scholarly journals Genome-wide association study reveals genetic link between diarrhea-associated Entamoeba histolytica infection and inflammatory bowel disease

2017 ◽  
Author(s):  
Genevieve L Wojcik ◽  
Chelsea Marie ◽  
Mayuresh M Abhyankar ◽  
Nobuya Yoshida ◽  
Koji Watanabe ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Association Study ◽  
Entamoeba Histolytica ◽  
Bowel Disease ◽  
Fixed Effects ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome ◽  
Inflammatory Bowel

AbstractDiarrhea is the second leading cause of death for children globally, causing 760,000 deaths each year in children under the age of 5. Amoebic dysentery contributes significantly to this burden, especially in developing countries. We hypothesize that genetic variation contributes to susceptibility to diarrhea-associated Entamoeba histolytica infection in Bangladeshi infants; thus, we conducted a genome-wide association study (GWAS) in two independent birth cohorts of diarrhea-associated E. histolytica infection. Cases were defined as children with at least one diarrheal episode positive for E. histolytica through either PCR or ELISA within the first year of life. Controls were children without any episodes positive for E. histolytica in the same time frame. Meta-analyses under a fixed-effects inverse variance weighting model identified variants in two neighboring genes on chromosome 10: CUL2 (cullin 2) and CREM (cAMP responsive element modulator) associated with E. histolytica infection, with SNP rs58000832 achieving genome-wide significance (Pmeta=4.2x10−10). Each additional risk allele (an intergenic insertion between CREM and CCNY) of rs58000832 conferred 2.5 increased odds of a diarrhea-associated E. histolytica infection. The most associated SNP within a gene was in an intron of CREM (rs58468685, Pmeta=2.3x10−9), which with CUL2, has been implicated as a susceptibility locus for Inflammatory Bowel Disease (IBD) and Crohn’s Disease. Gene expression resources suggest these loci are related to the higher expression of CREM, but not CUL2. 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.

scholarly journals Genome-Wide Association Study Reveals Genetic Link between Diarrhea-Associated Entamoeba histolytica Infection and Inflammatory Bowel Disease

mBio ◽  
2018 ◽  
Vol 9 (5) ◽  
Author(s):  
Genevieve L. Wojcik ◽  
Chelsea Marie ◽  
Mayuresh M. Abhyankar ◽  
Nobuya Yoshida ◽  
Koji Watanabe ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Association Study ◽  
Entamoeba Histolytica ◽  
Bowel Disease ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Content Type ◽  
Amebic Dysentery ◽  
Genome Wide ◽  
Inflammatory Bowel

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.

scholarly journals A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene

Science ◽  
2006 ◽  
Vol 314 (5804) ◽  
pp. 1461-1463 ◽  
Author(s):  
R. H. Duerr ◽  
K. D. Taylor ◽  
S. R. Brant ◽  
J. D. Rioux ◽  
M. S. Silverberg ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Association Study ◽  
Bowel Disease ◽  
Genome Wide Association Study ◽  
Disease Gene ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome ◽  
Inflammatory Bowel

scholarly journals Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

2016 ◽  
Author(s):  
Katrina M. de Lange ◽  
Loukas Moutsianas ◽  
James C. Lee ◽  
Christopher A. Lamb ◽  
Yang Luo ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Association Study ◽  
Bowel Disease ◽  
Genome Wide Association Study ◽  
Negative Regulator ◽  
Genome Wide Association ◽  
Primary Immune Deficiency ◽  
Genome Wide ◽  
A Genome ◽  
Inflammatory Bowel

Genetic association studies have identified 210 risk loci for inflammatory bowel disease1–7, which have revealed fundamental aspects of the molecular biology of the disease, including the roles of autophagy and Th17 cell signaling and development. We performed a genome-wide association study of 25,305 individuals, and meta-analyzed with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 26 new genome-wide significant loci, three of which contain integrin genes that encode molecules in pathways identified as important therapeutic targets in inflammatory bowel disease. The associated variants are also correlated with expression changes in response to immune stimulus at two of these genes (ITGA4, ITGB8) and at two previously implicated integrin loci (ITGAL, ICAM1). In all four cases, the stimulus-dependent expression increasing allele also increases disease risk. We applied summary statistic fine-mapping and identified likely causal missense variants in the primary immune deficiency gene PLCG2 and the negative regulator of inflammation, SLAMF8. Our results demonstrate that new common variant associations continue to identify genes and pathways of relevance to therapeutic target identification and prioritization.

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