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      Common variants upstream of KDR encoding VEGFR2 and in TTC39B associate with endometriosis

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          Abstract

          We conducted a genome-wide association scan (GWAS) of endometriosis using 25.5 million sequence variants detected through whole-genome sequencing (WGS) of 8,453 Icelanders and imputed into 1,840 cases and 129,016 control women, followed by testing of associated variants in Danish samples. Here we report the discovery of a new endometriosis susceptibility locus on 4q12 (rs17773813[G], OR=1.28; P=3.8 × 10 −11), upstream of KDR encoding vascular endothelial growth factor receptor 2 (VEGFR2). The variant correlates with disease severity ( P=0.0046) when moderate/severe endometriosis cases are tested against minimal/mild cases. We further report association of rs519664[T] in TTC39B on 9p22 with endometriosis ( P=4.8 × 10 −10; OR=1.29). The involvement of KDR in endometriosis risk highlights the importance of the VEGF pathway in the pathogenesis of the disease.

          Abstract

          Endometriosis is a common gynaecological disease but the underlying pathogenesis is poorly understood, however there is a strong familial component. Here the authors conduct a genome wide association study and identify a novel susceptibility locus that correlates with disease severity.

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          Most cited references27

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          The Danish Civil Registration System. A cohort of eight million persons.

          The Danish Civil Registration System (CRS) was established in 1968, where all persons alive and living in Denmark were registered. Among many other variables, it includes individual information on personal identification number, gender, date of birth, place of birth, place of residence, citizenship, continuously updated information on vital status, and the identity of parents and spouses. To evaluate the quality and completeness of the information recorded on persons in the CRS, we considered all persons registered on November 4, 2005, i.e. all persons who were alive and resident in Denmark at least one day from April 2, 1968 to November 4, 2005, or in Greenland from May 1, 1972 to November 4, 2005. A total of 8,176,097 persons were registered. On November 4, 2005, 5,427,687 (66.4%) were alive and resident in Denmark, 56,920 (0.7%) were alive and resident in Greenland, 2,141,373 (26.2%) were dead, 21,160 (0.3%) had disappeared, and 528,957 (6.5%) had emigrated. Among persons born in Denmark 1960 or later the CRS contains complete information on maternal identity. Among persons born in Denmark 1970 or later the CRS contains complete information on paternal identity. Among women born in Denmark April 1935 or later the CRS contains complete information on all their children. Among males born in Denmark April 1945 or later the CRS contains complete information on all their children. The CRS contains complete information on: a) immigrations and emigrations from 1971 onwards, b) permanent residence in a Danish municipality from 1971 onwards, c) permanent residence in a municipality in Greenland from May 1972 onwards, and d) full address in Denmark from 1977 onwards. Data from the CRS is an important research tool in epidemiological research, which enables Danish researchers to carry out representative population-based studies on e.g. the potential clustering of disease and death in families and the potential association between residence and disease and death.
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            Vascular endothelial growth factor is a secreted angiogenic mitogen.

            Vascular endothelial growth factor (VEGF) was purified from media conditioned by bovine pituitary folliculostellate cells (FC). VEGF is a heparin-binding growth factor specific for vascular endothelial cells that is able to induce angiogenesis in vivo. Complementary DNA clones for bovine and human VEGF were isolated from cDNA libraries prepared from FC and HL60 leukemia cells, respectively. These cDNAs encode hydrophilic proteins with sequences related to those of the A and B chains of platelet-derived growth factor. DNA sequencing suggests the existence of several molecular species of VEGF. VEGFs are secreted proteins, in contrast to other endothelial cell mitogens such as acidic or basic fibroblast growth factors and platelet-derived endothelial cell growth factor. Human 293 cells transfected with an expression vector containing a bovine or human VEGF cDNA insert secrete an endothelial cell mitogen that behaves like native VEGF.
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              The Danish National Birth Cohort--its background, structure and aim.

              It is well known that the time from conception to early childhood has importance for health conditions that reach into later stages of life. Recent research supports this view, and diseases such as cardiovascular morbidity, cancer, mental illnesses, asthma, and allergy may all have component causes that act early in life. Exposures in this period, which influence fetal growth, cell divisions, and organ functioning, may have long-lasting impact on health and disease susceptibility. To investigate these issues the Danish National Birth Cohort (Better health for mother and child) was established. A large cohort of pregnant women with long-term follow-up of the offspring was the obvious choice because many of the exposures of interest cannot be reconstructed with sufficient validity back in time. The study needs to be large, and it is aimed to recruit 100,000 women early in pregnancy, and to continue follow-up for decades. The Nordic countries are better suited for this kind of research than most other countries because of their population-based registers on diseases, demography and social conditions, linkable at the individual level by means of the unique ID-number given to all citizens. Exposure information is mainly collected by computer-assisted telephone interviews with the women twice during pregnancy and when their children are six and 18 months old. Participants are also asked to fill in a self-administered food frequency questionnaire in mid-pregnancy. Furthermore, a biological bank has been set up with blood taken from the mother twice during pregnancy and blood from the umbilical cord taken shortly after birth. Data collection started in 1996 and the project covered all regions in Denmark in 1999. By August 2000. a total of 60,000 pregnant women had been recruited to the study. It is expected that a large number of gene-environmental hypotheses need to be based on case-control analyses within a cohort like this.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                25 July 2016
                2016
                : 7
                : 12350
                Affiliations
                [1 ]deCODE Genetics/Amgen , 101 Reykjavik, Iceland
                [2 ]Department of Obstetrics and Gynecology, Landspitali University Hospital , 101 Reykjavik, Iceland
                [3 ]Department of Epidemiology Research, Statens Serum Institut , DK-2300 Copenhagen, Denmark
                [4 ]Department of Clinical Medicine, University of Copenhagen , DK-2100 Copenhagen, Denmark
                [5 ]Department of Medicine, Stanford University School of Medicine , Stanford, CA 94305, USA
                [6 ]School of Engineering and Natural Sciences, University of Iceland , 101 Reykjavik, Iceland
                [7 ]Faculty of Medicine, School of Health Sciences, University of Iceland , 101 Reykjavik, Iceland
                Author notes
                Author information
                http://orcid.org/0000-0003-1478-649X
                Article
                ncomms12350
                10.1038/ncomms12350
                4962463
                27453397
                d63a636f-a295-42f4-b013-fbb3362ffb38
                Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 08 March 2016
                : 24 June 2016
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