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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZAI1-GSM-M (J2))
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Baqar, Shahida
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University of Virginia
Internal Medicine/Medicine
Schools of Medicine
United States
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Lima, Aldo A M; Anstead, Gregory M; Zhang, Qiong et al. (2014) Effects of glutamine alone or in combination with zinc and vitamin A on growth, intestinal barrier function, stress and satiety-related hormones in Brazilian shantytown children. Clinics (Sao Paulo) 69:225-33
Guerrant, Richard L; DeBoer, Mark D; Moore, Sean R et al. (2013) The impoverished gut--a triple burden of diarrhoea, stunting and chronic disease. Nat Rev Gastroenterol Hepatol 10:220-9
Lima, Ila Fernanda Nunes; Quetz, Josiane da Silva; Guerrant, Richard Littleton et al. (2013) Enteroaggregative Escherichia coli quantification in children stool samples using quantitative PCR. APMIS 121:643-51
Lima, Ila Fernanda Nunes; Boisen, Nadia; Quetz, Josiane da Silva et al. (2013) Prevalence of enteroaggregative Escherichia coli and its virulence-related genes in a case-control study among children from north-eastern Brazil. J Med Microbiol 62:683-93
Lima, Aldo A M; Kvalsund, Michelle P; Souza, Paula P E de et al. (2013) Zinc, vitamin A, and glutamine supplementation in Brazilian shantytown children at risk for diarrhea results in sex-specific improvements in verbal learning. Clinics (Sao Paulo) 68:351-8
Mitter, Sumeet S; Oria, Reinaldo B; Kvalsund, Michelle P et al. (2012) Apolipoprotein E4 influences growth and cognitive responses to micronutrient supplementation in shantytown children from northeast Brazil. Clinics (Sao Paulo) 67:11-8
Preidis, Geoffrey A; Hill, Colin; Guerrant, Richard L et al. (2011) Probiotics, enteric and diarrheal diseases, and global health. Gastroenterology 140:8-14
Moore, Sean R; Lima, Noelia L; Soares, Alberto M et al. (2010) Prolonged episodes of acute diarrhea reduce growth and increase risk of persistent diarrhea in children. Gastroenterology 139:1156-64
da Silva Quetz, Josiane; Lima, Ila Fernanda Nunes; Havt, Alexandre et al. (2010) Campylobacter jejuni and Campylobacter coli in children from communities in Northeastern Brazil: molecular detection and relation to nutritional status. Diagn Microbiol Infect Dis 67:220-7
Lima, Aldo A M; Soares, Alberto M; Lima, Noelia L et al. (2010) Effects of vitamin A supplementation on intestinal barrier function, growth, total parasitic, and specific Giardia spp infections in Brazilian children: a prospective randomized, double-blind, placebo-controlled trial. J Pediatr Gastroenterol Nutr 50:309-15

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