학술논문
Pregnancy-Associated Bleeding and Genetics: Five Sequence Variants in the Myometrium and Progesterone Signaling Pathway are associated with postpartum hemorrhage.
Document Type
Author
Westergaard D; Department of Obstetrics and Gynaecology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Methods and Analysis, Statistics Denmark, Copenhagen, Denmark.; Steinthorsdottir V; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.; Stefansdottir L; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.; Rohde PD; Department of Health Science and Technology, Aalborg University, Gistrup, Denmark.; Wu X; Department of Clinical immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.; Geller F; Department of Clinical immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.; Tyrmi J; Centre for Child, Adolescent, and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.; Havulinna AS; Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.; Finnish Institute for Health and Welfare - THL, Helsinki, Finland.; Navais PS; Department of Obstetrics and Gynaecology, Institute of Clinical Science, University of Gothenburg, Gothenburg, Sweden.; Flatley C; Department of Obstetrics and Gynaecology, Institute of Clinical Science, University of Gothenburg, Gothenburg, Sweden.; Ostrowski SR; Department of Clinical immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.; Department of Clinical medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Pedersen OB; Department of Clinical immunology, Zealand University Hospital, Køge, Denmark.; Department of Clinical medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Erikstrup C; Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.; Sørensen E; Department of Clinical immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.; Mikkelsen C; Department of Clinical immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.; Brun MT; Clinical Immunological Research Unit, Department of Clinical Immunology, Odense University Hospital, Odense, Denmark.; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.; Jensen BA; Department of Clinical Immunology, Aalborg University Hospital, Aalborg, Denmark.; Brodersen T; Department of Clinical immunology, Zealand University Hospital, Køge, Denmark.; Ullum H; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.; Magnus P; Department of Genetics and Bioinformatics, Health Data and Digitalization, Norwegian Institute of Public Health, Oslo, Norway.; Andreassen OA; NORMENT Centre, University of Oslo, Oslo, Norway.; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.; Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.; Njolstad PR; Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway.; Children and Youth Clinic, Haukeland University Hospital, Bergen, Norway.; Kolte AM; Department of Obstetrics and Gynaecology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.; Krebs L; Department of Obstetrics and Gynaecology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.; Department of Clinical medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Nyegaard M; Department of Health Science and Technology, Aalborg University, Gistrup, Denmark.; Hansen TF; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Danish Headache Center, Department of neurology, Copenhagen University Hospital, Glostrup, Denmark.; Fenstra B; Department of Clinical immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.; Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.; Daly M; Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Lindgren CM; Big Data Institute Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.; Nuffield Department of Population Health, University of Oxford, Oxford, UK.; Wellcome Trust Centre Human Genetics, University of Oxford, Oxford, UK.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Thorleifsson G; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.; Stefansson OA; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.; Sveinbjornsson G; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.; Gudbjartsson DF; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.; School of Science and Engineering, Reykjavik University, Reykjavik, Iceland.; Thorsteinsdottir U; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.; Faculty of Medicine, School of Health Sciences, Reykjavik University, Reykjavik, Iceland.; Banasik K; Department of Obstetrics and Gynaecology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Jacobsson B; Department of Obstetrics and Gynaecology, Institute of Clinical Science, University of Gothenburg, Gothenburg, Sweden.; Department of Genetics and Bioinformatics, Health Data and Digitalization, Norwegian Institute of Public Health, Oslo, Norway.; Laisk T; Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia.; Laivuori H; Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.; Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.; Department of Obstetrics and Gynaecology, Tampere University Hospital, Tampere, Finland.; Centre for Child, Adolescent, and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.; Stefansson K; deCODE genetics/Amgen, Inc., Reykjavik, Iceland.; Faculty of Medicine, School of Health Sciences, Reykjavik University, Reykjavik, Iceland.; Brunak S; Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Nielsen HS; Department of Obstetrics and Gynaecology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.; Department of Clinical medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Source
Country of Publication: United States NLM ID: 101767986 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: medRxiv Subsets: PubMed not MEDLINE
Subject
Language
English
Abstract
Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severity of these complications in maternal-fetal health. Here, we investigated the genetic variation underlying aspects of pregnancy-associated bleeding and identified five loci associated with PPH through a meta-analysis of 21,512 cases and 259,500 controls. Functional annotation analysis indicated candidate genes, HAND2 , TBX3 , and RAP2C / FRMD7, at three loci and showed that at each locus, associated variants were located within binding sites for progesterone receptors (PGR). Furthermore, there were strong genetic correlations with birth weight, gestational duration, and uterine fibroids. Early bleeding during pregnancy (28,898 cases and 302,894 controls) yielded no genome-wide association signals, but showed strong genetic correlation with a variety of human traits, indicative of polygenic and pleiotropic effects. Our results suggest that postpartum bleeding is related to myometrium dysregulation, whereas early bleeding is a complex trait related to underlying health and possibly socioeconomic status.
Competing Interests: Competing interests H.S.N. obtained speaker fees from Ferring Pharmaceuticals, Merck A/S, AstraZeneca and Cook Medical. S.B. has ownership in Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S, ALK Abello and managing board memberships in Proscion A/S and Intomics A/S. All authors affiliated with deCODE genetics are employees of deCODE genetics, a subsidiary of Amgen.
Competing Interests: Competing interests H.S.N. obtained speaker fees from Ferring Pharmaceuticals, Merck A/S, AstraZeneca and Cook Medical. S.B. has ownership in Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S, ALK Abello and managing board memberships in Proscion A/S and Intomics A/S. All authors affiliated with deCODE genetics are employees of deCODE genetics, a subsidiary of Amgen.