title: Microsatellite polymorphism in the heme oxygenase-1 promoter is associated with nonsevere and late-onset preeclampsia.
abstract: Preeclampsia is a serious and phenotypically heterogeneous vascular pregnancy disorder. Heme oxygenase-1 (HO-1) is a stress response enzyme that may protect the maternal endothelium and facilitate adequate metabolic adaptation to pregnancy by its antioxidant and anti-inflammatory functions. HO-1 stress response is modulated by HO-1 gene (HMOX1) polymorphisms. Individuals with the long allele of a guanine-thymine (GTn) microsatellite repeat located in the promoter region of HMOX1 have a higher risk of cardiometabolic diseases compared with those with the short allele. We investigated whether the long GTn allele of HMOX1 is associated with subtypes of preeclampsia. The GTn repeat was genotyped in 759 patients and in 779 controls from the Finnish Genetics of Preeclampsia Consortium (FINNPEC) cohort using DNA fragment analysis. In subtype analyses, the long-long (LL) genotype was associated with nonsevere (additive model: odds ratio [OR], 1.94; 95% confidence interval [CI], 1.13-3.31; recessive model: OR, 1.39; 95% CI, 1.02-1.89) and late-onset (additive model: OR, 1.44; 95% CI, 1.02-2.05; recessive model: OR, 1.28; 95% CI, 1.02-1.59) preeclampsia and with preeclampsia without a small-for-gestational-age infant (recessive model: OR, 1.27; 95% CI, 1.02-1.58). The long allele was associated with nonsevere (OR, 1.35; 95% CI, 1.07-1.70) and late-onset (OR, 1.21; 95% CI, 1.03-1.42) preeclampsia and with preeclampsia without a small-for-gestational-age infant (OR, 1.19; 95% CI, 1.02-1.40). Moreover, both the LL genotype and the long allele were associated with preeclampsia in women who had smoked during pregnancy. In conclusion, the GTn long allele seems to predispose to late-onset, less severe form of preeclampsia. This finding supports the role of HO-1 in the pathogenesis of preeclampsia and suggests that the HO-1 pathway may provide a potential target for the treatment of preeclampsia.
authors.affiliation: From the Haartman Institute, Medical Genetics (T.K., M.M.K., A.T., J.K., H.L.), Research Programs Unit, Molecular Neurology (A.T.), Department of Clinical Chemistry (P.L.), and Institute for Molecular Medicine Finland (H.L.), University of Helsinki, Helsinki, Finland; Departments of Obstetrics and Gynecology (M.M.K., H.L.) and Clinical Chemistry (P.L.), Helsinki University Central Hospital, Helsinki, Finland; Department of Obstetrics and Gynecology, South-Karelia Central Hospital, Lappeenranta, Finland (M.M.K.); Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland (J.U.); Department of Obstetrics and Gynecology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland (S.H.); Department of Chronic Disease Prevention, Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland (E.K.); Department of Children, Young People, and Families, National Institute for Health and Welfare, Oulu, Finland (A.P.); Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (E.K.); Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland (E.K., A.P.); Department of Biosciences and Nutrition, and Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden (J.K.); Folkhälsan Institute of Genetics, Helsinki, Finland (J.K.); Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (K.K.); and Minerva Institute for Medical Research, Helsinki, Finland (P.L.). tea.kaartokallio@helsinki.fi.
authors.forename: Tea
authors.initials: T
authors.lastname: Kaartokallio
authors.affiliation: From the Haartman Institute, Medical Genetics (T.K., M.M.K., A.T., J.K., H.L.), Research Programs Unit, Molecular Neurology (A.T.), Department of Clinical Chemistry (P.L.), and Institute for Molecular Medicine Finland (H.L.), University of Helsinki, Helsinki, Finland; Departments of Obstetrics and Gynecology (M.M.K., H.L.) and Clinical Chemistry (P.L.), Helsinki University Central Hospital, Helsinki, Finland; Department of Obstetrics and Gynecology, South-Karelia Central Hospital, Lappeenranta, Finland (M.M.K.); Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland (J.U.); Department of Obstetrics and Gynecology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland (S.H.); Department of Chronic Disease Prevention, Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland (E.K.); Department of Children, Young People, and Families, National Institute for Health and Welfare, Oulu, Finland (A.P.); Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (E.K.); Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland (E.K., A.P.); Department of Biosciences and Nutrition, and Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden (J.K.); Folkhälsan Institute of Genetics, Helsinki, Finland (J.K.); Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (K.K.); and Minerva Institute for Medical Research, Helsinki, Finland (P.L.).
authors.forename: Miira M
authors.initials: MM
authors.lastname: Klemetti
authors.affiliation: From the Haartman Institute, Medical Genetics (T.K., M.M.K., A.T., J.K., H.L.), Research Programs Unit, Molecular Neurology (A.T.), Department of Clinical Chemistry (P.L.), and Institute for Molecular Medicine Finland (H.L.), University of Helsinki, Helsinki, Finland; Departments of Obstetrics and Gynecology (M.M.K., H.L.) and Clinical Chemistry (P.L.), Helsinki University Central Hospital, Helsinki, Finland; Department of Obstetrics and Gynecology, South-Karelia Central Hospital, Lappeenranta, Finland (M.M.K.); Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland (J.U.); Department of Obstetrics and Gynecology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland (S.H.); Department of Chronic Disease Prevention, Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland (E.K.); Department of Children, Young People, and Families, National Institute for Health and Welfare, Oulu, Finland (A.P.); Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (E.K.); Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland (E.K., A.P.); Department of Biosciences and Nutrition, and Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden (J.K.); Folkhälsan Institute of Genetics, Helsinki, Finland (J.K.); Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (K.K.); and Minerva Institute for Medical Research, Helsinki, Finland (P.L.).
authors.forename: Anni
authors.initials: A
authors.lastname: Timonen
authors.affiliation: From the Haartman Institute, Medical Genetics (T.K., M.M.K., A.T., J.K., H.L.), Research Programs Unit, Molecular Neurology (A.T.), Department of Clinical Chemistry (P.L.), and Institute for Molecular Medicine Finland (H.L.), University of Helsinki, Helsinki, Finland; Departments of Obstetrics and Gynecology (M.M.K., H.L.) and Clinical Chemistry (P.L.), Helsinki University Central Hospital, Helsinki, Finland; Department of Obstetrics and Gynecology, South-Karelia Central Hospital, Lappeenranta, Finland (M.M.K.); Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland (J.U.); Department of Obstetrics and Gynecology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland (S.H.); Department of Chronic Disease Prevention, Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland (E.K.); Department of Children, Young People, and Families, National Institute for Health and Welfare, Oulu, Finland (A.P.); Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (E.K.); Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland (E.K., A.P.); Department of Biosciences and Nutrition, and Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden (J.K.); Folkhälsan Institute of Genetics, Helsinki, Finland (J.K.); Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (K.K.); and Minerva Institute for Medical Research, Helsinki, Finland (P.L.).
authors.forename: Jukka
authors.initials: J
authors.lastname: Uotila
authors.affiliation: From the Haartman Institute, Medical Genetics (T.K., M.M.K., A.T., J.K., H.L.), Research Programs Unit, Molecular Neurology (A.T.), Department of Clinical Chemistry (P.L.), and Institute for Molecular Medicine Finland (H.L.), University of Helsinki, Helsinki, Finland; Departments of Obstetrics and Gynecology (M.M.K., H.L.) and Clinical Chemistry (P.L.), Helsinki University Central Hospital, Helsinki, Finland; Department of Obstetrics and Gynecology, South-Karelia Central Hospital, Lappeenranta, Finland (M.M.K.); Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland (J.U.); Department of Obstetrics and Gynecology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland (S.H.); Department of Chronic Disease Prevention, Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland (E.K.); Department of Children, Young People, and Families, National Institute for Health and Welfare, Oulu, Finland (A.P.); Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (E.K.); Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland (E.K., A.P.); Department of Biosciences and Nutrition, and Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden (J.K.); Folkhälsan Institute of Genetics, Helsinki, Finland (J.K.); Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (K.K.); and Minerva Institute for Medical Research, Helsinki, Finland (P.L.).
authors.forename: Seppo
authors.initials: S
authors.lastname: Heinonen
authors.affiliation: From the Haartman Institute, Medical Genetics (T.K., M.M.K., A.T., J.K., H.L.), Research Programs Unit, Molecular Neurology (A.T.), Department of Clinical Chemistry (P.L.), and Institute for Molecular Medicine Finland (H.L.), University of Helsinki, Helsinki, Finland; Departments of Obstetrics and Gynecology (M.M.K., H.L.) and Clinical Chemistry (P.L.), Helsinki University Central Hospital, Helsinki, Finland; Department of Obstetrics and Gynecology, South-Karelia Central Hospital, Lappeenranta, Finland (M.M.K.); Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland (J.U.); Department of Obstetrics and Gynecology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland (S.H.); Department of Chronic Disease Prevention, Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland (E.K.); Department of Children, Young People, and Families, National Institute for Health and Welfare, Oulu, Finland (A.P.); Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (E.K.); Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland (E.K., A.P.); Department of Biosciences and Nutrition, and Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden (J.K.); Folkhälsan Institute of Genetics, Helsinki, Finland (J.K.); Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (K.K.); and Minerva Institute for Medical Research, Helsinki, Finland (P.L.).
authors.forename: Eero
authors.initials: E
authors.lastname: Kajantie
authors.affiliation: From the Haartman Institute, Medical Genetics (T.K., M.M.K., A.T., J.K., H.L.), Research Programs Unit, Molecular Neurology (A.T.), Department of Clinical Chemistry (P.L.), and Institute for Molecular Medicine Finland (H.L.), University of Helsinki, Helsinki, Finland; Departments of Obstetrics and Gynecology (M.M.K., H.L.) and Clinical Chemistry (P.L.), Helsinki University Central Hospital, Helsinki, Finland; Department of Obstetrics and Gynecology, South-Karelia Central Hospital, Lappeenranta, Finland (M.M.K.); Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland (J.U.); Department of Obstetrics and Gynecology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland (S.H.); Department of Chronic Disease Prevention, Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland (E.K.); Department of Children, Young People, and Families, National Institute for Health and Welfare, Oulu, Finland (A.P.); Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (E.K.); Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland (E.K., A.P.); Department of Biosciences and Nutrition, and Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden (J.K.); Folkhälsan Institute of Genetics, Helsinki, Finland (J.K.); Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (K.K.); and Minerva Institute for Medical Research, Helsinki, Finland (P.L.).
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.affiliation: From the Haartman Institute, Medical Genetics (T.K., M.M.K., A.T., J.K., H.L.), Research Programs Unit, Molecular Neurology (A.T.), Department of Clinical Chemistry (P.L.), and Institute for Molecular Medicine Finland (H.L.), University of Helsinki, Helsinki, Finland; Departments of Obstetrics and Gynecology (M.M.K., H.L.) and Clinical Chemistry (P.L.), Helsinki University Central Hospital, Helsinki, Finland; Department of Obstetrics and Gynecology, South-Karelia Central Hospital, Lappeenranta, Finland (M.M.K.); Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland (J.U.); Department of Obstetrics and Gynecology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland (S.H.); Department of Chronic Disease Prevention, Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland (E.K.); Department of Children, Young People, and Families, National Institute for Health and Welfare, Oulu, Finland (A.P.); Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (E.K.); Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland (E.K., A.P.); Department of Biosciences and Nutrition, and Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden (J.K.); Folkhälsan Institute of Genetics, Helsinki, Finland (J.K.); Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (K.K.); and Minerva Institute for Medical Research, Helsinki, Finland (P.L.).
authors.forename: Katja
authors.initials: K
authors.lastname: Kivinen
authors.affiliation: From the Haartman Institute, Medical Genetics (T.K., M.M.K., A.T., J.K., H.L.), Research Programs Unit, Molecular Neurology (A.T.), Department of Clinical Chemistry (P.L.), and Institute for Molecular Medicine Finland (H.L.), University of Helsinki, Helsinki, Finland; Departments of Obstetrics and Gynecology (M.M.K., H.L.) and Clinical Chemistry (P.L.), Helsinki University Central Hospital, Helsinki, Finland; Department of Obstetrics and Gynecology, South-Karelia Central Hospital, Lappeenranta, Finland (M.M.K.); Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland (J.U.); Department of Obstetrics and Gynecology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland (S.H.); Department of Chronic Disease Prevention, Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland (E.K.); Department of Children, Young People, and Families, National Institute for Health and Welfare, Oulu, Finland (A.P.); Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (E.K.); Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland (E.K., A.P.); Department of Biosciences and Nutrition, and Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden (J.K.); Folkhälsan Institute of Genetics, Helsinki, Finland (J.K.); Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (K.K.); and Minerva Institute for Medical Research, Helsinki, Finland (P.L.).
authors.forename: Anneli
authors.initials: A
authors.lastname: Pouta
authors.affiliation: From the Haartman Institute, Medical Genetics (T.K., M.M.K., A.T., J.K., H.L.), Research Programs Unit, Molecular Neurology (A.T.), Department of Clinical Chemistry (P.L.), and Institute for Molecular Medicine Finland (H.L.), University of Helsinki, Helsinki, Finland; Departments of Obstetrics and Gynecology (M.M.K., H.L.) and Clinical Chemistry (P.L.), Helsinki University Central Hospital, Helsinki, Finland; Department of Obstetrics and Gynecology, South-Karelia Central Hospital, Lappeenranta, Finland (M.M.K.); Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland (J.U.); Department of Obstetrics and Gynecology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland (S.H.); Department of Chronic Disease Prevention, Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland (E.K.); Department of Children, Young People, and Families, National Institute for Health and Welfare, Oulu, Finland (A.P.); Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (E.K.); Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland (E.K., A.P.); Department of Biosciences and Nutrition, and Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden (J.K.); Folkhälsan Institute of Genetics, Helsinki, Finland (J.K.); Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (K.K.); and Minerva Institute for Medical Research, Helsinki, Finland (P.L.).
authors.forename: Päivi
authors.initials: P
authors.lastname: Lakkisto
authors.affiliation: From the Haartman Institute, Medical Genetics (T.K., M.M.K., A.T., J.K., H.L.), Research Programs Unit, Molecular Neurology (A.T.), Department of Clinical Chemistry (P.L.), and Institute for Molecular Medicine Finland (H.L.), University of Helsinki, Helsinki, Finland; Departments of Obstetrics and Gynecology (M.M.K., H.L.) and Clinical Chemistry (P.L.), Helsinki University Central Hospital, Helsinki, Finland; Department of Obstetrics and Gynecology, South-Karelia Central Hospital, Lappeenranta, Finland (M.M.K.); Department of Obstetrics and Gynecology, Tampere University Hospital, Tampere, Finland (J.U.); Department of Obstetrics and Gynecology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland (S.H.); Department of Chronic Disease Prevention, Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland (E.K.); Department of Children, Young People, and Families, National Institute for Health and Welfare, Oulu, Finland (A.P.); Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland (E.K.); Department of Obstetrics and Gynaecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland (E.K., A.P.); Department of Biosciences and Nutrition, and Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden (J.K.); Folkhälsan Institute of Genetics, Helsinki, Finland (J.K.); Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom (K.K.); and Minerva Institute for Medical Research, Helsinki, Finland (P.L.).
authors.forename: Hannele
authors.initials: H
authors.lastname: Laivuori
mesh_terms: D000328:Adult; D000483:Alleles; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051547:Heme Oxygenase-1 / Q000235:genetics*; D006801:Humans; D018895:Microsatellite Repeats; D011110:Polymorphism, Genetic; D011225:Pre-Eclampsia / Q000235:genetics*; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012720:Severity of Illness Index
chemical_list: D051547:Heme Oxygenase-1
keywords: heme oxygenase-1; preeclampsia; vascular diseases