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

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. 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. In infants, fetal weight trajectory correlated negatively with BMI change from birth to three months (R = -0.40, <i>p</i> = 0.004) and six months (R = -0.38, <i>p</i> = 0.012), as well as with skinfold, abdominal and arm circumferences. In children, supervised transcriptome analysis highlighted a pathway including <i>ARG1</i>. Unsupervised analysis had previously identified two SBP-differentiated groups; novel findings include <i>LATS1,</i> implicated in SBP GWAS, as the most significant gene, and <i>GHRL</i>, suggesting appetite-regulation mechanisms underlie SBP differences. Ornithine, a differentially expressed metabolite between fetal and childhood weight trajectory quartiles, together with <i>ARG1,</i> suggested involvement of the arginine-nitric oxide pathway. Early life indicators of cardiometabolic risk have been elucidated, highlighting pathways to inform future prevention.