Genome-Wide Association Study Reveals Genetic Link between Diarrhea-Associated <named-content content-type="genus-species">Entamoeba histolytica</named-content> Infection and Inflammatory Bowel Disease
ABSTRACT Entamoeba histolytica is the etiologic agent of amebic dysentery, though clinical manifestation of infection is highly variable ranging from subclinical colonization to invasive disease. We hypothesize that host genetics contribute to the variable outcomes of E. histolytica infection; thus,...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2018-11-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.01668-18 |
| _version_ | 1818434474545774592 |
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| author | Genevieve L. Wojcik Chelsea Marie Mayuresh M. Abhyankar Nobuya Yoshida Koji Watanabe Alexander J. Mentzer Tommy Carstensen Josyf Mychaleckyj Beth D. Kirkpatrick Stephen S. Rich Patrick Concannon Rashidul Haque George C. Tsokos William A. Petri Priya Duggal |
| author_facet | Genevieve L. Wojcik Chelsea Marie Mayuresh M. Abhyankar Nobuya Yoshida Koji Watanabe Alexander J. Mentzer Tommy Carstensen Josyf Mychaleckyj Beth D. Kirkpatrick Stephen S. Rich Patrick Concannon Rashidul Haque George C. Tsokos William A. Petri Priya Duggal |
| author_sort | Genevieve L. Wojcik |
| collection | DOAJ |
| description | ABSTRACT Entamoeba histolytica is the etiologic agent of amebic dysentery, though clinical manifestation of infection is highly variable ranging from subclinical colonization to invasive disease. We hypothesize that host genetics contribute to the variable outcomes of E. histolytica infection; thus, we conducted a genome-wide association study (GWAS) in two independent birth cohorts of Bangladeshi infants monitored for susceptibility to E. histolytica disease in the first year of life. Children with at least one diarrheal episode positive for E. histolytica (cases) were compared to children with no detectable E. histolytica infection in the same time frame (controls). Meta-analyses under a fixed-effect inverse variance weighting model identified multiple variants in a region of chromosome 10 containing loci associated with symptomatic E. histolytica infection. An intergenic insertion between CREM and CCNY (rs58000832) achieved genome-wide significance (P value from meta-analysis [Pmeta] = 6.05 × 10−9), and each additional risk allele of rs58000832 conferred 2.42 increased odds of a diarrhea-associated E. histolytica infection. The most strongly associated single nucleotide polymorphism (SNP) within a gene was in an intron of CREM (rs58468612; Pmeta = 8.94 × 10−8), which has been implicated as a susceptibility locus for inflammatory bowel disease (IBD). Gene expression resources suggest associated loci are related to the lower expression of CREM. Increased CREM expression is also observed in early E. histolytica infection. Further, CREM−/− mice were more susceptible to E. histolytica amebic colitis. These genetic associations reinforce the pathological similarities observed in gut inflammation between E. histolytica infection and IBD. IMPORTANCE Diarrhea is the second leading cause of death for children globally, causing 760,000 deaths each year in children less than 5 years old. Amebic dysentery contributes significantly to this burden, especially in developing countries. The identification of host factors that control or enable enteric pathogens has the potential to transform our understanding of disease predisposition, outcomes, and treatments. Our discovery of the transcriptional regulator cAMP-responsive element modulator (CREM) as a genetic modifier of susceptibility to amebic disease has implications for understanding the pathogenesis of other diarrheal infections. Further, emerging evidence for CREM in IBD susceptibility suggests that CREM is a critical regulator of enteric inflammation and may have broad therapeutic potential as a drug target across intestinal inflammatory diseases. |
| first_indexed | 2024-12-14T16:37:34Z |
| format | Article |
| id | doaj.art-30e31e72edca45648e51806ad021ee46 |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-14T16:37:34Z |
| publishDate | 2018-11-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-30e31e72edca45648e51806ad021ee462022-12-21T22:54:24ZengAmerican Society for MicrobiologymBio2150-75112018-11-019510.1128/mBio.01668-18Genome-Wide Association Study Reveals Genetic Link between Diarrhea-Associated <named-content content-type="genus-species">Entamoeba histolytica</named-content> Infection and Inflammatory Bowel DiseaseGenevieve L. Wojcik0Chelsea Marie1Mayuresh M. Abhyankar2Nobuya Yoshida3Koji Watanabe4Alexander J. Mentzer5Tommy Carstensen6Josyf Mychaleckyj7Beth D. Kirkpatrick8Stephen S. Rich9Patrick Concannon10Rashidul Haque11George C. Tsokos12William A. Petri13Priya Duggal14Department of Genetics, Stanford University School of Medicine, Stanford, California, USADivision of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USADivision of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USADepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USADivision of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USANuffield Department of Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United KingdomWellcome Trust Sanger Institute, Genome Campus, Oxford, United KingdomDepartment of Public Health Sciences, Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, Virginia, USAVaccine Testing Center, University of Vermont College of Medicine, Burlington, Vermont, USADepartment of Public Health Sciences, Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, Virginia, USAGenetics Institute and Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, USAInternational Centre for Diarrheal Disease Research, Dhaka, BangladeshDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USADivision of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USADepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USAABSTRACT Entamoeba histolytica is the etiologic agent of amebic dysentery, though clinical manifestation of infection is highly variable ranging from subclinical colonization to invasive disease. We hypothesize that host genetics contribute to the variable outcomes of E. histolytica infection; thus, we conducted a genome-wide association study (GWAS) in two independent birth cohorts of Bangladeshi infants monitored for susceptibility to E. histolytica disease in the first year of life. Children with at least one diarrheal episode positive for E. histolytica (cases) were compared to children with no detectable E. histolytica infection in the same time frame (controls). Meta-analyses under a fixed-effect inverse variance weighting model identified multiple variants in a region of chromosome 10 containing loci associated with symptomatic E. histolytica infection. An intergenic insertion between CREM and CCNY (rs58000832) achieved genome-wide significance (P value from meta-analysis [Pmeta] = 6.05 × 10−9), and each additional risk allele of rs58000832 conferred 2.42 increased odds of a diarrhea-associated E. histolytica infection. The most strongly associated single nucleotide polymorphism (SNP) within a gene was in an intron of CREM (rs58468612; Pmeta = 8.94 × 10−8), which has been implicated as a susceptibility locus for inflammatory bowel disease (IBD). Gene expression resources suggest associated loci are related to the lower expression of CREM. Increased CREM expression is also observed in early E. histolytica infection. Further, CREM−/− mice were more susceptible to E. histolytica amebic colitis. These genetic associations reinforce the pathological similarities observed in gut inflammation between E. histolytica infection and IBD. IMPORTANCE Diarrhea is the second leading cause of death for children globally, causing 760,000 deaths each year in children less than 5 years old. Amebic dysentery contributes significantly to this burden, especially in developing countries. The identification of host factors that control or enable enteric pathogens has the potential to transform our understanding of disease predisposition, outcomes, and treatments. Our discovery of the transcriptional regulator cAMP-responsive element modulator (CREM) as a genetic modifier of susceptibility to amebic disease has implications for understanding the pathogenesis of other diarrheal infections. Further, emerging evidence for CREM in IBD susceptibility suggests that CREM is a critical regulator of enteric inflammation and may have broad therapeutic potential as a drug target across intestinal inflammatory diseases.https://journals.asm.org/doi/10.1128/mBio.01668-18diarrheaepidemiologygenomicsinfectious diseaseprotozoapublic health |
| spellingShingle | Genevieve L. Wojcik Chelsea Marie Mayuresh M. Abhyankar Nobuya Yoshida Koji Watanabe Alexander J. Mentzer Tommy Carstensen Josyf Mychaleckyj Beth D. Kirkpatrick Stephen S. Rich Patrick Concannon Rashidul Haque George C. Tsokos William A. Petri Priya Duggal Genome-Wide Association Study Reveals Genetic Link between Diarrhea-Associated <named-content content-type="genus-species">Entamoeba histolytica</named-content> Infection and Inflammatory Bowel Disease mBio diarrhea epidemiology genomics infectious disease protozoa public health |
| title | Genome-Wide Association Study Reveals Genetic Link between Diarrhea-Associated <named-content content-type="genus-species">Entamoeba histolytica</named-content> Infection and Inflammatory Bowel Disease |
| title_full | Genome-Wide Association Study Reveals Genetic Link between Diarrhea-Associated <named-content content-type="genus-species">Entamoeba histolytica</named-content> Infection and Inflammatory Bowel Disease |
| title_fullStr | Genome-Wide Association Study Reveals Genetic Link between Diarrhea-Associated <named-content content-type="genus-species">Entamoeba histolytica</named-content> Infection and Inflammatory Bowel Disease |
| title_full_unstemmed | Genome-Wide Association Study Reveals Genetic Link between Diarrhea-Associated <named-content content-type="genus-species">Entamoeba histolytica</named-content> Infection and Inflammatory Bowel Disease |
| title_short | Genome-Wide Association Study Reveals Genetic Link between Diarrhea-Associated <named-content content-type="genus-species">Entamoeba histolytica</named-content> Infection and Inflammatory Bowel Disease |
| title_sort | genome wide association study reveals genetic link between diarrhea associated named content content type genus species entamoeba histolytica named content infection and inflammatory bowel disease |
| topic | diarrhea epidemiology genomics infectious disease protozoa public health |
| url | https://journals.asm.org/doi/10.1128/mBio.01668-18 |
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