Elucidating the high and heterogeneous risk of gestational diabetes among Asian Americans: an integrative approach of metabolomics, lifestyles, and social determinants

PROJECT SUMMARY/ABSTRACT Gestational diabetes mellitus (GDM), one of the most common and growing complications in pregnancy, presents striking racial and ethnic disparities. Asian American women are twice as likely to have GDM as non- Hispanic White women and there is also substantial heterogeneity in GDM rates across Asian subpopulations.

The molecular mechanisms and upstream determinants for the high and heterogeneous risk of GDM across Asian subpopulations remain largely understudied since they are under-represented in health research. As one of the fastest-growing racial and ethnic groups in the US, it is crucial to better understand the molecular

differences and similarities across Asian subpopulations to help elucidate the pathophysiology underlying their high and heterogeneous risk of GDM. Metabolomics is a powerful tool for comprehensively evaluating global metabolic signatures and understanding biological pathways. However, metabolomics studies among pregnant

individuals are still limited and most have no or few Asian Americans. This study aimed to fill the current data and knowledge gaps for GDM disparity research by using a highly cost-efficient design that leverages the existing and unique resources: the California (CA) Alpha-fetoprotein Screening Program (CA-AFSP) and the Pregnancy

Environment and Lifestyle Study (PETALS). In the discovery sample from the CA-AFSP program which covers >74% of the pregnant individuals in Southern CA, we propose to perform integrated untargeted and targeted metabolomic profiling using stored serum samples collected in early-mid pregnancy (15-19 gestational weeks)

from 1500 individuals of four Asian subpopulations (i.e., 375 each of Chinese, Filipinos, Indian, and Vietnamese). We will identify metabolomic signatures in early-mid pregnancy associated with GDM in the CA-AFSP program and determine which metabolites and pathways overlap across all Asian Americans or distinguish across Asian

subpopulations (Aim 1). We will construct an external validation set from the above four Asian subpopulations who participated in the PETALS cohort at Kaiser Permanente Northern CA. The PETALS is a well-characterized cohort with anthropometrics, multi-domain survey data, comprehensive health data from state-of-the-art

electronic health records, and serum metabolomics assessed at 16-19 gestational weeks. We will validate GDM- related metabolomic signatures in the PETALS cohort for all Asian Americans and each Asian subpopulation (Aim 2) and examine associations of upstream lifestyles and social determinants of health (SDOHs) with GDM

risk and metabolic signatures and whether metabolomic signatures partially mediate the association between upstream lifestyles and SDOHs with GDM risk (Aim 3). As the largest-scale study to date, our integrative approach encompassing metabolomics, lifestyles, and SDOHs provides an unparalleled opportunity to elucidate

mechanisms of the drastic racial and ethnic disparities in GDM and to inform precision preventions for the high- risk, heterogeneous Asian subpopulations. Thus, this study has the potential to improve minority health and health equality in our nation.