Advertisement

Examining extended human leukocyte antigen-G and HLA-F haplotypes: the HLA-G UTR-4 haplotype is associated with shorter time to pregnancy in an infertility treatment setting when both female and male partners are carriers

  • Line Lynge Nilsson
    Affiliations
    Center for Immune Regulation and Reproductive Immunology (CIRRI), Dept. of Clinical Biochemistry, the ReproHealth Research Consortium ZUH, Zealand University Hospital, Roskilde, Denmark

    Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
    Search for articles by this author
  • Thomas Scheike
    Affiliations
    Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
    Search for articles by this author
  • Cæcilie H. Langkilde
    Affiliations
    Center for Immune Regulation and Reproductive Immunology (CIRRI), Dept. of Clinical Biochemistry, the ReproHealth Research Consortium ZUH, Zealand University Hospital, Roskilde, Denmark

    Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
    Search for articles by this author
  • Nanna Jørgensen
    Affiliations
    Center for Immune Regulation and Reproductive Immunology (CIRRI), Dept. of Clinical Biochemistry, the ReproHealth Research Consortium ZUH, Zealand University Hospital, Roskilde, Denmark

    Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
    Search for articles by this author
  • Micha B. Hornstrup
    Affiliations
    The Fertility Clinic, Department of Obstetrics and Gynecology, the ReproHealth Research Consortium, Zealand University Hospital, Køge, Denmark
    Search for articles by this author
  • Trine L. Perin
    Affiliations
    The Fertility Clinic, Department of Obstetrics and Gynecology, the ReproHealth Research Consortium, Zealand University Hospital, Køge, Denmark
    Search for articles by this author
  • Tina Funck
    Affiliations
    Center for Immune Regulation and Reproductive Immunology (CIRRI), Dept. of Clinical Biochemistry, the ReproHealth Research Consortium ZUH, Zealand University Hospital, Roskilde, Denmark
    Search for articles by this author
  • Anette Lindhard
    Affiliations
    The Fertility Clinic, Department of Obstetrics and Gynecology, the ReproHealth Research Consortium, Zealand University Hospital, Køge, Denmark
    Search for articles by this author
  • Thomas Vauvert F. Hviid
    Correspondence
    Reprint requests: Thomas Vauvert F. Hviid, D.M.Sc., Department of Clinical Biochemistry, Zealand University Hospital and University of Copenhagen, Sygehusvej 10, DK-4000 Roskilde, Denmark.
    Affiliations
    Center for Immune Regulation and Reproductive Immunology (CIRRI), Dept. of Clinical Biochemistry, the ReproHealth Research Consortium ZUH, Zealand University Hospital, Roskilde, Denmark

    Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
    Search for articles by this author

      Objective

      To study the impact of extended human leukocyte antigen (HLA)-G and HLA-F haplotypes on time to pregnancy as measured by the number of treatment cycles in a cohort of couples in infertility treatment.

      Design

      Prospective cohort study of couples undergoing infertility treatment.

      Setting

      University hospital.

      Patient(s)

      A cohort of 127 couples and four single women in infertility treatment.

      Intervention(s)

      Next-generation sequencing of the HLA-G gene and genotyping of three HLA-F locus single-nucleotide polymorphisms (SNPs).

      Main Outcome Measure(s)

      Extended HLA-F.HLA-G haplotypes, HLA-G promoter haplotypes and HLA-G 3′UTR haplotypes and their association with time to pregnancy as measured by number of treatment cycles until achievement of pregnancy with a live birth. Linkage disequilibrium between HLA-G variations and three HLA-F locus SNPs that impact time to pregnancy.

      Result(s)

      The effect of the HLA-G 3′UTR haplotype, UTR-4, was significantly increased, or modified, if the partner was a carrier compared to being a noncarrier. Extended HLA-F.HLA-G haplotypes, HLA-G promoter haplotypes, and the HLA-G 14 bp indel of the female partners were not associated with time to pregnancy. However, a trend for an association of the HLA-G 14bp insertion allele with a higher frequency of miscarriage than the 14bp deletion allele was observed. Certain HLA-G variations are in linkage disequilibrium with three HLA-F locus SNPs that influence time to pregnancy.

      Conclusion(s)

      HLA-G UTR-4 is significantly associated with time to pregnancy in couples undergoing infertility treatment. The findings could imply that both male and female HLA class Ib genetics have clinical relevance in reproduction.
      Examen de los haplotipos extendidos del antígeno leucocitario humano G y HLA-F: el haplotipo HLA-G UTR-4 se asocia con un tiempo para lograr embarazo más corto en un entorno de tratamiento de infertilidad cuando tanto la pareja femenina como la masculina son portadores.

      Objetivo

      Estudiar el impacto de los haplotipos del antígeno leucocitario humano extendido (HLA) -G y HLA-F en el tiempo para lograr gestación, medido por el número de ciclos de tratamiento en una cohorte de parejas en tratamiento de infertilidad.

      Diseño

      Estudio de cohorte prospectivo de parejas sometidas a tratamiento de infertilidad.

      Entorno

      Hospital universitario.

      Paciente (s)

      Una cohorte de 127 parejas y cuatro mujeres solteras en tratamiento de infertilidad.

      Intervención (es)

      Secuenciación de próxima generación del gen HLA-G y genotipado de tres polimorfismos de nucleótido único (SNP) del locus HLA-F.

      Medida (s) principal (es) de resultado

      haplotipos HLA-F.HLA-G extendidos, haplotipos HLA-G promotores y haplotipos HLA-G 3’ UTR y su asociación con el tiempo hasta el embarazo, medido por el número de ciclos de tratamiento hasta el logro del embarazo con un nacido vivo. Desequilibrio de enlace entre las variaciones de HLA-G y tres SNP del locus HLA-F que afectan el tiempo hasta el embarazo.

      Resultado (s)

      : El efecto del haplotipo HLA-G 3’ UTR, UTR-4, aumentó o se modificó significativamente si la pareja era portadora en comparación con no serlo. Los haplotipos HLA-F.HLA-G extendidos, los haplotipos promotores HLA-G y el indel HLA-G 14 pb de las parejas femeninas no se asociaron con el tiempo hasta el embarazo. Sin embargo, se observó una tendencia a una asociación del alelo de inserción HLA-G de 14 pb con una mayor frecuencia de aborto espontáneo que el alelo de deleción de 14 pb. Ciertas variaciones de HLA-G están en desequilibrio de ligamiento con tres SNP del locus HLA-F que influyen en el tiempo hasta el embarazo.

      Conclusión (es)

      HLA-G UTR-4 está significativamente asociado con el tiempo hasta el embarazo en parejas que se someten a un tratamiento de infertilidad. Los hallazgos podrían implicar que tanto la genética HLA de clase lb masculina como la femenina tienen relevancia clínica en la reproducción.

      Key Words

      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to Fertility and Sterility
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • World Health Organization
        Infertility is a global public health issue.
        (Available at:)
        • Gelbaya T.A.
        • Potdar N.
        • Jeve Y.B.
        • Nardo L.G.
        Definition and epidemiology of unexplained infertility.
        Obstet Gynecol Surv. 2014; 69: 109-115
        • Kovats S.
        • Main E.K.
        • Librach C.
        • Stubblebine M.
        • Fisher S.J.
        • Demars R.
        A class I antigen, HLA-G, expressed in human trophoblasts.
        Science. 1990; 248: 220-223
        • Persson G.
        • Melsted W.N.
        • Nilsson L.L.
        • Hviid T.V.F.
        HLA class Ib in pregnancy and pregnancy-related disorders.
        Immunogenetics. 2017; 69: 581-595
        • Djurisic S.
        • Hviid T.V.F.
        HLA class Ib molecules and immune cells in pregnancy and preeclampsia.
        Front Immunol. 2014; 5
        • Fuzzi B.
        • Rizzo R.
        • Criscuoli L.
        • Noci I.
        • Melchiorri L.
        • Scarselli B.
        • et al.
        HLA-G expression in early embryos is a fundamental prerequisite for the obtainment of pregnancy.
        Eur J Immunol. 2002; 32: 311-315
        • Giacomini E.
        • Vago R.
        • Sanchez A.M.
        • Podini P.
        • Zarovni N.
        • Murdica V.
        • et al.
        Secretome of in vitro cultured human embryos contains extracellular vesicles that are uptaken by the maternal side.
        Sci Rep. 2017; 7: 5210
        • Hviid T.V.F.
        • Hylenius S.
        • Rørbye C.
        • Nielsen L.G.
        HLA-G allelic variants are associated with differences in the HLA-G mRNA isoform profile and HLA-G mRNA levels.
        Immunogenetics. 2003; 55: 63-79
        • Rousseau P.
        • le Discorde M.
        • Mouillot G.
        • Marcou C.
        • Carosella E.D.
        • Moreau P.
        The 14 bp deletion-insertion polymorphism in the 3′ UT region of the HLA-G gene influences HLA-G mRNA stability.
        Hum Immunol. 2003; 64: 1005-1010
        • Monti M.
        • Lupoli R.
        • Sosa Fernandez L.M.
        • Cirillo F.
        • di Minno M.N.D.
        Association of human leukocyte antigen-G 14 bp polymorphism with recurrent pregnancy loss in European countries: a meta-analysis of literature studies.
        Fertil Steril. 2019; 112: 577-585.e3
        • Yie S.M.
        • Li L.H.
        • Xiao R.
        • Librach C.L.
        A single base-pair mutation in the 3′-untranslated region of HLA-G mRNA is associated with pre-eclampsia.
        Mol Hum Reprod. 2008; 14: 649-653
        • Poras I.
        • Yaghi L.
        • Martelli-Palomino G.
        • Mendes C.T.
        • Muniz Y.C.N.
        • Cagnin N.F.
        • et al.
        Haplotypes of the HLA-G 3′ untranslated region respond to endogenous factors of HLA-G+ and HLA-G− cell lines differentially.
        PLoS One. 2017; 12e0169032
        • Martelli-Palomino G.
        • Pancotto J.A.
        • Muniz Y.C.
        • Mendes-Junior C.T.
        • Castelli E.C.
        • Massaro J.D.
        • et al.
        Polymorphic sites at the 3′ untranslated region of the HLA-G gene are associated with differential HLA-G soluble levels in the Brazilian and French population.
        PLoS One. 2013; 8e71742
        • Meuleman T.
        • Drabbels J.
        • van Lith J.M.M.
        • Dekkers O.M.
        • Rozemuller E.
        • Cretu-Stancu M.
        • et al.
        Lower frequency of the HLA-G UTR-4 haplotype in women with unexplained recurrent miscarriage.
        J Reprod Immunol. 2018; 126: 46-52
        • Hviid T.V.F.
        • Rizzo R.
        • Melchiorri L.
        • Stignani M.
        • Baricordi O.R.
        Polymorphism in the 5′ upstream regulatory and 3′ untranslated regions of the HLA-G gene in relation to soluble HLA-G and IL-10 expression.
        Hum Immunol. 2006; 67: 53-62
        • Castelli E.C.
        • Veiga-Castelli L.C.
        • Yaghi L.
        • Moreau P.
        • Donadi E.A.
        Transcriptional and posttranscriptional regulations of the HLA-G Gene.
        J Immunol Res. 2014; 2014: 734068
        • Yie S.M.
        • Li L.H.
        • Li G.M.
        • Xiao R.
        • Librach C.L.
        Progesterone enhances HLA-G gene expression in JEG-3 choriocarcinoma cells and human cytotrophoblasts in vitro.
        Hum Reprod. 2006; 21: 46-51
        • Kofod L.
        • Lindhard A.
        • Bzorek M.
        • Eriksen J.O.
        • Larsen L.G.
        • Hviid T.V.F.
        Endometrial immune markers are potential predictors of normal fertility and pregnancy after in vitro fertilization.
        Am J Reprod Immunol. 2017; 78
        • Burrows C.K.
        • Kosova G.
        • Herman C.
        • Patterson K.
        • Hartmann K.E.
        • Velez Edwards D.R.
        • et al.
        Expression quantitative trait locus mapping studies in mid-secretory phase endometrial cells identifies HLA-F and TAP2 as fecundability-associated genes.
        PLOS Genet. 2016; 12e1005858
        • Mika K.M.
        • Li X.
        • DeMayo F.J.
        • Lynch V.J.
        An ancient fecundability-associated polymorphism creates a GATA2 binding site in a distal enhancer of HLA-F.
        Am J Hum Genet. 2018; 103: 509-521
        • Cooper T.G.
        • Noonan E.
        • von Eckardstein S.
        • Auger J.
        • Baker H.W.G.
        • Behre H.M.
        • et al.
        World Health Organization reference values for human semen characteristics.
        Hum Reprod Update. 2010; 16: 231-245
        • Dahl M.
        • Perin T.L.
        • Djurisic S.
        • Rasmussen M.
        • Ohlsson J.
        • Buus S.
        • et al.
        Soluble human leukocyte antigen-G in seminal plasma is associated with HLA-G genotype: possible implications for fertility success.
        Am J Reprod Immunol. 2014; 72: 89-105
        • Nilsson L.L.
        • Funck T.
        • Kjersgaard N.D.
        • Hviid T.V.F.
        Next-generation sequencing of HLA-G based on long-range polymerase chain reaction.
        HLA. 2018; 92: 144-153
        • Stephens M.
        • Donnelly P.
        A comparison of bayesian methods for haplotype reconstruction from population genotype data.
        Am J Hum Genet. 2003; 73: 1162-1169
        • Castelli E.C.
        • Mendes-Junior C.T.
        • Veiga-Castelli L.C.
        • Roger M.
        • Moreau P.
        • Donadi E.A.
        A comprehensive study of polymorphic sites along the HLA-G gene: implication for gene regulation and evolution.
        Mol Biol Evol. 2011; 28: 3069-3086
        • Scheike T.H.
        • Keiding N.
        Design and analysis of time-to-pregnancy.
        Stat Methods Med Res. 2006; 15: 127-140
        • Barrett J.C.
        • Fry B.
        • Maller J.
        • Daly M.J.
        Haploview: analysis and visualization of LD and haplotype maps.
        Bioinformatics. 2005; 21: 263-265
        • Dias F.C.
        • Bertol B.C.
        • Poras I.
        • Souto B.M.
        • Mendes-Junior C.T.
        • Castelli E.C.
        • et al.
        The genetic diversity within the 1.4 kb HLA-G 5′ upstream regulatory region moderately impacts on cellular microenvironment responses.
        Sci Rep. 2018; 8
        • Ishitani A.
        • Sageshima N.
        • Lee N.
        • Dorofeeva N.
        • Hatake K.
        • Marquardt H.
        • et al.
        Protein expression and peptide binding suggest unique and interacting functional roles for HLA-E, F, and G in maternal-placental immune recognition.
        J Immunol. 2003; 171: 1376-1384
        • Larsen M.H.
        • Hylenius S.
        • Andersen A.M.N.
        • Hviid T.V.F.
        The 3′-untranslated region of the HLA-G gene in relation to pre-eclampsia: revisited.
        Tissue Antigens. 2010; 75: 253-261
        • Hylenius S.
        • Andersen A.M.N.
        • Melbye M.
        • Hviid T.V.F.
        Association between HLA-G genotype and risk of pre-eclampsia: a case-control study using family triads.
        Mol Hum Reprod. 2004; 10: 237-246
        • Nilsson L.L.
        • Djurisic S.
        • Andersen A.-M.N.
        • Melbye M.
        • Bjerre D.
        • Ferrero-Miliani L.
        • et al.
        Distribution of HLA-G extended haplotypes and one HLA-E polymorphism in a large-scale study of mother-child dyads with and without severe preeclampsia and eclampsia.
        HLA. 2016; 88: 172-186
        • Amodio G.
        • Canti V.
        • Maggio L.
        • Rosa S.
        • Castiglioni M.T.
        • Rovere-Querini P.
        • et al.
        Association of genetic variants in the 3′UTR of HLA-G with recurrent pregnancy loss.
        Hum Immunol. 2016; 77: 886-891
        • Wang X.
        • Jiang W.
        • Zhang D.
        Association of 14-bp insertion/deletion polymorphism of HLA-G gene with unexplained recurrent spontaneous abortion: a meta-analysis.
        Tissue Antigens. 2013; 81: 108-115
        • da Silva Nardi F.
        • Slowik R.
        • Michelon T.
        • Dos Santos Manvailer L.F.
        • Wagner B.
        • Neumann J.
        • et al.
        High amounts of total and extracellular vesicle-derived soluble HLA-G are associated with HLA-G 14-bp deletion variant in women with embryo implantation failure.
        Am J Reprod Immunol. 2016; 75: 661-671
        • Hviid T.V.F.
        • Hylenius S.
        • Lindhard A.
        • Christiansen O.B.
        Association between human leukocyte antigen-G genotype and success of in vitro fertilization and pregnancy outcome.
        Tissue Antigens. 2004; 64: 66-69
        • Michita R.T.
        • Zambra F.M.B.
        • Fraga L.R.
        • Sanseverino M.T.V.
        • Callegari-Jacques S.M.
        • Vianna P.
        • et al.
        A tug-of-war between tolerance and rejection—new evidence for 3′UTR HLA-G haplotypes influence in recurrent pregnancy loss.
        Hum Immunol. 2016; 77: 892-897
        • Djurisic S.
        • Teiblum S.
        • Tolstrup C.K.
        • Christiansen O.B.
        • Hviid T.V.F.
        Allelic imbalance modulates surface expression of the tolerance-inducing HLA-G molecule on primary trophoblast cells.
        Mol Hum Reprod. 2015; 21: 281-295
        • Ober C.
        • Billstrand C.
        • Kuldanek S.
        • Tan Z.
        The miscarriage-associated HLA-G −725G allele influences transcription rates in JEG-3 cells.
        Hum Reprod. 2006; 21: 1743-1748
        • Ober C.
        • Aldrich C.L.
        • Chervoneva I.
        • Billstrand C.
        • Rahimov F.
        • Gray H.L.
        • et al.
        Variation in the HLA-G promoter region influences miscarriage rates.
        Am J Hum Genet. 2003; 72: 1425-1435
        • Rohn H.
        • Schwich E.
        • Tomoya Michita R.
        • Schramm S.
        • Dolff S.
        • Gäckler A.
        • et al.
        HLA-G 3′ untranslated region gene variants are promising prognostic factors for BK polyomavirus replication and acute rejection after living-donor kidney transplant.
        Hum Immunol. 2020; 81: 141-146
        • Shaikly V.R.
        • Morrison I.E.G.
        • Taranissi M.
        • Noble C.V.
        • Withey A.D.
        • Cherry R.J.
        • et al.
        Analysis of HLA-G in maternal plasma, follicular fluid, and preimplantation embryos reveal an asymmetric pattern of expression.
        J Immunol. 2008; 180: 4330-4337
        • Niu Z.
        • Wang L.
        • Pang R.T.K.
        • Guo Y.
        • Yeung W.S.B.
        • Yao Y.
        A meta-analysis of the impact of human leukocyte antigen-G on the outcomes of IVF/ICSI.
        Reprod Biomed Online. 2017; 34: 611-618
        • West R.C.
        • Ming H.
        • Logsdon D.M.
        • Sun J.
        • Rajput S.K.
        • Kile R.A.
        • et al.
        Dynamics of trophoblast differentiation in peri-implantation–stage human embryos.
        Proc Natl Acad Sci U S A. 2019; 116: 22635-22644