Decreased function of fatty acid desaturase 1 is associated with placental foetal vascular malperfusion and highlights the key role of the maternal–foetal interface

BACKGROUND: Placental foetal vascular malperfusion (PFVM) is a chronic disorder characterised by impaired blood flow and abnormal vascular development, inducing adverse neonatal outcomes. Long chain polyunsaturated fatty acids (LC-PUFAs) play a crucial role in placenta health. We aimed to explore the role of genetic variation in LC-PUFA metabolism in PFVM risk as well as underlying mechanisms. METHODS: Associations were examined between two functional polymorphisms (rs174538 and rs174556) of the fatty acid desaturase 1 (FADS1) gene encoding the rate-limiting enzyme for LC-PUFA metabolism and PFVM among pregnant women (n = 646). Placental transcriptomes were correlated with PFVM and FADS1 genotypes. Various assays were performed in human umbilical vein endothelial cells and trophoblasts with FADS1 inhibitor and LC-PUFA interventions to characterise their function changes. FINDINGS: Low-function alleles of both polymorphisms were significantly associated with increased PFVM risk and decreased placental FADS1 transcription level. In placenta tissue, lower FADS1 expression is also associated with PFVM. PFVM-associated genes are enriched to pathways related to immune responses, apoptosis, and angiogenesis, which overlap with the genes and pathways associated with the risk alleles and demonstrate a cell-type enrichment to endothelial cells. In vitro, FADS1 inhibition impairs multiple functions of and interactions between endothelial and trophoblast cells. These impairments are reversed by LC-PUFA supplementation. INTERPRETATION: These findings highlight the impact of maternal LC-PUFA homoeostasis in placenta health and suggest that maternal FADS1 variants can potentially be an early diagnostic marker for PFVM. Our data supports PUFA metabolism as a precision therapeutic or preventive target to reduce placental dysfunction risk. FUNDING: NIH, Wayne State University and Michigan State University.