Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome

Kidney Int. 2020 Nov;98(5):1308-1322. doi: 10.1016/j.kint.2020.05.029. Epub 2020 Jun 14.

Abstract

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 (Pmeta=6.71E-28, OR=1.88) and TNFSF15 (Pmeta=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).

Keywords: glomerulus; nephrotic syndrome; pediatric nephrology; podocyte.

Publication types

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

MeSH terms

  • Alleles
  • Child
  • Genome-Wide Association Study
  • Haplotypes
  • Humans
  • Membrane Proteins
  • Mutation
  • Nephrotic Syndrome* / drug therapy
  • Nephrotic Syndrome* / genetics
  • Steroids
  • Tumor Necrosis Factor Ligand Superfamily Member 15 / genetics

Substances

  • Membrane Proteins
  • Steroids
  • TNFSF15 protein, human
  • Tumor Necrosis Factor Ligand Superfamily Member 15
  • nephrin