Juhanson Peeter, Rull Kristiina, Kikas Triin, Laivuori Hannele, Vaas Pille, Kajantie Eero, Heinonen Seppo, Laan Maris
Human Molecular Genetics Research Group (P.J., K.R., T.K., M.L.), Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia; Department of Obstetrics and Gynaecology (K.R., P.V.), University of Tartu, and Women's Clinic of Tartu University Hospital (K.R., P.V.), Tartu 51014, Estonia; Medical and Clinical Genetics (H.L.), University of Helsinki and Helsinki University Hospital, and Institute for Molecular Medicine Finland (H.L.), University of Helsinki, FIN-00014 Helsinki, Finland; Obstetrics and Gynecology (H.L., S.H.) and Children's Hospital (E.K.), Helsinki University Hospital and University of Helsinki, FIN-00029 Helsinki, Finland; Chronic Disease Prevention Unit (E.K.), National Institute for Health and Welfare, FIN-00271 Helsinki, Finland; Research Unit of Pediatrics, Pediatric Neurology, Pediatric Surgery, Child Psychiatry, Dermatology, Clinical Genetics, Obstetrics and Gynecology, Otorhinolaryngology, Ophtalmology (E.K.), Medical Research Center Oulu, Oulu University Hospital and University of Oulu, FIN-90014 Oulu, Finland; and Institute of Biomedicine and Translational Medicine (M.L.), University of Tartu, Tartu 50411, Estonia.
J Clin Endocrinol Metab. 2016 Dec;101(12):4799-4807. doi: 10.1210/jc.2016-1873. Epub 2016 Sep 7.
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.
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, Mann-Whitney U test). Statistical significance was enhanced after adjustment for cofactors (linear regression, P = 1.8 × 10). 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]).
Increased STC1 hormone represents a hallmark of late-onset PE. STC1 gene variants modulate placental gene expression and maternal hormone levels.
本研究首次对人类孕期的鲽鱼钙蛋白-1（STC1）激素进行了全面分析，评估了足月时循环STC1的临床、生活方式和遗传决定因素。
设计、地点与参与者：参与者包括在爱沙尼亚的“胎儿和/或母体代谢重编程”（REPROMETA）研究（2006 - 2011年）中招募的分娩时患有（n = 50）和未患有（n = 316）先兆子痫（PE）的女性。遗传关联分析将REPROMETA研究和芬兰先兆子痫遗传学联盟（2008 - 2011年）研究中的PE病例（n = 597）和对照（n = 623）进行了合并。
通过酶联免疫吸附测定法（ELISA）测量产妇产后血浆STC1（n = 366），并通过TaqMan定量逆转录聚合酶链反应（RT-PCR）测量胎盘STC1基因表达（n = 120）。使用Sequenom MassArray进行基因分型。
与非PE组相比，PE组的STC1血浆水平显著更高（中位数为1952 pg/mL；范围为1030 - 4284 pg/mL），非PE组中位数为1562 pg/mL；范围为423 - 3781 pg/mL；曼-惠特尼U检验，P = 3.7×10）。在对协变量进行调整后，统计学显著性增强（线性回归，P = 1.8×10）。STC1测量值与产妇吸烟呈负相关。孕前体重指数仅在PE患者中与STC1呈正相关（r = 0.45；P = .001）。对于STC1单核苷酸多态性rs3758089（C等位基因：次要等位基因频率为5%；线性回归：β = 249.2 pg/mL；P = .014）和rs12678447（G等位基因：次要等位基因频率为7%；β = 147.0 pg/mL；P = .082），检测到与激素浓度最强的遗传关联。rs12678447胎盘基因型与STC1基因表达显著相关（P = .014）。REPROMETA/芬兰先兆子痫遗传学联盟的荟萃分析表明，rs12678447 G等位基因携带者发生晚发型PE的风险增加（P = .05；优势比 = 1.38 [0.98 - 1.93]）。
STC1激素水平升高是晚发型PE的一个标志。STC1基因变异调节胎盘基因表达和母体激素水平。
