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The Histidine-rich Glycoprotein in Reproduction
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Reproduktiv hälsa/Sundström-Poromaa)
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Infertility affects 15% of reproductive-aged couples. The milieu surrounding the growing embryo is of outmost importance, and should be optimised during in vitro fertilisation (IVF). Many biological processes, such as angiogenesis, coagulation, and immune processes need to be well regulated for a pregnancy to occur and progress normally. Histidine-rich glycoprotein (HRG) is a plasma protein that regulates components of these systems by building complexes with various ligands. A single nucleotide polymorphism (SNP) in HRG, denoted HRG C633T, seem to be of importance for IVF treatment outcomes. The aim of this thesis was to further investigate the proposed human fertility effects of the HRG C633T SNP.

According to the findings of this thesis, the HRG C633T genotype is associated with primary recurrent miscarriage. Male HRG C633T genotype is associated with semen characteristics in infertile men, and pregnancy rates following IVF. However, the distribution of the HRG C633T SNP does not differ between infertile and fertile couples.

We further examined the role of the region surrounding the HRG C633T SNP for regulation of endometrial angiogenesis and human embryo development. The region affects primary endometrial endothelial cell migration, proliferation and tube-formation in vitro but does not appear to affect human embryo development. No effect of the HRG peptide was noted on the secretome of human embryos. However, early embryos secrete proteins into the surrounding culture media and the level of secretion of VEGF-A, IL-6, EMMPRIN and PlGF is greater in embryos of higher developmental stages.

In conclusion, the HRG C633T genotype appears to play a role only if infertility is established. The region surrounding HRG C633T SNP is of relevance in vitro for regulation of human endometrial endothelial cell angiogenesis. To predict which embryos to transfer in IVF, we have highlighted a number of proteins of interest for further investigation.     

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1244
Keyword [en]
Angiogenesis, embryo culture medium, embryogenesis, embryonic secretome, endometrium, histidine-rich glycoprotein, human embryo development, human embryo implantation, human endometrial endothelial cells, in vitro fertilisation, infertility, male infertility, proximity extension assay, recurrent miscarriage, single nucleotide polymorphism, sperm quality, time-lapse technique, vascular endothelial growth factor
National Category
Medical and Health Sciences Obstetrics, Gynecology and Reproductive Medicine Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-300769ISBN: 978-91-554-9648-7OAI: oai:DiVA.org:uu-300769DiVA: diva2:952381
Public defence
2016-09-30, Auditorium minus, Museum Gustavianum, Akademigatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-09-09 Created: 2016-08-12 Last updated: 2016-09-13
List of papers
1. Histidine-rich glycoprotein gene polymorphism in patients with recurrent miscarriage
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2013 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 92, no 8, 974-977 p.Article in journal (Refereed) Published
Abstract [en]

Association between the histidine-rich glycoprotein (HRG) C633T single nucleotide polymorphism (SNP) and recurrent miscarriage was investigated in a case-control study. The cases constituted 187 women with recurrent miscarriage that were compared with 395 controls who had delivered a child and had no history of miscarriage. Blood samples were collected from each woman, genomic DNA was extracted and genotyped for the HRG C633T SNP. In the whole study population, the percentage of miscarriage was the same, regardless of genotype (C/C 31.2%, C/T 32.9% and T/T 32.5%). However, an association between homozygous T/T carriers and recurrent miscarriage was detected in a subgroup of women with primary recurrent miscarriage (odds ratio 2.44, 95% CI 1.01-5.92). Our results indicate an important role for the HRG C633T SNP in the occurrence of recurrent miscarriage.

Place, publisher, year, edition, pages
John Wiley & Sons, 2013
Keyword
Genotype, histidine-rich glycoprotein, infertility, recurrent miscarriage, single nucleotide polymorphism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-207015 (URN)10.1111/aogs.12155 (DOI)000321820100015 ()
Available from: 2013-09-10 Created: 2013-09-09 Last updated: 2016-08-26
2. Histidine-rich glycoprotein derived peptides affect endometrial angiogenesis in vitro but has no effect on embryo development.
Open this publication in new window or tab >>Histidine-rich glycoprotein derived peptides affect endometrial angiogenesis in vitro but has no effect on embryo development.
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2016 (English)In: Systems biology in reproductive medicine, ISSN 1939-6376, Vol. 62, no 3, 192-200 p.Article in journal (Refereed) Published
Abstract [en]

UNLABELLED: Histidine-rich glycoprotein (HRG) is an abundant plasma protein involved in multiple biological processes including immunology, vascularisation, and coagulation. These processes are of importance in regulating embryo development and implantation. A specific polymorphism in the HRG gene, HRG C633T, has an impact on various aspects of fertility, such as oocyte quality, endometrial receptivity, and possibly the capacity of the embryo itself to implant. To further examine the potential role of the HRG C633T polymorphism in regulating endometrial angiogenesis and on embryo development, two HRG peptides were constructed. These HRG peptides correspond to the amino acids 169-203 of the protein which, in turn, reflects the C633T polymorphism in the gene. The HRG proline or serine peptides were added to cultures of primary human endometrial endothelial (HEE) cells and to human embryos in vitro. The HRG peptides inhibited vascular endothelial growth factor (VEGF) induced proliferation and migration and promoted tube formation of HEE cells. The embryos were monitored using a time-lapse system (EmbryoScope®). Except for a prolonged time from first cleavage after thawing to development of the morula, no difference in embryo morphokinetics or embryo quality was noted in human embryos cultured in the presence of the HRG proline peptide. Taken together, these results suggest that treatment with a specific HRG peptide might prime the endometrium for implantation and be beneficial for adequate placentation. However, addition of a specific HRG proline peptide to human embryos has no beneficial effects in terms of embryo development.

ABBREVIATIONS: HRG: histidine-rich glycoprotein; HEE: human endometrial endothelial; VEGF: vascular endothelial growth factor; TSP: thrombospondin; SNP; single nucleotide polymorphism; IVF: in vitro fertilization; CLESH-1: CD36 LIMPII Emp structural homology domain-1; ECM: endothelial cell medium; FBS: fetal bovine serum; cDNA: complementary DNA.

Place, publisher, year, edition, pages
Taylor & Francis Group, 2016
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-296209 (URN)10.3109/19396368.2016.1156785 (DOI)000375863600004 ()27030529 (PubMedID)
Funder
Swedish Research Council, D0277901 D0277902Swedish Society of MedicineStiftelsen Olle Engkvist Byggmästare
Available from: 2016-06-14 Created: 2016-06-14 Last updated: 2016-08-26
3. The effect of a specific histidine-rich glycoprotein polymorphism on male infertility and semen parameters.
Open this publication in new window or tab >>The effect of a specific histidine-rich glycoprotein polymorphism on male infertility and semen parameters.
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2016 (English)In: Reproductive Biomedicine Online, ISSN 1472-6483, E-ISSN 1472-6491, Vol. 33, no 2, 180-188 p.Article in journal (Refereed) Published
Abstract [en]

In women, there is evidence that a single nucleotide polymorphism (SNP) in the histidine-rich glycoprotein (HRG) named HRG C633T is relevant for a number of fertility outcomes including recurrent miscarriage, ovarian response and pregnancy outcome after IVF. This case-control study was designed to investigate whether the HRG C633T SNP is important for male infertility and pregnancy rate following IVF. Cases were 139 infertile couples and controls were 196 pregnant couples. The 335 couples all contributed with one blood sample per partner. Genomic DNA was extracted and genotyping was performed using a TaqMan® SNP Genotyping Assay. Information on pregnancy rate and semen parameters was derived from medical records. Infertile couples in which the male partner was a homozygous carrier of the HRG C633T SNP had significantly lower (P < 0.01) pregnancy rate following IVF in comparison with couples where the male partner was a heterozygous HRG C633T SNP carrier. Male homozygous HRG 633T SNP carriers had overall lower total sperm count, sperm concentration, motility score and yield after preparation. In conclusion, once infertility is established the HRG C633T SNP seems to be important for male infertility and pregnancy rate following IVF.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-296211 (URN)10.1016/j.rbmo.2016.05.004 (DOI)000380751000009 ()27210772 (PubMedID)
External cooperation:
Funder
Swedish Research Council, D0277902, D0277901Swedish Society of MedicineStiftelsen Olle Engkvist Byggmästare
Available from: 2016-06-14 Created: 2016-06-14 Last updated: 2016-09-14Bibliographically approved
4. Spent culture medium from single human embryos; differential secretomics between blastocysts and arrested embryos
Open this publication in new window or tab >>Spent culture medium from single human embryos; differential secretomics between blastocysts and arrested embryos
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-300766 (URN)
Available from: 2016-08-12 Created: 2016-08-12 Last updated: 2016-08-26

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