247