Pregnancy-Associated Plasma Protein A Polymorphisms in Patients with Risk Pregnancies ( pregnancy-associated plasma protein A / PAPPA / pregnancy / preeclampsia / preterm labour / single nucleotide polymorphism / SNP / gene sequencing )

Pregnant women are often threatened by hypertension, symptoms of preterm labour, hepatopathy, and other. These complications might be the consequence of genetic factors together with involvement of environmental factors. We were searching for three polymorphisms Arg654Lys, Ala678Pro and Thr686Ala in exon 5, and two polymorphisms Phe802Leu, Ser827Ser/Leu in exon 7, and for the new mutations in exons 5 and 7 of the pregnancy-associated plasma protein A gene in the studied group consisting of 203 women – 79 pregnant women in time of preterm labour, 24 pregnant women suffering from preeclampsia, and 100 healthy pregnant and non-pregnant women serving as controls. We did not find any divergence from wild-type form of these polymorphisms in any of the studied groups, which led us to the hypothesis that these polymorphisms are not associated with our studied group of Caucasian origin. However, further studies with a larger group of subjects are needed to confirm our results. Introduction Pregnancy-associated plasma protein A (PAPP-A) is a homotetrameric glycoprotein originally found by Lin et al. (1974) in the plasma of pregnant women. PAPP-A exists in pregnancy serum as a heterotetrameric 2 : 2 complex with the proform of eosinophil major basic protein (proMBP), called PAPP-A/proMBP complex (Oxvig et al., 1993). This insulin-like growth factorbinding protein (IGFBP) proteinase (Lawrence et al., 1999) belongs to the metzincin superfamily of metalloproteinases (Bode et al., 1993) and is mainly produced by the placental syncytiotrophoblast during pregnancy. PAPP-A is also expressed in ovarian granulosa cells, and in non-reproductive tissues, such as fibroblasts, osteoblasts and vascular smooth muscle cells (Overgaard et al., 1999). PAPP-A is one of the most important biochemical markers of foetal aneuplodies in pregnancies. Its low maternal serum level in the first trimester of pregnancy is characteristic for Down syndrome foetus development (Brambati et al., 1990). On the contrary, PAPP-A serum levels are significantly increased in preeclamptic pregnancies (Lin et al., 1977). Klopper (1982) showed that the change is most marked in more severe grades of preeclampsia, and the higher level of PAPP-A preceded the advent of hypertension and albuminuria. Moreover, Bayes-Genis et al. (2001) hypothesed that PAPP-A might be a promising marker of acute coronary syndromes. The human PAPPA gene is located on chromosome 9q33.1, spans over 200 kb of DNA, and contains 22 exons (Overgaard et al., 2003). In the present study, we analysed five PAPPA polymorphisms (Arg654Lys, Ala678Pro, Thr686Ala, Phe802Leu, Ser827Ser/Leu) and searched for the new mutations in exons 5 and 7 of the PAPPA gene in the pregnancies complicated with preeclampsia or preterm labour, and in healthy pregnant and non-pregnant women as controls to improve our understanding of the genetic background of these complications in pregnancy. Received May 31, 2010. Accepted August 12, 2010. The study was supported by grants GAUK 258051–41508 and SVV-2010-260512. Corresponding author: Marta Kalousová, Charles University in Prague, First Faculty of Medicine and General University Hospital, Institute of Clinical Chemistry and Laboratory Diagnostics, Na bojišti 3, 120 00 Prague 2, Czech Republic. Phone: (+420) 224 966 620; Fax: (+420) 224 962 848; e-mail: marta. kalousova@seznam.cz, mkalousova@hotmail.com Abbreviations: AGT – angiotensinogen, AMI – acute myocardial infarction, eNOS – endothelial nitric oxide synthase, IGFBP – insulin-like growth factor-binding protein, NCBI – The National Center for Biotechnology Information, PAPP-A – pregnancy-associated plasma protein A, PCR – polymerase chain reaction, proMBP – proeosinophil major basic protein, RPL – recurrent pregnancy loss.