Polymorphisms of thrombophilic and vasoactive genes and severe preeclampsia: a pilot study.
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 solid-phase 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, angiotensinogen (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.


CONCLUSIONS
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.
Tempfer
Clemens B
CB
Department of Obstetrics and Gynecology, Albert-Ludwig University Medical School, Freiburg, Germany. tempfer@frk.ukl.uni-freiburg.de
Jirecek
Stefan
S
Riener
Eva-Katrin
EK
Zeisler
Harald
H
Denschlag
Dominik
D
Hefler
Lukas
L
Husslein
Peter W
PW
D000328:Adult; D000808:Angiotensinogen / Q000235:genetics; D001777:Blood Coagulation / Q000235:genetics*; D001779:Blood Coagulation Factors / Q000235:genetics; D001808:Blood Vessels / Q000503:physiopathology*; D016022:Case-Control Studies; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D006801:Humans; D019001:Nitric Oxide Synthase / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D020411:Oligonucleotide Array Sequence Analysis; D010865:Pilot Projects; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics*; D011225:Pre-Eclampsia / Q000235:genetics*; D011247:Pregnancy; D011516:Prothrombin / Q000235:genetics; D018161:Receptors, Mineralocorticoid / Q000235:genetics
D001779:Blood Coagulation Factors; D047628:Estrogen Receptor alpha; D017395:Plasminogen Activator Inhibitor 1; D018161:Receptors, Mineralocorticoid; C037685:platelet factor V; D000808:Angiotensinogen; D011516:Prothrombin; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III