Transcriptome and Metabolome Analyses Uncover Genes and Pathways Linking Growth Trajectories to Cardiometabolic Risk Markers in Childhood

Background: Small for gestational age (SGA) is often used as a proxy for fetal growth restriction (FGR), yet not all FGR fetuses are born SGA. SGA individuals, particularly those with catch-up growth, have increased cardiometabolic risk. We therefore studied infants and children from pregnancies at increased FGR risk, irrespective of birthweight. Methods: Two cohorts enriched for suboptimal fetal growth were recruited: an infant cohort (N = 80) to examine relationships between fetal weight trajectory and postnatal growth and a cohort of children aged 3–7 years (N = 80), 31 of whom provided blood samples for transcriptome and metabolome analyses. Results: In infants, fetal weight trajectory correlated negatively with BMI change from birth to three months (R = −0.40, p = 0.004) and six months (R = −0.38, p = 0.012), as well as with skinfold, abdominal and arm circumferences. In children, supervised transcriptome analysis highlighted a pathway including ARG1. Unsupervised analysis had previously identified two SBP-differentiated groups; novel findings include LATS1, implicated in SBP GWAS, as the most significant gene, and GHRL, suggesting appetite-regulation mechanisms underlie SBP differences. Ornithine, a differentially expressed metabolite between fetal and childhood weight trajectory quartiles, together with ARG1, suggested involvement of the arginine-nitric oxide pathway. Conclusion: Early life indicators of cardiometabolic risk have been elucidated, highlighting pathways to inform future prevention.