Background: Child health is shaped by cumulative interactions with environments even before birth. However, our understanding of the underlying biological mechanisms remains far from complete. Plasma proteomics may offer unique opportunities to understand underpinning biological processes that respond to early nutritional exposure, reflect ongoing health conditions, or mediate health consequences. The overall goal of this thesis is to evaluate applications of plasma proteomics in discovering new bio-signatures or generating hypotheses with regard to prenatal micronutrient (MN) supplementation and childhood inflammation and cognitive function. Methods: In 1999-2001, a double-blind randomized trial of antenatal micronutrient supplementation was conducted in the rural District of Sarlahi, Nepal. Pregnant women received either vitamin A alone as the control, or with folic acid, iron-folic acid, iron-folic acid-zinc, or a multiple micronutrient supplement containing all three plus 11 other vitamins and minerals from early pregnancy to 3 months postpartum. From 2006-2007, children born during this trial were followed up at the age of 6-8 years for plasma specimen collection and a year later for the assessment of cognitive function by psychological tests. We applied quantitative proteomics to identify proteins in plasma of 500 Nepalese children that co-vary with a plasma inflammation biomarker, alpha-1-acid glycoprotein (AGP) and general intellectual function, measured by an immunoradial diffusion assay and the Universal Nonverbal Intelligence Test (UNIT), respectively. We evaluated the effects of antenatal micronutrient supplementation by examining differentially abundant proteins and enriched gene sets by maternal MN intervention (each compared to the control group). A subset of children (n=249) who had both proteomics and psychological test outcomes were included for the analysis of child cognitive outcome.Results: Among 982 proteins quantified in >10% of total samples, 99 were strongly associated with AGP at a family-wise error rate of 0.1%. Positively associated proteins include known positive acute phase proteins and numerous unexpected intracellular signaling proteins. Negatively associated proteins were secretory hepatic proteins involved in transporting lipids, micronutrients, growth factors and sex hormones, and extra-hepatic proteins regulating extracellular matrix metabolism. Among 751 proteins quantified in >10% of the sub-samples, 9 and 13 proteins were positively and negatively associated with the UNIT score, passing a false discovery rate (FDR) threshold of 5%, respectively. In fully adjusted models, associations of 7 proteins involved in subclinical inflammation remained significant, explaining an additional 5~9 % of variance in the UNIT score. Lastly, there were no overall effects of antenatal micronutrient supplementation on plasma protein profiles of children. In sex-stratified analyses, maternal folic acid supplementation increased the relative abundance of nesprin-1 by 50.9 (95% CI: 24.7, 82.8) % among boys and positively enriched 4 gene sets related to cytoskeleton and organ development among girls (all passing FDR threshold of 5%).Conclusions: Our findings suggest that a vast plasma proteome reflects homeostatic control of inflammation, low-degree chronic inflammation is an important risk factor for child development, and there was no prominent long-term effects of prenatal micronutrient supplementation on childhood plasma proteome. Further studies should be followed to evaluate future public health use of plasma biomarkers of chronic inflammation and potential health consequences of subtle but enduring gene-specific and functional changes by maternal folic acid supplementation in undernourished populations.
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THE CHILDHOOD PLASMA PROTEOME: DISCOVERING ITS APPLICATIONS IN PUBLIC HEALTH
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