Stanniocalcin-1 Hormone in Nonpreeclamptic and Preeclamptic Pregnancy: Clinical, Life-Style, and Genetic Modulators

Abstract

Context and objectives: The study represents the first comprehensive analysis of Stanniocalcin-1 (STC1) hormone in human pregnancy, assessing clinical, lifestyle, and genetic determinants of circulating STC1 at term.

Design, setting, and participants: Participants included women with (n = 50) and without (n = 316) preeclampsia (PE) at delivery, recruited in the REPROgrammed fetal and/or maternal METAbolism (REPROMETA) study (2006-2011, Estonia). Genetic association analysis combined PE cases (n = 597) and controls (n = 623) from the REPROMETA and Finnish Genetics of Preeclampsia Consortium (2008-2011) studies.

Main outcome measure(s): Maternal postpartum plasma STC1 was measured by ELISA (n = 366) and placental STC1 gene expression by TaqMan quantitative RT-PCR (n = 120). Genotyping was performed using Sequenom MassArray.

Results: Significantly higher STC1 plasma level was measured for the PE (median, 1952 pg/mL; 1030-4284 pg/mL) compared with non-PE group (median, 1562 pg/mL; 423-3781 pg/mL; P = 3.7 × 10^-4, Mann-Whitney U test). Statistical significance was enhanced after adjustment for cofactors (linear regression, P = 1.8 × 10^-6). STC1 measurements were negatively correlated with maternal smoking. Prepregnancy body mass index had a positive correlation with STC1 only among PE patients (r = 0.45; P = .001). The strongest genetic association with hormone concentrations was detected for STC1 single nucleotide polymorphisms rs3758089 (C allele: minor allele frequency, 5%; linear regression: β = 249.2 pg/mL; P = .014) and rs12678447 (G allele: minor allele frequency, 7%; β = 147.0 pg/mL; P = .082). rs12678447 placental genotypes were significantly associated with STC1 gene expression (P = .014). The REPROMETA/Finnish Genetics of Preeclampsia Consortium meta-analysis suggested an increased risk to develop late-onset PE for the rs12678447 G allele carriers (P = .05; odds ratio = 1.38 [0.98-1.93]).

Conclusions: Increased STC1 hormone represents a hallmark of late-onset PE. STC1 gene variants modulate placental gene expression and maternal hormone levels.

Figure 1.

Maternal postpartum plasma STC1 hormone levels in the REPROMETA study sample subgrouped based on (A) the pregnancy outcome, (B) delivery mode and smoking status, and (C) maternal age and prepregnancy BMI. The boxes represent the 25th and 75th percentiles; median is denoted as the line that bisects the boxes. The whiskers are lines extending from each end of the box covering the extent of the data on 1.5x interquartile range; circles represent the outlier values. Statistical significance in comparisons of median STC1 values among groups was tested with Mann-Whitney U test (MW). Additionally, linear regression (LR) model was applied to adjust for the delivery mode, smoking status, maternal age, and prepregnancy BMI as covariates. Associations between STC1 and maternal age and prepregnancy BMI were assessed with LR. Regression line was plotted separately for PE (n = 50, discontinuous line) and non-PE (n = 316, continuous line) study groups, respectively. non-PE, all pregnancies without PE.

Figure 2.

Genetic effects of the STC1 gene polymorphisms in the REPROMETA study sample shown for (A) the maternal genomic variants on maternal plasma STC1 level and (B) the placental genomic variants on placental STC1 gene expression. STC1 hormone levels in maternal plasma were measured using ELISA (DY2958; R&D Systems). Placental gene expression levels were determined using TaqMan RT-qPCR (assay ID 4331182). Boxes represent the 25th and 75th percentiles; median is denoted as the line that bisects the boxes. The whiskers are lines extending from each end of the box covering the extent of the data on 1.5x interquartile range; circles represent the outlier values. Statistical significance between the minor allele carriers and major allele homozygotes was tested using Mann-Whitney U test (MW) comparing median values of the distributions. In parallel, linear regression (LR) analysis was applied to adjust for possible confounding factors. Testing associations between genetic variants and circulating STC1 hormone levels were adjusted by the study group (PE or non-PE), delivery mode, maternal age, smoking status, and prepregnancy BMI. SNP gene expression association tests were adjusted for the study group and delivery mode.