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Histidine-Rich Glycoprotein Polymorphism and Pregnancy Outcome: a pilot study
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. (Obstetrisk forskning/Axelsson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. (Obstetrisk forskning/Axelsson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. (Klinisk och experimentell reproduktionsbiologi/Olovsson)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. (Obstetrisk forskning/Axelsson)
2011 (English)In: Reproductive Biomedicine Online, ISSN 1472-6483, E-ISSN 1472-6491, Vol. 23, no 2, 213-219 p.Article in journal (Refereed) Published
Abstract [en]

Histidine-rich glycoprotein (HRG) is involved in fibrinolysis and coagulation, the immune system and angiogenesis. These processes are all crucial in establishing and maintaining pregnancy. The primary aim of this pilot study was to determine if HRG affects pregnancy outcome. The secondary aim was to investigate if a specific genetic polymorphism (rs9898 C/T) in the HRG gene is associated with pregnancy results. The polymorphism leads to expression of either a serine or proline residue at position 186 in the protein sequence. In this study, women undergoing IVF were included. The genetic polymorphism in the HRG gene was analysed by Western blot and single nucleotide polymorphism analysis. None of the women homozygous for the serine at residue 186 became pregnant whereas the women homozygous for proline at residue 186 had higher than expected pregnancy rates. As far as is known,this is the first study to show that a specific genetic polymorphism in the HRG gene of a woman affects her chances of becoming pregnant after IVF. The results may be essential in improving advice and IVF treatment for couples with unexplained infertility.

We have found a new test which might potentially improve advice and treatment for infertile couples considering IVF treatment. Histidine-rich glycoprotein (HRG) is involved in the system preventing blood clots or excess bleeding, the immune system and the system regulating blood vessel formation. Tight regulation of these processes is necessary for a pregnancy to be successful. This study examines how a specific genetic variant of HRG can affect pregnancy rates after IVF. The genetic polymorphism leads to expression of two different protein variations. One variation has a serine amino acid attached at position 186 and the other variation has a proline amino acid attached at the same position. Which variation a women produces is inherited co-dominantly. In this study, women undergoing IVF were included. To determine which variation each woman had, two different methods were used: Western blot and single nucleotide polymorphism analysis. The experimental results were then related to the woman’s medical records. None of the women who only produced the variation of HRG with a serine attached became pregnant, whereas the women who produced only the proline variation had higher than expected pregnancy rates. We show for the first time that the genetic background of a woman may affect her chances of becoming pregnant after IVF. The results might be essential in improving advice and IVF treatment for infertile couples.

Place, publisher, year, edition, pages
2011. Vol. 23, no 2, 213-219 p.
Keyword [en]
angiogenesis, fertility, histidine-rich glycoprotein, IVF, polymorphism, pregnancy
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
URN: urn:nbn:se:uu:diva-159556DOI: 10.1016/j.rbmo.2011.04.004ISI: 000303044500009PubMedID: 21665544OAI: oai:DiVA.org:uu-159556DiVA: diva2:445612
Available from: 2011-10-04 Created: 2011-10-04 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Biological Markers of Fertility
Open this publication in new window or tab >>Biological Markers of Fertility
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Infertility affects 15 % of couples, which corresponds to 60 - 80 million worldwide. The microenvironments in which the oocyte, embryo and fetus mature are vital to the establishment and development of a healthy pregnancy. Different biological systems, such as angiogenesis, the immune system and apoptosis need to be adequately regulated for pregnancy to occur and progress normally. The overall aim of this thesis was to investigate the impact of Histidine-rich glycoprotein (HRG) and Src homology 2 domain-containing adapter protein B (SHB) on human female fertility.

HRG is a plasma protein that regulates angiogenesis, the immune system, coagulation/fibrinolysis and apoptosis, by building complexes with various ligands. The impact of HRG on fertility is studied here for the first time. HRG is present in follicular fluid, the Fallopian tube, endometrium, myometrium and placenta. HRG distribution within embryo nuclei depends on developmental stage. Blastocysts express and secrete HRG. The HRG C633T single nucleotide polymorphism (SNP) appears to affect the chance of pregnancy and, correspondingly, parameters associated with pregnancy in IVF. Additionally, this HRG genotype may increase the risk in IVF of only developing embryos unfit for transfer.

SHB is an adaptor protein involved in intracellular signaling complexes that regulate angiogenesis, the immune system and cell proliferation/apoptosis. Shb knockout mice have altered oocyte/follicle maturation and impaired embryogenesis. The impact of three SHB polymorphisms (rs2025439, rs13298451 and rs7873102) on human fertility is studied for the first time. The SNP prevalences did not differ between infertile and fertile women. BMI, gonadotropin dosages, the percentage of immature oocytes, the number of fertilized oocytes, the percentage of good-quality embryos and the day of embryo transfer seems to be affected by SHB genotype.

In conclusion, HRG and SHB appear to influence female fertility. They are potential biomarkers that might be used for predicting pregnancy chance in infertile women. Knowledge of these genotypes may improve patient counseling and individualization of treatment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 73 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1048
Keyword
angiogenesis, embryogenesis, female reproductive tract, fertility, fertilization, Histidine-rich glycoprotein, intron, in vitro fertilization, oocyte, ovarian response, pregnancy, single nucleotide polymorphism, Src homology 2 domain-containing adapter protein B
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-234067 (URN)978-91-554-9085-0 (ISBN)
Public defence
2014-12-05, Sal IX, Universitetshuset, Övre Slottsgatan 2, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-11-14 Created: 2014-10-14 Last updated: 2015-02-03Bibliographically approved

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Nordqvist, SarahKårehed, KarinStavreus-Evers, AnneliÅkerud, Helena

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