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Published on: June 29, 2013
Fetal gender and gestational age differentially affect PCSK9 levels in intrauterine growth restriction
Ulrich Pecks1,2, Werner Rath3, Nicolai Maass3
1Department of Obstetrics and Gynecology, University Hospital of the RWTH, Aachen, Germany. Ulrich.Pecks@uksh.de.
Insights
PCSK9 (proprotein convertase subtilisin/kexin type 9) plays a role in fetal growth by influencing fetal Low Density Lipoprotein-Cholesterol (LDL-C) metabolism. Lower fetal PCSK9 levels are observed in intrauterine growth restriction (IUGR), particularly in males born preterm.
Area of Science:
- Reproductive biology and maternal-fetal medicine
- Lipid metabolism and cardiovascular health
- Genetics and developmental disorders
Background:
- Intrauterine growth restriction (IUGR) is associated with altered maternal and fetal Low Density Lipoprotein-Cholesterol (LDL-C) levels.
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL-C catabolism by binding to the LDL receptor.
- The role of PCSK9 in lipid metabolism and placental transport in IUGR requires further investigation.
Purpose of the Study:
- To investigate the role of PCSK9 in modulating lipid metabolism and placental transport in intrauterine growth restriction (IUGR).
- To compare maternal and fetal PCSK9 levels and placental expression in IUGR versus control pregnancies.
Main Methods:
- Study included 172 women (70 IUGR, 102 controls).
- Maternal and fetal serum PCSK9 and LDL-C levels were measured.
- Placental LDL-receptor and PCSK9 expression analyzed via immunohistochemistry; statistical analyses included non-parametric tests and multivariate regression.
Main Results:
- Fetal PCSK9 levels independently predicted fetal LDL-C levels.
- Lower fetal PCSK9 concentrations were found in IUGR (137.1 ng/mL) compared to controls (176.8 ng/mL) (p=0.0005).
- LDL-receptor was significantly upregulated in IUGR placentas (p=0.0063), with no correlation to PCSK9 expression.
Conclusions:
- PCSK9 influences fetal LDL-C metabolism and impaired fetal growth, with effects dependent on gestational age and fetal gender.
- Findings suggest potential for individualized, gender-specific pharmacotherapy targeting PCSK9 in specific IUGR subgroups.
- Further research is needed to identify IUGR subgroups that may benefit from targeted interventions.
Background:
Maternal and fetal Low Density Lipoprotein-Cholesterol (LDL-C) concentrations are compromised in intrauterine growth restriction (IUGR). Generally, LDL-C catabolism is under control of PCSK9 by binding to the LDL-receptor leading to its degradation. Hence, we hypothesized a role for PCSK9 in the modulation of lipid metabolism and placental transport in IUGR.
Methods:
172 women, 70 IUGR and 102 controls were included in the study. Maternal and fetal serum PCSK9 levels and lipid profiles including LDL-C were measured. Placental LDL-receptor and PCSK9 expressions were estimated by tissue microarray immunohistochemistry, and analyzed by two blinded observers using an immunoreactivity score. Non-parametric tests and multivariate regression analyses were used for statistical estimations.
Results:
PCSK9 levels in the maternal and fetal compartment independently predicted LDL-C levels (maternal compartment: adjusted R 2 = 0.2526; coefficient b i = 0.0938, standard error s bi =0.0217, rpartial = 0.4420, t-value = 4.323, p < 0.0001; fetal compartment: adjusted R 2 = 0.2929; b i = 0.1156, s bi =0.020, rpartial = 0.5494, t-value = 5.81, p < 0.0001). We did not find significant differences in maternal PCSK9 concentrations between IUGR and controls. However, we found lower fetal serum PCSK9 concentrations in IUGR than in controls (IUGR median 137.1 ng/mL (95% CI 94.8-160.0) vs. controls 176.8 (154.6-202.5), p = 0.0005). When subgrouping according to early onset, late onset IUGR, and fetal gender differences remained consistent only for male neonates born before 34 weeks of gestation. In the placenta we found no correlation between PCSK9 and LDL-receptor expression patterns. However, the LDL-receptor was significantly upregulated in IUGR when compared to controls (p = 0.0063).
Conclusions:
Our results suggest that PCSK9 play a role in impaired fetal growth by controlling fetal LDL-C metabolism, which seems to be dependent on gestational age and fetal gender. This underlines the need to identify subgroups of IUGR that may benefit from individualized and gender-specific pharmacotherapy in future studies.
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