Host Genome-Wide Association Study of Infant Susceptibility to -Associated Diarrhea.

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, exposure is ubiquitous while infection is heterogenous. To characterize host-genetic susceptibility to -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 -associated diarrhea ( = 143) and controls were infants with no -associated diarrhea in the first 13 months of life ( = 446). -associated diarrhea was identified via quantitative PCR (qPCR) threshold cycle ( ) distributions for the gene, carried by all four species and enteroinvasive Host GWAS were performed under an additive genetic model. A joint analysis identified protective loci on chromosomes 11 (rs582240, within the pseudogene; = 6.40 × 10; odds ratio [OR], 0.43) and 8 (rs12550437, within the lincRNA ; = 1.49 × 10; OR, 0.48). Conditional analyses identified two previously suggestive loci, a protective locus on chromosome 7 (rs10266841, within the 3' untranslated region [UTR] of ; = 1.48 × 10; OR, 0.44) and a risk-associated locus on chromosome 10 (rs2801847, an intronic variant within ; = 8.37 × 10; 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 -associated diarrhea may provide insight into vaccine and drug development efforts for -associated diarrheal disease.