title: Association between maternal micronutrient status, oxidative stress, and common genetic variants in antioxidant enzymes at 15 weeks׳ gestation in nulliparous women who subsequently develop preeclampsia.
abstract: Preeclampsia is a pregnancy-specific condition affecting 2-7% of women and a leading cause of perinatal and maternal morbidity and mortality. Deficiencies of specific micronutrient antioxidant activities associated with copper, selenium, zinc, and manganese have previously been linked to preeclampsia at the time of disease. Our aims were to investigate whether maternal plasma micronutrient concentrations and related antioxidant enzyme activities are altered before preeclampsia onset and to examine the dependence on genetic variations in these antioxidant enzymes. Predisease plasma samples (15±1 weeks׳ gestation) were obtained from women enrolled in the international Screening for Pregnancy Endpoints (SCOPE) study who subsequently developed preeclampsia (n=244) and from age- and BMI-matched normotensive controls (n=472). Micronutrient concentrations were measured by inductively coupled plasma mass spectrometry; associated antioxidant enzyme activities, selenoprotein-P, ceruloplasmin concentration and activity, antioxidant capacity, and markers of oxidative stress were measured by colorimetric assays. Sixty-four tag-single-nucleotide polymorphisms (SNPs) within genes encoding the antioxidant enzymes and selenoprotein-P were genotyped using allele-specific competitive PCR. Plasma copper and ceruloplasmin concentrations were modestly but significantly elevated in women who subsequently developed preeclampsia (both P<0.001) compared to controls (median (IQR), copper, 1957.4 (1787, 2177.5) vs 1850.0 (1663.5, 2051.5) µg/L; ceruloplasmin, 2.5 (1.4, 3.2) vs 2.2 (1.2, 3.0) µg/ml). There were no differences in other micronutrients or enzymes between groups. No relationship was observed between genotype for SNPs and antioxidant enzyme activity. This analysis of a prospective cohort study reports maternal micronutrient concentrations in combination with associated antioxidant enzymes and SNPs in their encoding genes in women at 15 weeks׳ gestation that subsequently developed preeclampsia. The modest elevation in copper may contribute to oxidative stress, later in pregnancy, in those women that go on to develop preeclampsia. The lack of evidence to support the hypothesis that functional SNPs influence antioxidant enzyme activity in pregnant women argues against a role for these genes in the etiology of preeclampsia.
authors.affiliation: Division of Women׳s Health, King׳s College London, Women׳s Health Academic Centre, KHP, London SE1 7EH, UK. Electronic address: hiten.mistry@kcl.ac.uk.
authors.forename: Hiten D
authors.initials: HD
authors.lastname: Mistry
authors.affiliation: Division of Women׳s Health, King׳s College London, Women׳s Health Academic Centre, KHP, London SE1 7EH, UK.
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Gill
authors.affiliation: Department of Obstetrics & Gynaecology, School of Medicine, University of Nottingham, Nottingham NG5 1PB, UK.
authors.forename: Lesia O
authors.initials: LO
authors.lastname: Kurlak
authors.affiliation: Division of Women׳s Health, King׳s College London, Women׳s Health Academic Centre, KHP, London SE1 7EH, UK.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Seed
authors.affiliation: Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK.
authors.forename: John E
authors.initials: JE
authors.lastname: Hesketh
authors.affiliation: Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle Upon Tyne NE2 4HH, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Méplan
authors.affiliation: Institute for Experimental Endocrinology, Universitaetsmedizin Berlin, 13353 Berlin, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Schomburg
authors.affiliation: Division of Women׳s Health, King׳s College London, Women׳s Health Academic Centre, KHP, London SE1 7EH, UK.
authors.forename: Lucy C
authors.initials: LC
authors.lastname: Chappell
authors.affiliation: School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Morgan
authors.affiliation: Division of Women׳s Health, King׳s College London, Women׳s Health Academic Centre, KHP, London SE1 7EH, UK.
authors.forename: Lucilla
authors.initials: L
authors.lastname: Poston
mesh_terms: D000328:Adult; D000975:Antioxidants / Q000378:metabolism; D016022:Case-Control Studies; D002570:Ceruloplasmin / Q000378:metabolism; D003300:Copper / Q000097:blood; D005260:Female; D005865:Gestational Age; D005979:Glutathione Peroxidase / Q000235:genetics*; D006801:Humans; D007390:International Agencies; D018977:Micronutrients; D018384:Oxidative Stress; D010298:Parity; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011225:Pre-Eclampsia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011446:Prospective Studies; D051149:Selenoprotein P / Q000235:genetics*; D013482:Superoxide Dismutase / Q000235:genetics*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D000975:Antioxidants; D018977:Micronutrients; D051149:Selenoprotein P; D017392:Thiobarbituric Acid Reactive Substances; D003300:Copper; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D002570:Ceruloplasmin
keywords: Antioxidants; Free radicals; Hypertension; Micronutrients; Oxidative stress; Preeclampsia; Pregnancy