Host genome wide association study of infant susceptibility to Shigella-associated diarrhea.

<i>Shigella</i> is a leading cause of moderate-to-severe diarrhea globally and the causative agent of shigellosis and bacillary dysentery. Associated with 80-165 million cases of diarrhea and over 13% of diarrheal deaths, in many regions <i>Shigella</i> exposure is ubiquitous while infection is heterogenous. To characterize host-genetic susceptibility to <i>Shigella</i>-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 <i>Shigella</i>-associated diarrhea (n=143) and controls were infants with no <i>Shigella</i>-associated diarrhea in the first 13 months of life (n=446). <i>Shigella</i>-associated diarrhea was identified via qPCR Ct distributions for the ipaH gene, carried by all four <i>Shigella</i> species and enteroinvasive <i>Escherichia coli</i> Host GWAS were performed under an additive genetic model. A joint analysis identified protective loci on chromosomes 11 (rs582240, within the <i>KRT18P59</i> pseudogene, P=6.40x10^-8, OR=0.43) and 8 (rs12550437, within the lincRNA <i>RP11-115J16.1</i>, P=1.49x10^-7, OR=0.48). Conditional analyses identified two previously suggestive loci, a protective locus on chromosome 7 (rs10266841, within the 3'-UTR of <i>CYTH3</i>, P_conditional=1.48x10^-7, OR=0.44) and a risk-associated locus on chromosome 10 (rs2801847, an intronic variant within <i>MPP7</i>, P_conditional=8.37x10^-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 <i>Shigella</i>-associated diarrhea may provide insight into vaccine and drug development efforts for <i>Shigella</i>-associated diarrheal disease.