TY - JOUR
T1 - Host genome-wide association study of infant susceptibility to Shigella-associated Diarrhea
AU - Duchen, Dylan
AU - Haque, Rashidul
AU - Chen, Laura
AU - Wojcik, Genevieve
AU - Korpe, Poonum
AU - Nayak, Uma
AU - Mentzer, Alexander J.
AU - Kirkpatrick, Beth
AU - Petri, William A.
AU - Duggal, Priya
N1 - Publisher Copyright:
Copyright © 2021 Duchen et al.
PY - 2021/6
Y1 - 2021/6
N2 - 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 (CT) 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 * 1028; odds ratio [OR], 0.43) and 8 (rs12550437, within the lincRNA RP11-115J16.1; P = 1.49 * 1027; OR, 0.48). Conditional analyses identified two previously suggestive loci, a protective locus on chromosome 7 (rs10266841, within the 39 untranslated region [UTR] of CYTH3; Pconditional = 1.48 * 1027; OR, 0.44) and a risk-associated locus on chromosome 10 (rs2801847, an intronic variant within MPP7; Pconditional = 8.37 * 1028; 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.
AB - 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 (CT) 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 * 1028; odds ratio [OR], 0.43) and 8 (rs12550437, within the lincRNA RP11-115J16.1; P = 1.49 * 1027; OR, 0.48). Conditional analyses identified two previously suggestive loci, a protective locus on chromosome 7 (rs10266841, within the 39 untranslated region [UTR] of CYTH3; Pconditional = 1.48 * 1027; OR, 0.44) and a risk-associated locus on chromosome 10 (rs2801847, an intronic variant within MPP7; Pconditional = 8.37 * 1028; 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.
KW - Diarrhea
KW - GWAS
KW - Shigella
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U2 - 10.1128/IAI.00012-21
DO - 10.1128/IAI.00012-21
M3 - Article
C2 - 33649051
AN - SCOPUS:85106266572
SN - 0019-9567
VL - 89
JO - Infection and immunity
JF - Infection and immunity
IS - 6
M1 - e00012
ER -