Host genetic susceptibility to severe diarrhea: A gene-candidate association study in children living in Gambia and Kenya

Background: Pediatric diarrhea remains an important cause of morbidity and mortality in the developing countries. The Global Enteric Multicenter Study (GEMS) is a prospective collaborative study to determine the pathogen-specific, severe diarrhea-associated attributable disease burden of diarrhea in Africa and Asia in children \u3c 5 yrs. of age. We conducted a host gene-candidate study that examined the association of host fecal DNA (fDNA) single nucleotide polymorphisms (SNPs) and severe diarrhea in clinics in Kenya and Gambia. Methods: Inpatient and outpatient cases of acute severe diarrhea (SD) were matched with healthy controls from the same area. SD cases were further stratified as diarrhea with vomiting (DV), diarrhea without vomiting (DNV) and bloody diarrhea (BD). Using an iPLEX Sequenom platform, we studied de-identified fDNA for the presence of SNPs (N=144) in 26 genes that code for host proteins involved in pathogen attachment, inflammation, innate and acquired immune responses to enteropathogens. We analyzed the distribution of genotypes in a site-specific manner comparing cases vs. controls. A multivariate analysis adjusted for potential confounding factors for diarrhea including age, weight for height and weight for age z scores. Results: Clinical and genotype data were available in 1,164 subjects. SD in Gambian children (N=336) was associated with SNPs in ABO, CD180, MBL2 and SELPLG genes while SD in Kenyan (N=828) children was associated with SNPs in C3orf23, CASP1, CISH, FUT2 and IL12B genes. DV in Gambian children was associated with SNPs in CD180 and SELPLG genes while DV in Kenyan children was associated with SNPs in CISH gene. DNV in Gambian children was associated with SNPs in CD180, IL12B, MBL2 and SELPLG genes while DNV in Kenyan children was associated with SNPs in C3orf23, CASP1, CORO1C and FUT2 genes. BD in Gambian children was associated with SNPs in NOD2 gene and SELPLG genes while BD in Kenyan children was associated with SNPs in CD14, CD180, CFTR, FUT2 and IL12B genes. Conclusions: In the two populations of African children living in Gambia and Kenya, distinct SNPs were associated with the clinical syndromes of SD, DV, DWV and BD. SNPs in genes that code for molecules involved in pathogen attachment, inflammation, innate and acquired immune responses to enteropathogens are associated with diarrhea in Africa children