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Polymorphisms of Thrombophilic and Vasoactive Genes and Severe Preeclampsia: A Pilot Study

Department of Obstetrics and Gynecology, Albert-Ludwig University Medical School, Freiburg, Germany; Department of Obstetrics and Gynecology, University of Vienna Medical School, Vienna, Austria; Department of Obstetrics & Gynecology, University of Freiburg Medical School, Hugstetter Strasse 55, D-79106, Freiburg, Germany tempfer{at}frk.ukl.uni-freiburg.de

Stefan Jirecek, MD

Eva Katrin Riener, MD

Harald Zeisler, MD

Dominik Denschlag, MD

Lukas Hefler, MD

Peter W. Husslein, MD

Department of Obstetrics and Gynecology, Albert-Ludwig University Medical School, Freiburg, Germany; Department of Obstetrics and Gynecology, University of Vienna Medical School, Vienna, Austria

Objective: Carriage of thrombophilic and vasoactive polymorphic alleles has been associated with various pregnancy complications. The effect of carrying multiple polymorphisms is not known. We conducted a case-control study to determine the association between eight polymorphisms of thrombophilic and vasoactive genes and the risk of severe preeclampsia.

Methods: The following polymorphisms were analyzed by sequencing-on-chip-technology using solidphase polymerase chain reaction on oligonucleotide microarrays: factor 5 (F5) Leiden, factor 2 (F2)-prothrombin G20210A, plasminogen activator inhibitor (PAI)-1 4G/5G, nitric oxide synthase (NOS) 3 T768C, NOS 3 Glu298Asp, angiotensiongen (AGT) Met235Thr, estrogen receptor (ER) alpha Pvu II, and mineralcorticoid receptor (MLR) Ser810Leu. The study comprised 24 patients with severe preeclampsia and 24 controls from a cohort of consecutive white women treated at the Obstetrics Department of the University of Vienna Medical School. Genotypes were correlated with clinical data.

Results: The investigated polymorphisms did not influence the risk of severe preeclampsia independently. When separately considering the simultaneous carriage of multiple thrombophilic or vasoactive polymorphisms, neither the combined carriage of thrombophilic polymorphisms (F5 Leiden, F2 G20210A, PAI-1 4G/5G), nor the combined carriage of vasoactive polymorphisms (NOS 3 T768C, NOS 3 Glu298Asp, AGT Met235Thr) conferred an increased risk of severe preeclampsia. Cumulative genotype frequencies for at least two homozygous mutant genotypes, however, were nine of 24 (38%) and two of 24 (8%) for the study and control groups, respectively (P < .05). All of these nine women with severe preeclampsia had at least two homozygous mutant genotypes of four polymorphisms, ie, F5 Leiden, NOS 3 T768C, NOS 3 Glu298Asp, or ER alpha Pvu II.

Conclusion: Our data fail to document an independent significant influence of the investigated polymorphisms on the risk of severe preeclampsia. In an attempt to build a multigenetic model of severe preeclampsia, the combination of F5 Leiden, NOS 3 T768C, NOS 3 Glu298Asp, and ER alpha Pvu II was the most effective combination to predict the presence of severe preeclampsia in this small series of white women.

Key Words: Preeclampsia • risk • gene • polymorphism • multigenetic model

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