Transethnic, Genome-Wide Analysis Reveals Immune-Related Risk Alleles and Phenotypic Correlates in Pediatric Steroid-Sensitive Nephrotic Syndrome

J Am Soc Nephrol. 2018 Jul;29(7):2000-2013. doi: 10.1681/ASN.2017111185. Epub 2018 Jun 14.

Abstract

Background Steroid-sensitive nephrotic syndrome (SSNS) is a childhood disease with unclear pathophysiology and genetic architecture. We investigated the genomic basis of SSNS in children recruited in Europe and the biopsy-based North American NEPTUNE cohort.Methods We performed three ancestry-matched, genome-wide association studies (GWAS) in 273 children with NS (Children Cohort Nephrosis and Virus [NEPHROVIR] cohort: 132 European, 56 African, and 85 Maghrebian) followed by independent replication in 112 European children, transethnic meta-analysis, and conditional analysis. GWAS alleles were used to perform glomerular cis-expression quantitative trait loci studies in 39 children in the NEPTUNE cohort and epidemiologic studies in GWAS and NEPTUNE (97 children) cohorts.Results Transethnic meta-analysis identified one SSNS-associated single-nucleotide polymorphism (SNP) rs1063348 in the 3' untranslated region of HLA-DQB1 (P=9.3×10-23). Conditional analysis identified two additional independent risk alleles upstream of HLA-DRB1 (rs28366266, P=3.7×10-11) and in the 3' untranslated region of BTNL2 (rs9348883, P=9.4×10-7) within introns of HCG23 and LOC101929163 These three risk alleles were independent of the risk haplotype DRB1*07:01-DQA1*02:01-DQB1*02:02 identified in European patients. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS. Increased burden of risk alleles across independent loci was associated with higher odds of SSNS, with younger age of onset across all cohorts, and with increased odds of complete remission across histologies in NEPTUNE children. rs1063348 associated with decreased glomerular expression of HLA-DRB1, HLA-DRB5, and HLA-DQB1.Conclusions Transethnic GWAS empowered discovery of three independent risk SNPs for pediatric SSNS. Characterization of these SNPs provide an entry for understanding immune dysregulation in NS and introducing a genomically defined classification.

Keywords: focal segmental glomerulosclerosis; gene expression; genetic renal disease; genome-wide association study; nephrotic syndrome; pediatrics.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Africa, Northern / ethnology
  • African Continental Ancestry Group / genetics
  • Alleles
  • Butyrophilins / genetics
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Cohort Studies
  • European Continental Ancestry Group / genetics
  • Female
  • France / ethnology
  • Genome-Wide Association Study
  • HLA-DQ Antigens / genetics*
  • HLA-DQ beta-Chains / genetics
  • HLA-DR Antigens / genetics*
  • HLA-DRB1 Chains / genetics
  • HLA-DRB5 Chains / genetics
  • Humans
  • Italy / ethnology
  • Male
  • Nephrotic Syndrome / drug therapy
  • Nephrotic Syndrome / ethnology*
  • Nephrotic Syndrome / genetics*
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Spain / ethnology
  • Steroids / therapeutic use*

Substances

  • BTNL2 protein, human
  • Butyrophilins
  • HLA-DQ Antigens
  • HLA-DQ beta-Chains
  • HLA-DQB1 antigen
  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • HLA-DRB5 Chains
  • Steroids