Maternal Glycemia During Pregnancy and CREBRF-Linked Pathways to Early Life Growth and Metabolic Health in American Samoa (The GROW Together Study) - PROJECT SUMMARY: Gestational diabetes mellitus (GDM) has lasting consequences for infant health, increasing lifetime risk of obesity and type 2 diabetes beginning in utero. As GDM rates rise globally, there is a need to better understand and mitigate this risk. Most studies of GDM-related disease risk are limited in three key ways: (1) treating GDM as a binary condition rather than capturing the severity and timing of maternal dysglycemia; (2) focusing on infant body size instead of body composition or metabolic markers that better reflect metabolic programming; and (3) overlooking protective mechanisms, including genetic factors, that may buffer adverse prenatal exposures. We were recently funded to prospectively examine glycemic control across pregnancy and postpartum in Pacific Islander women in American Samoa (a U.S. territory), where GDM prevalence is more than four times higher than among individuals in the continental U.S. That study, GROW (R01DK139672, n=350 women), includes three pregnancy visits (10-14, 24-28, and 32-36 weeks) and four postpartum visits (6 weeks and 6, 12, and 18 months), with extensive glucose monitoring, including repeated frequently sampled oral glucose tolerance tests (fs-OGTT) and continuous glucose monitoring (CGM). While GROW focuses on maternal glucose regulation and transition to type 2 diabetes, it does not follow infants to assess how maternal glycemia affects early growth or metabolic health. Therefore, we propose this study, GROW Together, which will follow infants born to GROW participants from birth to 18 months to examine how maternal glycemia influences early life metabolic health. A key feature of both studies is the focus on CREBRF rs373863828, a variant with a minor allele (A) uniquely common among Pacific Islanders (~25.9%), including American Samoans. The A allele is associated with lower fasting glucose in adults, and our data suggest it may buffer infants against maternal dysglycemia to mitigate prenatal programming of metabolic risk. In GROW Together we will perform infant CREBRF genotyping and assess infant body composition (dual energy x-ray absorptiometry-derived fat, lean, and bone mass) and size (weight, length, BMI z score, skinfold thicknesses, circumferences), and metabolic markers (e.g., insulin, glucose, C-peptide, etc.) at birth, 6 weeks, and 6, 12, and 18 months. In addition, we will assess infant metabolic health through CGM at 12 months. Linking these data with the prenatal maternal glycemia and genotype data from GROW, we will examine (1) how maternal glycemia across pregnancy influences infant body composition and metabolic marker trajectories, (2) whether infant body composition mediates the association between maternal glycemia across pregnancy and infant metabolic markers, and (3) how maternal-infant CREBRF genotype combinations shape maternal and infant metabolic health. Findings from this study will provide critical insights into the developmental origins of metabolic health, informing early interventions and precision health strategies to improve maternal-child outcomes in a high-risk population while offering biologically relevant insights for other groups.
