Effect of Antenatal Micronutrient Supplementation on the Plasma Proteome in School Aged Children in Nepal
Sun Eun Lee *
Center for Human Nutrition and Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimiore, MD, USA
Keith P. West, Jr.
Center for Human Nutrition and Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimiore, MD, USA.
Robert N Cole
Mass Spectrometry and Proteomics Core Facility, Johns Hopkins School of Medicine, Baltimiore, MD, USA.
Ingo Ruczinski
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimiore, MD, USA.
Kerry Schulze
Center for Human Nutrition and Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimiore, MD, USA.
Lee Wu
Center for Human Nutrition and Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimiore, MD, USA.
James D. Yager
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimiore, MD, USA.
John Groopman
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimiore, MD, USA.
Parul Christian
Center for Human Nutrition and Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimiore, MD, USA.
*Author to whom correspondence should be addressed.
Abstract
Objectives: Antenatal micronutrient interventions may influence maternal and offspring health in chronically undernourished settings; however, molecular mechanisms remain largely unexplored. We examined effects of multiple combinations of antenatal micronutrients as supplements on the plasma proteome of offspring at 6-8 years of age.
Methods: We applied quantitative mass spectrometry to measure plasma protein abundance in 500 children whose mothers had been randomized to receive daily supplements of folic acid (FA), iron-folic acid (IFA), iron-folic acid-zinc (IFAZn), multiple micronutrient (MM), or placebo (control) from 1st trimester to 3 months postpartum (all tablets contained vitamin A). We identified differentially abundant proteins and sets of proteins sharing a common biological function by enrichment analysis using the Gene Ontology (GO) database.
Results: With a relaxed discovery threshold (false discovery rate <0.25), maternal FA supplementation increased the abundance of insulin-like growth factor-1 (IGF1) by 33.7 (95% CI: 14.7-55.8)%; maternal IFA supplementation increased tissue inhibitor of metalloproteinase 1 by 12.5 (5.9-19.6)%. All supplements containing iron-folic acid increased IGF1, IGF2, and IGF-binding protein 5 by 23.9 (9.1-40.7)%, 28.6 (10.7-49.4)%, and 23.7 (10.5-38.5)%, respectively, and decreased stromal interaction molecule 1 by 63.3 (36.7-78.8)%. With a discovery threshold of 0.05, maternal IFA supplementation negatively enriched proteins localized in microtubules (GO:5874) with an enrichment score (ES) of -0.62 and maternal IFA and MM supplementation positively enriched proteins with growth factor activity (GO:8083) with ES of 0.70 and 0.75, respectively (all p-values <0.0001).
Conclusions: Antenatal micronutrient supplementation exerts subtle metabolic effects on proteins involved in regulating growth/development and intracellular structure in school-aged children.