CREBRF Genomics, Gestational Diabetes, and Early Life Body Size in American Samoa

ABSTRACT: Childhood obesity is a significant public health problem and key risk factor for chronic conditions in adulthood. As such, there is critical need to understand childhood obesity etiology and identify opportunities for the earliest possible interventions to promote wellness across the lifespan. To that end, the objective of this

proposal is to use metabolomics to better understand the foundations of variation in adiposity and body composition (e.g., fat mass, lean mass, bone mass, weight-for-age) in infancy and early life. The long-term training goal of this project is to support Dr. Heinsberg in becoming an independent investigator with a program

of research dedicated to understanding and preventing obesity and improving maternal/child health. The mentored K99 will focus on participants from the nation of Samoa, as Pacific Islanders have the highest risk of obesity-related complications in the world, are one of the fastest-growing U.S. populations, but are

underrepresented in health research. In Pacific Islander adults, a missense variant (rs373863828) in CREB3 Regulatory Factor (CREBRF) has an effect on body mass index larger than any other common variant. Paradoxically, the obesity-risk allele is protective against diabetes, making its functional role unclear and

necessitating further mechanistic study before intervention can be considered. The obesity phenotypes of the variant are not present at birth but present clinically later in childhood. Given the results of CREBRF pre-clinical modeling and our preliminary work in infants, we hypothesize that the biological effects of the variant are

present much earlier in life. To investigate this hypothesis, the K99 will draw from the Foafoaga o le Ola (“Beginning of Life”) Samoan infant cohort study. Existing resources include infant CREBRF genotype data, biospecimens, and body composition measured using dual-energy X-ray absorptiometry as well as rich

behavioral/environmental data for mother-infant dyads at 1 week, 4 months, and 20 months post-birth. We will use temporal, untargeted metabolomics to increase our understanding of the biochemical mechanisms of the CREBRF variant with an emphasis on behavior/environment (Aim 1) and the foundations of body composition

over the first two years of life (Aim 2). The results are expected to provide knowledge that can be translated to improved child wellness and health equity in Samoa and Pacific Islander communities in the U.S. With access to existing biospecimens and rich data from a geographically isolated birth cohort, unparalleled mentorship,

and superb resources, the training environment is truly outstanding. K99 training goals to support the transition to independence include (1) metabolomic data collection/analysis, (2) metabolomic data interpretation in obese phenotypes, (3) conduct of childhood obesity research in underrepresented groups, and (4) career

development. In the R00, the K99 methods will be applied to study early life adiposity in a more diverse sample (Aim 3). The insights gained will provide critical context for future work to prevent childhood obesity, promote wellness, and optimize precision medicine for public health.