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Hypertension. 2018 Jan;71(1):95-102. doi: 10.1161/HYPERTENSIONAHA.117.10425. Epub 2017 Dec 4.

Fetal Microsatellite in the Heme Oxygenase 1 Promoter Is Associated With Severe and Early-Onset Preeclampsia.

Author information

1
From Medical and Clinical Genetics, Helsinki University Hospital (T.K., S.U., M.M.K., H.L.), Obstetrics and Gynaecology, Helsinki University Hospital (M.M.K., S.H.), Abdominal Center, Nephrology, Helsinki University Hospital (I.T.), Clinical Chemistry and Hematology, Helsinki University Hospital (P.L.), Children's Hospital, Helsinki University Central Hospital (E.K.), Molecular Neurology Research Program (J.K.), and Institute for Molecular Medicine Finland, HiLIFE Unit (H.L.), University of Helsinki, Finland; Department of Obstetrics and Gynecology, South-Karelia Central Hospital, Lappeenranta, Finland (M.M.K.); Bioinformatics Center, University of Eastern Finland, Kuopio (J.P.); Department of Clinical Chemistry, University of Turku (K.P.), and Saske Screening Center, Turku University Central Hospital (K.P.), Finland; Eastern Finland Laboratory Centre, Kuopio (K.P., J.R.); Minerva Foundation Institute for Medical Research, Helsinki, Finland (I.T., P.L.); Chronic Disease Prevention Unit (E.K.) and Department of Government Services (A.P.), National Institute for Health and Welfare, Helsinki, Finland; PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, Finland (E.K., A.P.); Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden (J.K.); Folkhälsan Institute of Genetics, Helsinki, Finland (J.K.); Department of Medical and Molecular Genetics, King's College London, United Kingdom (J.K.); Division of Cardiovascular Medicine, University of Cambridge, United Kingdom (K.K.); Faculty of Medicine and Life Sciences, University of Tampere, Finland (H.L.); and Department of Obstetrics and Gynecology, Tampere University Hospital, Finland (H.L.). tea.kaartokallio@helsinki.fi.
2
From Medical and Clinical Genetics, Helsinki University Hospital (T.K., S.U., M.M.K., H.L.), Obstetrics and Gynaecology, Helsinki University Hospital (M.M.K., S.H.), Abdominal Center, Nephrology, Helsinki University Hospital (I.T.), Clinical Chemistry and Hematology, Helsinki University Hospital (P.L.), Children's Hospital, Helsinki University Central Hospital (E.K.), Molecular Neurology Research Program (J.K.), and Institute for Molecular Medicine Finland, HiLIFE Unit (H.L.), University of Helsinki, Finland; Department of Obstetrics and Gynecology, South-Karelia Central Hospital, Lappeenranta, Finland (M.M.K.); Bioinformatics Center, University of Eastern Finland, Kuopio (J.P.); Department of Clinical Chemistry, University of Turku (K.P.), and Saske Screening Center, Turku University Central Hospital (K.P.), Finland; Eastern Finland Laboratory Centre, Kuopio (K.P., J.R.); Minerva Foundation Institute for Medical Research, Helsinki, Finland (I.T., P.L.); Chronic Disease Prevention Unit (E.K.) and Department of Government Services (A.P.), National Institute for Health and Welfare, Helsinki, Finland; PEDEGO Research Unit, MRC Oulu, Oulu University Hospital and University of Oulu, Finland (E.K., A.P.); Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden (J.K.); Folkhälsan Institute of Genetics, Helsinki, Finland (J.K.); Department of Medical and Molecular Genetics, King's College London, United Kingdom (J.K.); Division of Cardiovascular Medicine, University of Cambridge, United Kingdom (K.K.); Faculty of Medicine and Life Sciences, University of Tampere, Finland (H.L.); and Department of Obstetrics and Gynecology, Tampere University Hospital, Finland (H.L.).

Abstract

Preeclampsia is a vascular pregnancy disorder that often involves impaired placental development. HO-1 (heme oxygenase 1, encoded by HMOX1) is a stress response enzyme crucial for endothelial and placental function. Long version of the guanine-thymine (GTn) microsatellite in the HMOX1 promoter decreases HO-1 expression, and the long maternal repeat is associated with late-onset preeclampsia. Our aim was to study whether the length of fetal repeat is associated with mother's preeclampsia, whether the length of fetal and maternal repeats affect HO-1 levels in placenta and maternal serum, and whether HO-1 levels are altered in preeclampsia. We genotyped the repeat in the cord blood of 609 preeclamptic and 745 nonpreeclamptic neonates. HO-1 levels were measured in 36 placental samples, and in the first (222 cases/243 controls) and third (176 cases/53 controls) pregnancy trimester serum samples using enzyme-linked immunosorbent assay. The long fetal GTn repeat was associated with preeclampsia and its severe and early-onset subtypes. Interaction analysis suggested the maternal and fetal effects to be independent. Placental or serum HO-1 levels were not altered in preeclamptics, possibly reflecting heterogeneity of preeclampsia. Carriers of the long fetal and maternal repeats had lower placental and serum HO-1 levels, respectively, providing functional evidence for the association. We conclude that the long fetal GTn repeat may increase mother's risk for especially severe and early-onset preeclampsia. The fetal and maternal risk alleles likely predispose to different disease subtypes.

KEYWORDS:

heme oxygenase 1; placenta; preeclampsia; pregnancy; serum

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