Preconception Maternal Nutrition, Offspring DNA Methylation, and Infant Growth in Low Resource Settings

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PROJECT ABSTRACT Growth stunting is a global health problem that impacts ~149 million children under 5 years of age living primarily in low-and-middle income-countries, particularly low-income countries. Mothers and infants are particularly vulnerable to the impacts of malnutrition, including inadequacy of micronutrients which contributes to stunted growth resulting in life-long morbidity and mortality, lower education achievement, and loss of human capital. The goal of this proposal is to determine if a preconception maternal nutrition supplement can alter targeted and epigenome-wide DNA methylation (DNAme) in infants born in regions prone to high rates of growth stunting. DNAme is an epigenetic mechanism that regulates gene transcription, and thus, phenotypical differences and risk for noncommunicable diseases. Specifically, we will test if maternal consumption of a small quantity lipid-based nutrient supplement (sqLNS) prior to conception alters infant DNAme at birth and beyond, and if these epigenetic changes are associated with growth during the first two years of life. We will examine DNAme of specific genomic regions called human metastable epialleles (MEs); MEs are systemic epigenetic marks that can be detected at birth and known to be altered by maternal nutritional status at conception in low resource settings. In addition, several epigenetic clocks (Horvath, PhenoAge, Hannum) have been developed that estimate: 1) chronological age with ≥ 96% accuracy; 2) phenotypic age; and 3) epigenetic age acceleration (EAA). Estimates of epigenetic age provide indications of life and health span. Obesity, cardiovascular disease, cancers, and type 2 diabetes mellitus have been shown to be strongly associated with increased EAA, potentially reducing life and health span. However, there are a paucity of studies addressing MEs and EAA in the context of growth stunting, low resource settings, and in response to a preconception maternal nutritional intervention. This proposal leverages a completed randomized controlled trial (NCT01883193, Women First, WF) in mother-infant dyads from the Democratic Republic of the Congo (DRC), Guatemala, India, and Pakistan. The WF RCT was comprised of three treatment arms: Arm 1 = women consumed sqLNS ≥ 3 months prior to conception until delivery; Arm 2 = women consumed the same sqLNS commencing at 12 weeks gestion until delivery; and Arm 3 = no sqLNS was consumed. We propose the following aims to advance our understanding of maternal nutrition and offspring health and growth via DNAme changes: Aim 1: Test if timing of sqLNS alters DNAme of specific genomic regions called human metastable epialleles (MEs) at birth (placenta N = 463) and 3 months postnatally (buccal N = 391) using EPIC 850K arrays. Aim 2: Determine maternal and infant factors that impact infant epigenetic and gestational age acceleration (GAA, placenta N =463). Aim 3: Targeted DNAme profiles (MEs & EAA) and epigenome-wide DNAme will be predictive of neonatal anthropometry and growth in the first 2 years of life (placenta N = 463).