Genetic Identification of Two Novel Loci Associated with Steroid-Sensitive Nephrotic Syndrome

J Am Soc Nephrol. 2019 Aug;30(8):1375-1384. doi: 10.1681/ASN.2018101054. Epub 2019 Jul 1.

Abstract

Background: Steroid-sensitive nephrotic syndrome (SSNS), the most common form of nephrotic syndrome in childhood, is considered an autoimmune disease with an established classic HLA association. However, the precise etiology of the disease is unclear. In other autoimmune diseases, the identification of loci outside the classic HLA region by genome-wide association studies (GWAS) has provided critical insights into disease pathogenesis. Previously conducted GWAS of SSNS have not identified non-HLA loci achieving genome-wide significance.

Methods: In an attempt to identify additional loci associated with SSNS, we conducted a GWAS of a large cohort of European ancestry comprising 422 ethnically homogeneous pediatric patients and 5642 ethnically matched controls.

Results: The GWAS found three loci that achieved genome-wide significance, which explain approximately 14% of the genetic risk for SSNS. It confirmed the previously reported association with the HLA-DR/DQ region (lead single-nucleotide polymorphism [SNP] rs9273542, P=1.59×10-43; odds ratio [OR], 3.39; 95% confidence interval [95% CI], 2.86 to 4.03) and identified two additional loci outside the HLA region on chromosomes 4q13.3 and 6q22.1. The latter contains the calcium homeostasis modulator family member 6 gene CALHM6 (previously called FAM26F). CALHM6 is implicated in immune response modulation; the lead SNP (rs2637678, P=1.27×10-17; OR, 0.51; 95% CI, 0.44 to 0.60) exhibits strong expression quantitative trait loci effects, the risk allele being associated with lower lymphocytic expression of CALHM6.

Conclusions: Because CALHM6 is implicated in regulating the immune response to infection, this may provide an explanation for the typical triggering of SSNS onset by infections. Our results suggest that a genetically conferred risk of immune dysregulation may be a key component in the pathogenesis of SSNS.

Keywords: CALHM6; FAM26F; GWAS; HLA; SSNS.

Publication types

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

MeSH terms

  • Alleles
  • Androgen-Binding Protein / genetics
  • Calcium Channels / genetics*
  • Child
  • Databases, Factual
  • Epitopes / chemistry
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • HLA-DQ alpha-Chains / genetics
  • HLA-DQ beta-Chains / genetics
  • HLA-DRB1 Chains / genetics
  • Humans
  • Immune System
  • Male
  • Membrane Glycoproteins / genetics*
  • Nephrotic Syndrome / drug therapy
  • Nephrotic Syndrome / genetics*
  • Odds Ratio
  • Peptides / chemistry
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Steroids / therapeutic use*

Substances

  • Androgen-Binding Protein
  • CALHM6 protein, human
  • Calcium Channels
  • Epitopes
  • HLA-DQ alpha-Chains
  • HLA-DQ beta-Chains
  • HLA-DRB1 Chains
  • Membrane Glycoproteins
  • PARM-1 protein, human
  • Peptides
  • Steroids