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

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

Asha R Kallianpur  1   2 , Yuki Bradford  3 , Rajal K Mody  4 , Katie N Garman  5 , Nicole Comstock  6 , Sarah L Lathrop  7 , Carol Lyons  8 , Amy Saupe  9 , Katie Wymore  10 , Jeffrey A Canter  11 , Lana M Olson  12 , Amanda Palmer  13 , Timothy F Jones  5
Affiliations

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

Asha R Kallianpur et al. J Infect Dis. .

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.

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Conflict of interest statement

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Study flow diagram, showing sample sizes available for genetic analyses. Suspected hemolytic-uremic syndrome (HUS) is defined as physician-diagnosed HUS. Probable HUS is defined as HUS that met 3 of 4 laboratory criteria, including thrombocytopenia, hemolytic anemia, and/or renal failure, in the setting of Shiga toxin–producing Escherichia coli (STEC) exposure. Confirmed HUS is defined as HUS that met all 4 laboratory criteria. CDC, Centers for Disease Control and Prevention; Ctrls, controls; MD, physician; QC, quality control; WGA, whole-genome amplification.
Figure 2.
Figure 2.
Manhattan plots showing single-nucleotide polymorphism (SNP) associations with specific postdiarrheal hemolytic-uremic syndrome (D+HUS) case definitions and outcomes in the Centers for Disease Control and Prevention–FoodNet Shiga toxin–producing Escherichia coli study. A, Suspected, probable, or confirmed D+HUS (outcome 1). B, Probable or confirmed D+HUS (outcome 2). C, Confirmed D+HUS (outcome 3).
See this image and copyright information in PMC

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