Oral Presentation Australian Society for Microbiology Annual Scientific Meeting 2017

Role of CREM/ICER in Innate Immunity to Amebic Colitis (#113)

Bill Petri 1 , Genevieve L Wojcik 2 , Chelsea Marie 3 , Mayuresh M Abhyankar 3 , Nobuya Yoshida 4 , Koji Watanabe 3 , Josyf Mychaleckyj 5 , Beth D Kirkpatrick 6 , Stephen S Rich 5 , Patrick Concannon 7 , Rashidul Haque 8 , George C Tsokos 4 , Priva Duggal 9
  1. University of Virginia, Charlottesville, VA, United States
  2. Department of Genetics, Stanford University School of Medicine, Stanford, CA
  3. Department of Medicine: Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, VA
  4. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
  5. Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA
  6. University of Vermont College of Medicine and Vaccine Testing Center, Burlington, VT
  7. Genetics Institute and Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Florida, FL
  8. International Centre for Diarrheal Disease Research, Bangladesh
  9. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

To investigate possible genetic susceptibility to symptomatic Entamoeba histolytica infection in Bangladeshi infants, we conducted a genome-wide association study (GWAS) in two independent birth cohorts of symptomatic infection. Cases were defined as children with at least one diarrheal episode positive for amebiasis through either PCR or ELISA within the first year of life, while controls were children without any episodes in the same time frame (DBC: 65 cases, 309 controls; PROVIDE: 112 cases, 323 controls). The NIH Birth Cohort and the PROVIDE cohort were analyzed separately, using univariate logistic regression with an additive mode of inheritance. Results were meta-analyzed under a fixed-effects inverse variance weighting model. The top results were found within two neighboring genes on chromosome 10: CUL2 (cullin 2) and CREM (cAMP responsive element modulator). A total of 4 SNPs (single nucleotide polymorphisms) met genome-wide significance (P<5E-08) in the joint analysis. The top SNP was rs2148483 with a Pmeta of 6.48E-09, with additional risk allele at this locus conferred 2.3 times the odds of a symptomatic EH infection. This allele has previously been implicated as a susceptibility locus for Inflammatory Bowel Disease and Crohn’s Disease. These genetic associations reinforce the pathological similarities observed in gut inflammation between amebic infection and IBD. Mice genetically knocked out for CREM had increased susceptibility to amebiasis.  Further research will be directed to elucidate the underlying mechanisms for CREM-mediated protection from both amebic colitis and inflammatory bowel disease.