1574. Polymorphisms in IL-1RN, GP1BA, TLR4, and B2M Genes May Confer Susceptibility to Hemolytic-Uremic Syndrome (HUS) after Shiga Toxin-Producing Escherichia coli Infection
Session: Poster Abstract Session: Microbial and Host Genetic Factors in Disease
Saturday, October 5, 2013
Room: The Moscone Center: Poster Hall C
Posters
  • FINALAKIDWeekPoster2013 8x42.pdf (445.0 kB)
  • Background: Hemolytic-uremic syndrome (HUS) following Shiga toxin-producing Escherichia coli (STEC) infection is a public health hazard for which no specific treatment exists. Underlying host immune dysregulation and inappropriate complement activation are implicated in non-STEC-related (atypical) HUS pathogenesis. Genomic factors predisposing individuals to HUS after STEC infection remain uncharacterized.

    Methods: Patients with culture-confirmed STEC diarrhea, identified through the CDC FoodNet surveillance system from 2007-2012, were enrolled in a genetic study. Thrombocytopenia, anemia, elevated serum creatinine, and red cell fragments defined confirmed HUS (all 4 criteria), and probable HUS (first 3); suspected HUS was defined as any other physician-diagnosed case. Genomic DNA from mouthwash samples was genotyped at candidate gene loci (previously linked to non-diarrheal HUS, complement-pathway- or immune-mediated renal or vascular injury). Genetic associations with HUS were evaluated by logistic regression, adjusting for age, sex, race, and antibiotic use.

    Results: Among 766 patients (mean age 28 years, 3% non-white, 60% female), 41 met laboratory criteria for probable HUS, 32 had confirmed HUS, and 87 had suspected HUS. Of 73 genes analyzed, 16 (related to cytokine signaling, extrinsic coagulation and complement pathways, platelet function, pathogen recognition, iron transport, endothelial function, and prostaglandin synthesis) were associated with development of HUS in multivariate-adjusted analyses (P<0.05). Three of 21 statistically significant SNPs (rs315951 in IL-1RN, rs121908064 in GP1BA, and rs4986791 in TLR4) were more significantly associated with one or more of confirmed, probable, and suspected HUS, including in race-stratified analyses [adjusted odds ratios (ORs) ranging from 0.4 (IL-1RN) to 27.4 (GP1BA), all P≤0.01]. B2M rs16966334 (OR range=3.9-5.2) and GP1BA rs121908064 (OR range=16.2-27.4) were associated with risk of HUS by all definitions (all P<0.05). 

    Conclusion: Polymorphisms in genes regulating key aspects of the innate immune response to bacterial infection (e.g., IL-1RN, GP1BA, TLR4, and B2M) may confer susceptibility to STEC-related HUS.  While the results of this exploratory genetic study require validation, they may suggest potential therapeutic targets.

    Asha R. Kallianpur, MD, MPH1, Yuki Bradford, Ph.D.2, Rajal K. Mody, MD, MPH3, Lana M. Olson, M.S.2, Katie N. Garman, M.P.H., C.H.E.S.4, Jeffrey A. Canter, M.D., M.P.H.2, Timothy F. Jones, MD4 and the Centers for Disease Control FoodNet STEC Genomics Study Group, (1)Genomic Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, (2)Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, TN, (3)Division of Foodborne, Waterborne, and Environmental Diseases, CDC, Atlanta, GA, (4)Tennessee Department of Health, Nashville, TN

    Disclosures:

    A. R. Kallianpur, None

    Y. Bradford, None

    R. K. Mody, None

    L. M. Olson, None

    K. N. Garman, None

    J. A. Canter, None

    T. F. Jones, None

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