Open AccessHost Genome-Wide Association Study of Infant Susceptibility toShigella-Associated Diarrhea
Author(s) -
Dylan Duchen,
Rashidul Haque,
Laura Chen,
Genevieve L. Wojcik,
Poonum Korpe,
Uma Nayak,
Alexander J. Mentzer,
Beth D. Kirkpatrick,
William A. Petri,
Priya Duggal
Publication year - 2021
Publication title -
infection and immunity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.508
H-Index - 220
eISSN - 1070-6313
pISSN - 0019-9567
DOI - 10.1128/iai.00012-21
Subject(s) - shigellosis , shigella , diarrhea , biology , diarrheal disease , bacillary dysentery , dysentery , diarrheal diseases , microbiology and biotechnology , shigella flexneri , virology , immunology , medicine , salmonella , bacteria , genetics , escherichia coli , gene
Shigella is a leading cause of moderate-to-severe diarrhea globally and the causative agent of shigellosis and bacillary dysentery. Associated with 80 to 165 million cases of diarrhea and >13% of diarrheal deaths, in many regions, Shigella exposure is ubiquitous while infection is heterogenous. To characterize host-genetic susceptibility to Shigella -associated diarrhea, we performed two independent genome-wide association studies (GWAS) including Bangladeshi infants from the PROVIDE and CBC birth cohorts in Dhaka, Bangladesh. Cases were infants with Shigella -associated diarrhea ( n = 143) and controls were infants with no Shigella -associated diarrhea in the first 13 months of life ( n = 446). Shigella -associated diarrhea was identified via quantitative PCR (qPCR) threshold cycle ( C T ) distributions for the ipaH gene, carried by all four Shigella species and enteroinvasive Escherichia coli . Host GWAS were performed under an additive genetic model. A joint analysis identified protective loci on chromosomes 11 (rs582240, within the KRT18P59 pseudogene; P = 6.40 × 10 −8 ; odds ratio [OR], 0.43) and 8 (rs12550437, within the lincRNA RP11-115J16.1 ; P = 1.49 × 10 −7 ; OR, 0.48). Conditional analyses identified two previously suggestive loci, a protective locus on chromosome 7 (rs10266841, within the 3′ untranslated region [UTR] of CYTH3 ; P conditional = 1.48 × 10 −7 ; OR, 0.44) and a risk-associated locus on chromosome 10 (rs2801847, an intronic variant within MPP7 ; P conditional = 8.37 × 10 −8 ; OR, 5.51). These loci have all been indirectly linked to bacterial type 3 secretion system (T3SS) activity, its components, and bacterial effectors delivered into host cells. Host genetic factors that may affect bacterial T3SS activity and are associated with the host response to Shigella -associated diarrhea may provide insight into vaccine and drug development efforts for Shigella -associated diarrheal disease.