Newborns with sickle cell trait have distinct peripheral blood molecular signatures across the first week of life

gene to identify those with SCT and investigate immune development using single-omics and multiomics approaches. We identified 118 newborns (~17%) with SCT and 4 (0.6%) with sickle cell disease (SCD). Newborns with SCT demonstrated distinct molecular signatures across day of life (DOL) 0, 1, 3, and 7, compared with those without, including reduction of DOL 3 plasma proteins (eg, cysteine-rich secretory protein-3, inter-α-trypsin inhibitor 1, tetranectin, and cadherin-5). Additionally, we observed enrichment of pathways previously associated with SCD, such as the Jison sickle cell pathway, along with those linked to hematologic (chronic leukemia), hepatic (liver cancer), and renal (aging kidney) functions and disorders. These SCT-based associations were validated in an independent cohort of 45 neonates. Despite the absence of overt early clinical phenotypes, SCT-associated changes manifest in the first week of life at the molecular level. Monitoring and characterizing these associations may enable the identification of future disease risks and the development of preventive strategies. This trial was registered at www.clinicaltrials.gov as #NCT03246230.