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Published on: January 26, 2024
Placental weight may influence preeclampsia or eclampsia risk through modulating lipid metabolism: a mediation
Zhen Li1, Liang Chen1, Haoan Tang2
1NHC Key Laboratory of Birth Defect for Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, China.
Insights
Higher placental weight (PW) is linked to reduced preeclampsia/eclampsia (PE/E) risk, potentially mediated by very large high-density lipoprotein (HDL) lipids. This study explores the causal relationship between placental size and PE/E through lipid metabolism.
Area of Science:
- Obstetrics and Gynecology
- Metabolic Disorders
- Genetics
Background:
- Preeclampsia/eclampsia (PE/E) is a major cause of maternal and perinatal mortality.
- Abnormal lipid profiles are common in PE/E, but the causal link between placental growth and PE/E risk via lipid metabolism is unclear.
Purpose of the Study:
- To investigate the causal effect of placental weight (PW) on PE/E risk.
- To explore the role of lipid metabolism as a mediator in the PW-PE/E relationship.
Main Methods:
- Two-sample Mendelian randomization (MR) was employed using GWAS data for PW, metabolic biomarkers (NMR), and PE/E.
- Analyses included PW → PE/E, PW → biomarkers, and biomarker → PE/E, with FDR correction for multiple testing.
- Mediation analyses used two-step MR and multivariable MR (MVMR) to assess indirect and direct effects.
Main Results:
- Genetically predicted higher PW was associated with a significantly lower risk of PE/E (OR = 0.52, p = 0.013).
- PW was linked to specific lipid biomarkers, particularly very large high-density lipoprotein (HDL) components.
- Mediation analysis suggested partial mediation through very large HDL lipids (e.g., total lipids ~10.4%).
Conclusions:
- Findings support a protective association between higher PW and reduced PE/E risk.
- Very large HDL lipid pathways may partially mediate this protective effect.
- Results provide evidence consistent with mediation, acknowledging MR assumptions and potential overlapping pathways.
Introduction:
Preeclampsia/eclampsia (PE/E) is a leading cause of maternal and perinatal morbidity and mortality and is closely linked to placental dysfunction and maternal metabolic disturbance. Although abnormal lipid profiles are consistently observed in PE/E, whether placental growth - proxied by placental weight (PW) - causally influences PE/E risk through lipid metabolism remains unclear.
Methods:
We performed two-sample Mendelian randomization (MR) using summary statistics from a genome-wide association study (GWAS) of PW in term singleton pregnancies (19,861 child-mother-father trios), nuclear magnetic resonance (NMR)-based metabolic biomarkers in UK Biobank (∼120,000 participants of European ancestry), and PE/E GWAS data from FinnGen (9717 cases and 259,181 controls). We assessed (i) PW → PE/E, (ii) PW → 249 metabolic biomarkers, and (iii) biomarker → PE/E. Multiple testing across biomarkers was controlled using false discovery rate (FDR). Candidate mediators were taken forward to mediation analyses using two-step MR (product-of-coefficients) and multivariable MR (MVMR) as a sensitivity analysis to estimate direct effects.
Results:
Genetically predicted higher PW (maternal genetic component) was associated with lower PE/E risk (inverse-variance weighted odds ratio (OR) per 1 SD increase in PW = 0.52, p = 0.013). PW was associated with a subset of lipid-related biomarkers after FDR correction, predominantly very large high-density lipoprotein (HDL) lipid components. Mediation analyses were consistent with partial mediation via very large HDL lipids, including total lipids (estimated mediated proportion ∼10.4%), cholesteryl esters (∼3.9%), and phospholipids (∼3.4%).
Conclusion:
These MR findings support a protective association of higher PW with PE/E risk and are consistent with a partial contribution of very large HDL lipid pathways. Given the assumptions of MR mediation and the possibility of overlapping metabolic pathways, these results should be interpreted as evidence consistent with mediation rather than definitive mechanistic proof.
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