This project will examine the long-term impact of zinc and Vitamin A, with or without glutamine or arginine, using completed clinical trials of interventions for diarrhea in children in northeast Brazil. It will collect long-term follow up data (anthropometry and cognitive development) on these populations and will then conduct a genome wide association study (GWAS) to assess host genetic determinants of diarrhea susceptibility and impact and of intervention outcomes. In a separate population, the project will build on an existing pedigree database to double the number of individuals studied, and to allow staged replicate studies of GWAS findings using salivary DNA. The project will collect pedigree, anthropometry, and diarrhea records and genotype the commonest pathogens. Thus we shall address the microbial and host genetic determinants of 5 phenotypic outcomes of enteric infections and malnutrition as well as the effects of micronutrient and nutrient therapy on these outcomes: 1. specific infection, 2. overt diarrhea, 3. intestinal inflammation and absorptive function, 4. stunted growth, and 5. cognitive impairment. More specifically, the aims are to: 1. In long-term follow-up of at least 400 children from completed clinical trials: a) Assess the long- term impact of zinc, Vitamin A, glutamine, and arginine (ZAQR) by collecting follow-up data on anthropometry and cognitive development in children from 2 completed ICIDR clinical trials, b) Conduct a Genome Wide Association Study on salivary DNA from these 400 children to assess host genetic determinants of short-term (intestinal barrier function, intestinal inflammation, and diarrhea burdens) and long-term (growth and cognition) benefits of ZAQR. 2. In a pedigree cohort of families of >500 children with detailed diarrhea data over 1-2 years: a) Expand pilot pedigree analyses to >2000 individuals in families including >500 children with diarrhea records for at least 12m from birth-3yo (existing database includes >1000 individuals of whom 277 are children with diarrhea surveillance) to quantify Cryptosporidium, Giardia, and enteropathic E. coli (EAEC, EPEC, and ETEC). b) Assess the role of genotype of top pathogens in determining their impact (i.e., C. parvum/hominis;Giardia assemblage and EAEC, EPEC and ETEC genotypes), c) Further define host genetic determinants of infection outcomes with 1536 chip analyses of DNA from >1440 persons in the pedigreed population as an independent replicate of GWAS findings in Aim 1 above.
This project will document the long-term impact of diarrhea and malnutrition-as well as the benefits of major interventions-on growth and cognitive development. It will link these outcomes and intervention effectiveness with host genetic analyses, using linkage, SNP, and GWAS approaches. This study will launch state-of-the-art human genetic studies in an endemic area to help elucidate key mechanisms and effective interventions for all children where cognitive function is threatened by enteric infections and malnutrition.
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