Genetic Susceptibility to Postdiarrheal Hemolytic-Uremic Syndrome After Shiga Toxin-Producing Escherichia coli Infection: A Centers for Disease Control and Prevention FoodNet Study

J Infect Dis. 2018 Mar 5;217(6):1000-1010. doi: 10.1093/infdis/jix633.

Abstract

Background: Postdiarrheal hemolytic-uremic syndrome (D+HUS) following Shiga toxin-producing Escherichia coli (STEC) infection is a serious condition lacking specific treatment. Host immune dysregulation and genetic susceptibility to complement hyperactivation are implicated in non-STEC-related HUS. However, genetic susceptibility to D+HUS remains largely uncharacterized.

Methods: Patients with culture-confirmed STEC diarrhea, identified through the Centers for Disease Control and Prevention FoodNet surveillance system (2007-2012), were serotyped and classified by laboratory and/or clinical criteria as having suspected, probable, or confirmed D+HUS or as controls and underwent genotyping at 200 loci linked to nondiarrheal HUS or similar pathologies. Genetic associations with D+HUS were explored by multivariable regression, with adjustment for known risk factors.

Results: Of 641 enrollees with STEC O157:H7, 80 had suspected D+HUS (41 with probable and 32 with confirmed D+HUS). Twelve genes related to cytokine signaling, complement pathways, platelet function, pathogen recognition, iron transport, and endothelial function were associated with D+HUS in multivariable-adjusted analyses (P ≤ .05). Of 12 significant single-nucleotide polymorphisms (SNPs), 5 were associated with all levels of D+HUS (intergenic SNP rs10874639, TFRC rs3804141, EDN1 rs5370, GP1BA rs121908064, and B2M rs16966334), and 7 SNPs (6 non-complement related) were associated with confirmed D+HUS (all P < .05).

Conclusions: Polymorphisms in many non-complement-related genes may contribute to D+HUS susceptibility. These results require replication, but they suggest novel therapeutic targets in patients with D+HUS.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Centers for Disease Control and Prevention, U.S.*
  • Child
  • Child, Preschool
  • Diarrhea / complications
  • Diarrhea / microbiology
  • Escherichia coli Infections / complications*
  • Escherichia coli Infections / microbiology*
  • Female
  • Genetic Predisposition to Disease*
  • Hemolytic-Uremic Syndrome / genetics*
  • Hemolytic-Uremic Syndrome / pathology
  • Humans
  • Male
  • Risk Factors
  • Shiga-Toxigenic Escherichia coli / pathogenicity*
  • United States