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Original article
Gene polymorphisms and HLA-G expression in spontaneous abortions
Polimorfismos genéticos y expresión del HLA-G en abortos espontáneos
Virginia García-Láeza,c,
Corresponding author
, Vicente Serraa,c, José Bellvera,c, Jaime Ferroa,c, Carmina Vidala,c, José María De los Santosa,c, Mari Carmen Rubiob, Julio Martínb, Carmen Martínezb, María José De los Santosa,c
a Instituto Valenciano de Infertilidad, Universidad de Valencia, Plaza de la Policía Local 3, 46015 Valencia, Spain
b IVIomics, Parc Cientific Universitat de València, Calle Catedrático Agustín Escardino, 9, 46980 Valencia, Spain
c INCLIVA, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Although the cause of pregnancy loss is multifactorial&#44; it can be generally divided into two main causes&#58; embryologically driven causes&#44; mainly due to an abnormal karyotype&#44; and maternally driven causes&#44; which affect the endometrium and&#47;or placental development &#40;<a class="elsevierStyleCrossRefs" href="#bib0150">Li et al&#46;&#44; 2002&#59; Aplin&#44; 2000</a>&#41;&#46; The aetiology is unknown in approximately 50&#37; of abortion cases &#40;<a class="elsevierStyleCrossRef" href="#bib0220">Pandey et al&#46;&#44; 2005</a>&#41;&#44; but it has been postulated that a proportion of these pregnancy losses may be due to immune causes&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Recognition of foreign cells is rendered by the expression of Major Histocompatibility Complex &#40;MHC&#41; molecules on the cell surface&#46; During pregnancy&#44; the maternal immune system should recognise foetal trophoblast cells as foreign if they express paternal MHC molecules&#46; However&#44; foetal extra-villous cytotrophoblast cells do not express the classical MHC type I molecules&#44; HLA-A and HLA-B&#44; and MHC type II molecules are also absent&#46; Instead&#44; HLA-G and HLA-E are expressed in the human cytotrophoblast&#44; specifically in extra-villous cytotrophoblast of the placenta by them invading their way through the maternal decidua&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The different expression pattern of antigens HLA-G and HLA-E&#44; as compared to other MHC molecules&#44; together with the high degree of conservation of their sequences during evolution&#44; predict a clear implication in the modulation of these molecules in immune responses&#44; such as foeto-maternal recognition responses to maintain the semi-allogenic embryo&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Some functions performed by HLA-G include the suppression of the cytolytic and cytotoxic activity of NK cells and Tc lymphocytes &#40;CD8&#41; &#40;<a class="elsevierStyleCrossRefs" href="#bib0265">Rouas-Freiss et al&#46;&#44; 1997&#59; Kapasi et al&#46;&#44; 2000&#59; Contini et al&#46;&#44; 2003</a>&#41;&#44; the alteration of local cytokine secretion towards a compatible physiological situation with implantation &#40;<a class="elsevierStyleCrossRefs" href="#bib0255">Rieger et al&#46;&#44; 2002&#59; Loke and King&#44; 2000</a>&#41;&#44; and the possible participation in the regulation and stabilisation of the superficial HLA-E expression across the leader peptide&#46; HLA-G encodes the leader peptide linked to the HLA-E molecule&#44; a necessary process for its superficial expression and stability&#46; Both&#44; the leader peptide and the HLA-G molecule are very important for the HLA-E expression &#40;<a class="elsevierStyleCrossRefs" href="#bib0135">Lee et al&#46;&#44; 1998a&#59; Lemaoult et al&#46;&#44; 2004</a>&#41;&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Surprisingly&#44; there are relatively very few studies into HLA-G expression and abortion&#44; this being the most common disorder in pregnancy&#46; Some authors have observed a lower HLA-G expression in cytotrophoblast &#40;<a class="elsevierStyleCrossRef" href="#bib0070">Emmer et al&#46;&#44; 2002</a>&#41; and serum &#40;<a class="elsevierStyleCrossRefs" href="#bib0030">Athanassakis et al&#46;&#44; 1999&#59; Pfeiffer et al&#46;&#44; 2000&#59; Alegre et al&#46;&#44; 2007</a>&#41; in recurrent spontaneous abortion &#40;RSA&#41; in comparison with pregnancies to term&#46; However&#44; there is still some controversy as to the role of these molecules in maintaining pregnancy&#46; In fact&#44; other authors have found no differences in the expression patterns of HLA-G and HLA-E in trophoblast between RSA and voluntary pregnancy interruption &#40;VPI&#41; &#40;<a class="elsevierStyleCrossRef" href="#bib0045">Bhalla et al&#46;&#44; 2006</a>&#41; or the expression levels of HLA-G between chromosomally normal RSA and RSA with trisomy 16 &#40;<a class="elsevierStyleCrossRef" href="#bib0225">Patel et al&#46;&#44; 2003</a>&#41;&#46; Similarly&#44; it has been shown that the soluble HLA-G levels in serum between RSA and alive newborns are similar &#40;<a class="elsevierStyleCrossRef" href="#bib0080">Gonzalez et al&#46;&#44; 2010</a>&#41;&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">From a genetic perspective&#44; certain polymorphisms have been associated with abortion in relation to the HLA-G gene &#40;<a class="elsevierStyleCrossRefs" href="#bib0230">Pfeiffer et al&#46;&#44; 2001&#59; Aldrich et al&#46;&#44; 2001&#59; Ober et al&#46;&#44; 2003&#59; Hviid et al&#46;&#44; 2004a&#59; Abbas et al&#46;&#44; 2004&#59; Tripathi et al&#46;&#44; 2004&#59; Xue et al&#46;&#44; 2007&#59; Zhu et al&#46;&#44; 2010</a>&#41;&#46; Interestingly&#44; some polymorphisms have functional consequences as they can affect the transcriptional regulation of mRNA &#40;<a class="elsevierStyleCrossRefs" href="#bib0205">Ober et al&#46;&#44; 2006&#59; Hiby et al&#46;&#44; 1999&#59; O&#8217;Brien et al&#46;&#44; 2001&#59; Rousseau et al&#46;&#44; 2003&#59; Hviid et al&#46;&#44; 2003&#59; Larsen and Hviid&#44; 2009</a>&#41; and the superficial expression of the protein level of HLA-G &#40;<a class="elsevierStyleCrossRefs" href="#bib0195">Ober et al&#46;&#44; 1998&#59; Rebmann et al&#46;&#44; 1999&#44; 2001&#59; Rizzo et al&#46;&#44; 2005&#59; Chen et al&#46;&#44; 2008&#59; Mendes-Junior et al&#46;&#44; 2010&#59; Gonzalez et al&#46;&#44; 2010</a>&#41;&#46; On the other hand&#44; some authors have reported no association between determined polymorphisms in peripheral blood and risk of abortion &#40;<a class="elsevierStyleCrossRefs" href="#bib0280">Sipak-Szmigiel et al&#46;&#44; 2007&#44; 2008&#59; Yan et al&#46;&#44; 2006&#59; Mendes-Junior et al&#46;&#44; 2007</a>&#41;&#44; and others have found no association between determined polymorphisms and the HLA-G expression in either peripheral blood or term placenta &#40;<a class="elsevierStyleCrossRef" href="#bib0110">Hviid et al&#46;&#44; 2004b</a>&#41;&#46; Therefore&#44; it is not very likely that one polymorphism will be capable of producing pregnancy loss&#46; This is due to the strong linkage disequilibrium that exists in the region of the HLA-G &#40;<a class="elsevierStyleCrossRef" href="#bib0210">Ober et al&#46;&#44; 1996</a>&#41;&#44; which favours that different loci tend to inherit in block&#46; For this reason&#44; some authors believe that the association between a given haplotype of HLA-G and spontaneous recurrent miscarriages is possible &#40;<a class="elsevierStyleCrossRef" href="#bib0035">Berger et al&#46;&#44; 2010</a>&#41;&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Regarding HLA-E&#44; it is noteworthy that it contains similar genetic and molecular characteristics to those of HLA-G &#40;<a class="elsevierStyleCrossRef" href="#bib0190">O&#8217;Callaghan and Bell&#44; 1998</a>&#41;&#46; The tissue surface expression is restricted to extra-villous cytotrophoblast and needs a leader peptide from other HLA molecules&#46; It also has low polymorphism and some of them can affect its expression and functions &#40;<a class="elsevierStyleCrossRef" href="#bib0140">Lee et al&#46;&#44; 1998b</a>&#41;&#46; It performs the immunosuppression functions of NK cells and T CD8&#43; lymphocytes &#40;<a class="elsevierStyleCrossRefs" href="#bib0050">Borrego et al&#46;&#44; 1998&#59; Braud et al&#46;&#44; 1998</a>&#41;&#46; Nonetheless&#44; it is thought that HLA-E is also especially involved in maintaining pregnancy&#44; although some authors found no differences in their expression between RSA and VPI &#40;<a class="elsevierStyleCrossRef" href="#bib0045">Bhalla et al&#46;&#44; 2006</a>&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Therefore&#44; in this study we aimed to determine the presence of polymorphisms in the HLA-G gene in samples of extremely highly purified trophoblast tissue of spontaneous abortions in both chromosomally normal and abnormal embryos and its association with the local expression of HLA-G and HLA-E in cytotrophoblast tissue&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Population</span><p id="par0045" class="elsevierStylePara elsevierViewall">This study was approved by the Institutional Review Board at the Instituto Valenciano de Infertilidad &#40;IVI Valencia&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">After obtaining the signed informed consent form a total of 90 patients were included in the study&#46; These patients reported spontaneous abortion between gestation weeks 6 and 11 with embryos stopped between week 4 and week 9&#46;5 of gestational age&#44; observed following morphological visualization at the time of hystero-embryoscopy&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">They underwent hystero-embryoscopic biopsies to selectively take only embryo tissue for the karyotyping analysis&#46; Briefly&#44; a Hamou examination and contact hysteroscope III with a Hopkins forward-oblique 30&#176; telescope&#44; 2&#46;9<span class="elsevierStyleHsp" style=""></span>mm in diameter and 30<span class="elsevierStyleHsp" style=""></span>cm length&#44; and a Bettocchi single-flow operating sheath&#44; size 3&#46;8<span class="elsevierStyleHsp" style=""></span>mm&#44; provided with a 5-Fr channel for semi rigid instruments &#40;Karl Storz GmbH&#44; Tuttlingem&#44; Germany&#41; was used&#46; Normal saline was used as the distending medium&#46; The hysteroscope was gently introduced into the uterine cavity without cervical dilatation&#46; The prominence of the gestational sac was located&#46; A small hole was made in the gestational sac wall using a 5-Fr biopsy spoon forceps &#40;Karl Storz GmbH&#41;&#46; The scope was introduced gradually in the extracelomic and amniotic cavities&#46; Direct embryo and chorion biopsies were taken and placed in saline solution&#46; This technology allows sample to be obtained with a minimal risk of mother-tissue contamination &#40;<a class="elsevierStyleCrossRef" href="#bib0075">Ferro et al&#46;&#44; 2003</a>&#41;&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">A total of 99 embryo cytotrophoblast samples were recovered from 90 patients because 9 of them presented two gestational sacs&#44; and it was possible to obtain a sample from both sacs&#46; These cytotrophoblasts samples were used to determine embryo karyotype and the genetic studies about on HLA-G polymorphisms and HLA-G immunostaining analysis&#46; Additionally maternal deciduas were employed to perform the genetic studies about the heteroparentality of the trophoblast sample&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">To accomplish this study&#44; the possible known reasons for pregnancy loss were analyzed and discarded in the normal karyotype cases&#44; such as chromosomal anomalies in the progenitors or the presence of uterine or endocrine anomalies or antiphospholipid syndrome in the patient &#40;<a class="elsevierStyleCrossRef" href="#bib0040">Beydoun and Saftlas&#44; 2005</a>&#41;&#46; Samples with chromosomal embryo anomalies were used as reference samples&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Gene polymorphisms</span><p id="par0070" class="elsevierStylePara elsevierViewall">After karyotyping 99 cytotrophoblast samples&#44; a total of 57 samples from 55 patients were included for the polymorphisms analysis&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The samples were randomly selected and attempts were made to include a similar number of patients in each group&#58; 30 samples with abnormal karyotype and 27 samples with normal karyotype&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">DNA extraction was done with organic solvents by the DNA isolation kit &#40;Gentra System&#46; Puregene TM&#44; USA&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The genetic studies were conducted to evaluate the heteroparentality of the trophoblast sample and the non-contamination with maternal decidua by analysing the generated fragments by a PCR multiplex with different combinations of polymorphic marker-type microsatellites CA &#40;data not shown&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">For the analysis of polymorphisms of greater interest use the following techniques and the primers shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">&#42; &#8722;725C<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>G polymorphism</span><p id="par0100" class="elsevierStylePara elsevierViewall">For the genetic analysis of &#8722;725C&#62;G polymorphism in the promoter region&#44; a PCR was done to amplify the genetic fragment of interest&#44; while the RFLP &#40;restriction fragment length polymorphism&#41; technology employed a StuI restriction enzyme&#46; The PCR product was digested when the C allele was present&#44; i&#46;e&#46; when polymorphism not present&#46; The PCR products were visualised in an automatic electrophoretic system &#40;ABI Prism 3130&#44; Applied Biosystem&#44; CA&#44; USA&#41; and by the GenneMapper 4&#46;0 program &#40;Applied Biosystems&#44; CA&#44; USA&#41;&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">&#42; Exon 3 polymorphism</span><p id="par0110" class="elsevierStylePara elsevierViewall">For the genetic analysis of the polymorphism in exon 3&#44; a PCR was done to amplify the genetic fragment of interest&#44; with sequencing done by the BigDye terminator v3&#46;1 sequencing kit in a 3700 DNA analyzer &#40;Applied Biosystem&#44; CA&#44; USA&#41;&#46; The obtained sequences were analysed by the SeqScape software&#44; version 2&#46;6&#44; and were compared to the reference sequence of the gene obtained from the following address&#58; <a href="http://www.ensembl.org/Homo_sapiens/Gene/Sequence?g=ENSG00000204632">http&#58;&#47;&#47;www&#46;ensembl&#46;org&#47;Homo&#95;sapiens&#47;Gene&#47;Sequence&#63;g&#61;ENSG00000204632</a>&#46; Information of the codons considered more interesting was acquired &#40;e&#46;g&#46;&#44; codons 93&#44; 110 and 130&#41;&#46;</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">&#42; INDEL 14-bp polymorphism</span><p id="par0120" class="elsevierStylePara elsevierViewall">The INDEL 14-bp variant was analysed by PCR and the PCR products were visualised by an automatic electrophoretic analysis system &#40;ABI Prism 3130&#41; and with the GenneMapper 4&#46;0 program &#40;Applied Biosystem&#44; CA&#44; USA&#41;&#46; The following were found&#58; a fragment of 211<span class="elsevierStyleHsp" style=""></span>bp for the samples that were homozygous for the deletion of 14<span class="elsevierStyleHsp" style=""></span>bp&#59; a 227<span class="elsevierStyleHsp" style=""></span>bp fragment for the samples that were homozygous for the insertion of 14<span class="elsevierStyleHsp" style=""></span>bp&#59; two fragments of 211<span class="elsevierStyleHsp" style=""></span>bp and 227<span class="elsevierStyleHsp" style=""></span>bp for the heterozygous samples&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Immunostaining</span><p id="par0125" class="elsevierStylePara elsevierViewall">In order to detect HLA-G in the embryonic cytotrophoblast samples&#44; 24 patients and 27 samples were employed&#46; The samples for this technology were randomly selected and attempts were made to include a similar number of patients in each group&#58; 13 abnormal karyotype samples and 14 normal karyotype samples&#46; We believe that this is a sufficiently representative number to determine the HLA-G expression&#44; especially as other studies have included a similar number of samples from different abortion types &#40;<a class="elsevierStyleCrossRefs" href="#bib0225">Patel et al&#46;&#44; 2003&#59; Bhalla et al&#46;&#44; 2006&#59; Emmer et al&#46;&#44; 2002&#59; Rabreau et al&#46;&#44; 2000&#59; Menier et al&#46;&#44; 2003&#59; Honig et al&#46;&#44; 2005&#59; Hviid et al&#46;&#44; 2004b</a>&#41;&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Trophoblast cells were cryo-embedded in an OCT compound &#40;Sakura&#46; Finetek Europe&#44; B&#46;V&#41;&#44; snap-frozen in liquid nitrogen and stored at &#8722;80<span class="elsevierStyleHsp" style=""></span>&#176;C until thin cryosections &#40;5<span class="elsevierStyleHsp" style=""></span>&#956;m&#41; were obtained&#46; HLA immunostaining quantification was done with the Vectastain Elite ABC Kit &#40;Vector Laboratory&#44; UK&#41;&#46; An MEM-G&#47;9 monoclonal antibody &#40;ABCAM&#59; ab7758&#41; was utilised at a dilution of 1&#58;500 for HLA-G detection and 4D12 &#40;MBL&#44; K0215-3&#41; at a dilution of 1&#58;100 for HLA-E detection&#46; A biotinylated secondary antibody and Avidin Biotin Complex &#40;ABC&#41; plus DAB were used as the detection system&#46; Tissues were counterstained with haematoxylin&#46; To test immunostaining specificity&#44; serial of cytotrophoblast was used in the absence of a primary antibody as negative control&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">All the sections were evaluated quantitatively in order to grade the intensity of the HLA-G expression by five researchers for internal consistency purposes&#46; The pattern of expression and the intensity of staining were evaluated as follows&#58; 1 no expression&#59; 2 weak expression&#59; 3 moderate expression&#59; 4 high expression&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Statistical analysis</span><p id="par0140" class="elsevierStylePara elsevierViewall">The statistical analysis was performed by the Statistical Package for Social Sciences 19&#46;0 &#40;SPSS Inc&#46;&#44; Chicago&#44; USA&#41;&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">A chi-square test was carried out for the statistical analysis of the presence of polymorphisms and haplotypes&#46; A non-parametric Mann&#8211;Whitney <span class="elsevierStyleItalic">U</span> and Kruskal&#8211;Wallis test was used for the statistical analysis of the HLA-G expression in polymorphisms and haplotypes&#44; where <span class="elsevierStyleItalic">p</span> values<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 were considered statistically different&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">To assess any possible differences found among the different observers of immunostaining&#44; a quadratic Kappa index was utilised&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Results</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Karyotype analysis and population characteristics</span><p id="par0155" class="elsevierStylePara elsevierViewall">With the 90 interventions and 99 samples of trophoblast&#44; it was possible to obtain chromosome results in 95 samples of trophoblast &#40;95&#46;95&#37;&#41;&#44; since in 4&#46;1&#37; &#40;4&#47;99&#41; of cases existed lack of fetal growth&#46; Among the 95 analyzed trophoblasts have to that 28&#46;4&#37; &#40;27&#47;95&#41; had a normal karyotype and 71&#46;6&#37; &#40;68&#47;95&#41; had abnormal karyotypes&#44; being the most frequent autosomal trisomies &#40;58&#46;8&#37;&#41;&#46; The chromosomal constitution of the pregnancy was based on the analysis of the trophoblast cells&#46; Only in 7&#46;3&#37; of the cases discrepancies between embryo and trophoblast cells were observed &#40;embryos normal and trophoblast abnormal&#41;&#44; these cases were considered as abnormal karyotype as it can be the cause of the miscarriage&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">The analyzed samples showed that 54&#46;7&#37; of the pregnancies had a masculine karyotype and 45&#46;2&#37; had a feminine one&#46; The average age of the patients was 34&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>3&#46;1 years&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Of all the patients included in this study&#44; 16&#46;7&#37; &#40;15&#47;90&#41; were considered recurrent abortions&#44; defined as &#8805;3 spontaneous pregnancy losses before 20 weeks of gestation&#44; and 83&#46;3&#37; &#40;75&#47;90&#41; were classified as spontaneous isolated abortions&#46; Also&#44; 23&#46;3&#37; &#40;21&#47;90&#41; of gestations were naturally conceived&#44; whereas 76&#46;7&#37; &#40;69&#47;90&#41; were achieved by assisted reproduction technology &#40;ART&#41;&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Polymorphisms in normal and abnormal cytotrophoblast samples</span><p id="par0350" class="elsevierStylePara elsevierViewall">All the samples showed heteroparental information&#44; therefore demonstrating the absence of maternal contamination &#40;results not shown&#41;&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Of the 57 samples of trophoblast genetically analysed for the HLA-G gene polymorphisms&#44; 47&#46;4&#37; &#40;27&#47;57&#41; had an embryonic normal karyotype and 52&#46;6&#37; &#40;30&#47;57&#41; an abnormal karyotype&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">No significant differences were observed for the presence of the different polymorphisms &#40;&#8722;725C&#62;G&#44; <span class="elsevierStyleItalic">X</span><span class="elsevierStyleSup">2</span>&#58; 0&#46;02&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;88&#41; &#40;codon 93&#44; CAC&#62;CAT&#44; <span class="elsevierStyleItalic">X</span><span class="elsevierStyleSup">2</span>&#58; 1&#46;04&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;30&#41; &#40;codon 110&#44; CTC&#62;ATC&#44; <span class="elsevierStyleItalic">X</span><span class="elsevierStyleSup">2</span>&#58; 0&#46;19&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;65&#41; &#40;codon 130&#44; del1597C&#44; <span class="elsevierStyleItalic">X</span><span class="elsevierStyleSup">2</span>&#58; 2&#46;5&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;11&#41; &#40;INDEL 14 pb&#44; <span class="elsevierStyleItalic">X</span><span class="elsevierStyleSup">2</span>&#58; 0&#46;003&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;95&#41; between abortions of normal and abnormal karyotypes&#46; No increased incidence of the polymorphisms in the normal karyotype samples was found &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Generation of haplotypes and distribution in our population</span><p id="par0185" class="elsevierStylePara elsevierViewall">After detect afore mentioned polymorphisms in the HLA-G gene&#44; a series of possible haplotypes was generated &#40;see <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> for details&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0190" class="elsevierStylePara elsevierViewall">On the one hand we can see the frequency of occurrence of each haplotype in our population&#46; Haplotypes 1 &#40;no presence of polymorphism&#41; and 2 &#40;INDEL 14pb&#41; were the most frequently found in our study population if compared to the rest of haplotypes&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">Also&#44; we can see the differences in the frequency of occurrence of a specific haplotype between normal and abnormal embryo karyotypes&#46; No significant differences were observed&#44; in any case&#44; in the frequency of a haplotype specific for HLA-G between the normal and abnormal karyotype samples&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">In addition&#44; we wanted to group the different haplotypes generated according to the theoretical HLA-G secretion according to the published data &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; Significant differences did not exist &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;99&#41; as for the distribution of the haplotypes secretors&#44; joined by levels of secretion&#44; between abortions of normal and abnormal karyotypes&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">HLA-G protein expression in normal and abnormal cytotrophoblast samples</span><p id="par0205" class="elsevierStylePara elsevierViewall">Immunostaining was performed on 25 patients&#46; Of the 27 trophoblast samples&#44; 13 showed an abnormal karyotype and 14 had a normal karyotype&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">All the samples &#40;100&#37;&#41; were positive for the HLA-G expression&#44; while the HLA-E expression was weakly positive in only 14 of the 27 samples &#40;51&#46;8&#37;&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0215" class="elsevierStylePara elsevierViewall">No significant differences &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;75&#41; were found in the mean HLA-G intensity in both the normal and abnormal karyotype samples &#40;2&#46;92 vs&#46; 2&#46;65&#44; respectively&#41;&#46; Neither the normal nor the abnormal types had significant differences &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;76&#41; at the HLA-E expression level &#40;1&#46;17 vs&#46; 1&#46;44&#44; respectively&#41;&#46; Finally&#44; there were no significant differences between observers &#40;quadratic Kappa index &#62;70&#37;&#41;&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Association between polymorphisms and haplotypes with the protein expression of HLA-G</span><p id="par0220" class="elsevierStylePara elsevierViewall">No association was observed between the presence of specific polymorphisms and HLA-G secretion at the cytotrophoblast level &#40;<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46; The presence of a particular polymorphism does not alter the expression of HLA-G &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;79&#41;&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0225" class="elsevierStylePara elsevierViewall">In addition&#44; as mentioned above&#44; the different generated haplotypes were grouped based on the theoretical HLA-G secretion in accordance with the literature&#46; There is a correlation between the theoretical grouping of haplotypes and the real secretion of HLA-G produced by these haplotypes &#40;<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>&#41;&#46; However&#44; no significant differences were found in the average of HLA-G expression by cytotrophoblast cells between the three types of secretory haplotypes &#40;2&#46;75 vs&#46; 3&#46;25 vs&#46; 2&#46;92&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;59&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Discussion</span><p id="par0230" class="elsevierStylePara elsevierViewall">Many causes for first trimester spontaneous abortions have been proposed&#46; Although the aetiology of the majority of spontaneous abortions lies in chromosomal anomalies&#44; their pathology is associated at the end with the immune system responses &#40;<a class="elsevierStyleCrossRefs" href="#bib0295">Vassiliadou et al&#46;&#44; 1999&#59; Olivares et al&#46;&#44; 2002</a>&#41;&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">In this study&#44; we decide to study the molecules of the HLA-G and HLA-E since they are good candidates to protect the embryo against the maternal immune system using several functions&#46; It has been observed that the presence of some polymorphisms in the HLA-G gene is related with an alteration in the levels of HLA-G expression &#40;<a class="elsevierStyleCrossRefs" href="#bib0165">Mendes-Junior et al&#46;&#44; 2010&#59; Rebmann et al&#46;&#44; 1999&#44; 2001&#59; Ober et al&#46;&#44; 1996&#59; Chen et al&#46;&#44; 2008&#59; Gonzalez et al&#46;&#44; 2010</a>&#41;&#46; Diminished or insufficient HLA-G expression can be associated with certain complications in pregnancy&#44; such as pregnancy loss &#40;<a class="elsevierStyleCrossRefs" href="#bib0235">Pfeiffer et al&#46;&#44; 2000&#44; 2001&#59; Athanassakis et al&#46;&#44; 1999&#59; Alegre et al&#46;&#44; 2007&#59; Emmer et al&#46;&#44; 2002</a>&#41;&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">In this study we aimed to determine the role of HLA-G by analyzing some genetic polymorphisms that might be relevant during pregnancy and which have been related with an altered HLA-G protein expression&#46; Besides&#44; we decided to evaluate the presence and quantity of the expression of this molecule&#44; and also of the HLA-E expression&#44; in the embryo cytotrophoblast of spontaneous abortion samples by comparing pregnancies which were probably arrested by a chromosomal vs&#46; a non-chromosomal cause&#46; However&#44; neither the HLA-G genotype nor the HLA-G and HLA-E protein expression were different in chromosomally abnormal miscarriages compared to the normal ones&#46; Furthermore no association was found between the HLA-G gen polymorphisms and local HLA expression in the trophoblast cells in any type of abortion&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">The novel aspect of this work lies in using embryo trophoblast samples from early-stage abortions&#44; using the technique known as hystero-embryoscopy&#44; with which&#44; almost certainly&#44; is not affected by maternal contamination and obtain high reliability of the embryonic karyotype diagnosed &#40;<a class="elsevierStyleCrossRef" href="#bib0075">Ferro et al&#46;&#44; 2003</a>&#41;&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Despite other studies have employed placenta tissue from the first pregnancy after VPI &#40;<a class="elsevierStyleCrossRefs" href="#bib0085">Hiby et al&#46;&#44; 1999&#59; Hviid et al&#46;&#44; 2003</a>&#41; or abortion &#40;<a class="elsevierStyleCrossRef" href="#bib0180">Moreau et al&#46;&#44; 2008</a>&#41;&#44; but they did not specify the method followed to obtain samples&#44; so it is assumed that chromosome determination was done by conventional curettage&#46; Some of the mentioned studies have looked for associations between certain genotypes with RNAm levels&#44; but they did not analyze the actual protein HLA-G presence on the cytotrophoblast cells&#46;</p><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Polymorphisms of the HLA-G gene and their distribution between normal and abnormal karyotype miscarriages</span><p id="par0260" class="elsevierStylePara elsevierViewall">According to our results&#44; no differences were found in the frequency of the studied polymorphisms between trophoblast samples with normal and abnormal karyotypes&#46; The frequency of the polymorphisms found in our study were within the range of other published data in women suffering of recurrent abortion &#40;<a class="elsevierStyleCrossRefs" href="#bib0095">Hviid et al&#46;&#44; 2002&#59; Aruna et al&#46;&#44; 2010&#59; Sipak-Szmigiel et al&#46;&#44; 2007</a>&#41;&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">Nowadays&#44; there are contradictory results among the various genetic studies conducted on HLA-G&#46; Some authors found no association between some polymorphisms and abortion&#44; while others believe that a deletion or mutation in the HLA-G gene can affect the generation of the final protein&#44; and can even lead to pregnancy loss&#46; The variations between studies might be due to study design&#44; small sample size&#44; use of a coding or non-coding region&#44; or even the analysed exon &#40;<a class="elsevierStyleCrossRef" href="#bib0095">Hviid et al&#46;&#44; 2002</a>&#41;&#46; Besides&#44; the results may vary depending on whether the polymorphisms in the HLA-G gene have been analysed in either the peripheral blood taken from the mother only&#44; from either parents&#44; or the foetal tissue itself that is unable to successfully achieve a term pregnancy&#46; In our study the analysis we carried out in abortive tissue&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Generated haplotypes</span><p id="par0270" class="elsevierStylePara elsevierViewall">After grouping the polymorphisms in haplotypes&#44; trophoblast samples that contain no polymorphisms in the HLA-G gene&#44; as are haplotype 1 &#40;wt&#41; and INDEL 14 pb polymorphisms &#40;haplotype 2&#41;&#44; were significantly &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; the most frequent in both chromosomally normal and abnormal samples&#46; To some extent&#44; this corroborates the low polymorphism of the HLA-G gene as compared with other classic HLAs&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">Despite no differences being observed in the distribution of a given polymorphism between normal and abnormal karyotype trophoblast samples&#44; we wanted to evaluate if the haplotypes could show differing frequencies between our two study populations&#46; However&#44; no significant differences were found in the distribution of these haplotypes generated between normal and abnormal karyotype samples&#46; In other words&#44; samples with a normal and abnormal karyotype present a similar incidence of frequency in appearing in a given haplotype &#40;see <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">The same occurred when we grouped the haplotypes obtained according to their theoretical protein-secreting HLA-G&#46; No significant differences were observed for the frequency of secreting HLA-G haplotypes&#44; which were grouped according to secretion levels&#44; between trophoblast samples with normal and abnormal karyotypes &#40;see <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">Although many studies have analysed the frequency of a certain haplotype in a group of individuals&#44; even today&#44; there is no study which compares the frequency with which a haplotype appears in spontaneous abortion patients&#44; and none has compared chromosomally normal and abnormal abortions&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Expression of HLA-G and HLA-E</span><p id="par0290" class="elsevierStylePara elsevierViewall">Variations the HLA-G gene can entail alterations in the immune response by either affecting the functionality and superficial expression of the HLA-G molecule &#40;<a class="elsevierStyleCrossRef" href="#bib0290">Van der Ven et al&#46;&#44; 1998</a>&#41; or by affecting the sequence of its leader peptide&#46; This sequence is indispensable for the superficial HLA-E expression&#44; which would imply in the embryo lacking protection against the mother &#40;<a class="elsevierStyleCrossRefs" href="#bib0115">Hviid et al&#46;&#44; 1999&#59; O&#8217;Callaghan and Bell&#44; 1998</a>&#41;&#46;</p><p id="par0295" class="elsevierStylePara elsevierViewall">According to the literature&#44; the polymorphisms studied in this project &#40;&#8722;725C&#62;G&#44; codon 93&#44; codon 110&#44; codon 130 and INDEL 14<span class="elsevierStyleHsp" style=""></span>bp&#41; do not relate with changes in the tertiary HLA-G structure&#46; In principle&#44; the interaction functions of this molecule with others should not be affected&#59; for example&#44; the inhibition of NK cells by the interaction with their receptors&#46; Nonetheless&#44; all these polymorphisms have been related with changes in the superficial HLA-G expression level&#44; so&#44; when the quantity of HLA-G increases excessively and when it also lowers&#44; some of its functions might be affected&#46;</p><p id="par0300" class="elsevierStylePara elsevierViewall">After detecting the presence of some HLA-G polymorphisms in our study samples&#44; we decided to evaluate the impact they have on the protein secretion of the HLA-G molecule in the embryonic trophoblast&#44; and its effect on the HLA-E expression&#46;</p><p id="par0305" class="elsevierStylePara elsevierViewall">According to our data&#44; the immunohistochemistry technique did not reveal significant differences in the HLA-G expression between trophoblast samples from normal and abnormal karyotype abortions&#46; Abnormal ones were employed as reference samples where the cause of abortion was almost certainly the chromosomal anomaly&#46; Thus&#44; we cannot state that in those cases of cause of abortion not known or chromosomally normal abortion&#40;s&#41; the cause of arrested pregnancy is an absent or diminished HLA-G expression in the foetal cytotrophoblast&#46; Besides&#44; our data coincide with those reported by other authors &#40;<a class="elsevierStyleCrossRefs" href="#bib0045">Bhalla et al&#46;&#44; 2006&#59; Patel et al&#46;&#44; 2003</a>&#41;&#44; where HLA-G does not appear to be a molecule that determines pregnancy maintenance&#46; Furthermore&#44; we wanted to see the distribution and intensity of the HLA-E protein expression in the trophoblast samples and whether its expression is somehow conditioned by HLA-G&#46; It is well-known that for the HLA-E expression to appear on the cell surface&#44; the presence of a leader peptide from other class I HLA molecules is required&#46; As mentioned earlier&#44; there is only one HLA-G expression in the cytotrophoblast&#44; so the HLA-E expression will be subjected to the leader peptide of HLA-G and&#44; therefore&#44; indirectly to the HLA-G expression&#46; After observing that some samples express HLA-G in the embryo cytotrophoblast&#44; but they cannot express HLA-E&#44; we can specify that the HLA-G expression is not determinant enough to lead to the HLA-E expression&#46; These data contradict findings reported by other authors &#40;<a class="elsevierStyleCrossRefs" href="#bib0120">Ishitani et al&#46;&#44; 2003&#59; Llano et al&#46;&#44; 1998</a>&#41; who believe that wherever a soluble HLA-G expression&#44; or one joined to the membrane&#44; is found&#44; there must be a HLA-E expression&#46; Hence&#44; we assume that many other factors must influence this surface expression mechanism&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">We observed a considerably and generally reduced HLA-E expression in our studied samples as compared to the HLA-G expression&#46; Besides&#44; and coinciding with the fact that no correlation was found with HLA-G&#44; we observed no significant differences in the HLA-E expression between the trophoblast samples from normal and abnormal karyotype abortions&#46; Therefore&#44; we can only assume that either their diminished expression or the fact that HLA-E was absent in some cases in the embryo cytotrophoblast is not responsible for pregnancy loss&#46; Our results coincide with those of similar study by another author &#40;<a class="elsevierStyleCrossRef" href="#bib0045">Bhalla et al&#46;&#44; 2006</a>&#41;&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Association between the studied polymorphisms&#44; and their corresponding haplotypes&#44; and the HLA-G protein expression</span><p id="par0320" class="elsevierStylePara elsevierViewall">In our study&#44; no significant differences were observed in the HLA-G expression for each polymorphism between normal and abnormal karyotype samples&#46; After grouping samples irrespectively of their embryonic karyotype&#44; and having taken the mean HLA-G expression&#44; no significant differences &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;79&#41; were obtained in the mean HLA-G expression between the trophoblast samples containing no polymorphism &#40;a value of 3&#46;1&#41; and those that did &#40;values of 2&#46;7&#8211;3&#46;1&#41;&#46; Therefore&#44; we deduce that the presence of a specific polymorphism does not influence the HLA-G expression levels in the trophoblast samples &#40;see <a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#41;&#46;</p><p id="par0325" class="elsevierStylePara elsevierViewall">Despite each polymorphism not presenting differences in the HLA-G expression&#44; we wished to see if there were any differences in the HLA-G expression when grouping polymorphisms and generating different haplotypes&#46; Haplotypes were grouped in function of their theoretical secretion of HLA-G described in the literature&#46; The HLA-G expression in the three generated secreting haplotypes corresponded to the theoretical secreting haplotype kind &#40;2&#46;75 for the low-secreting ones&#44; 3&#46;25 for the high-secreting ones and 2&#46;92 for the haplotypes that did not affect expression&#41; &#40;see <a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>&#41;&#46; However&#44; these differences in expression of HLA-G among the three generated secretory haplotypes were not statistically significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;59&#41;&#46; Besides&#44; no haplotype was found which presented a significantly higher HLA-G expression than another haplotype&#46; Also&#44; no significant differences were found in the HLA-G expression of the secreting haplotypes in accordance with a normal or abnormal karyotype kind&#46;</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Conclusion</span><p id="par0330" class="elsevierStylePara elsevierViewall">Based on the data obtained in the present study it seems that&#44; HLA-G production in the foetal-maternal interphase is carried out constitutively&#44; and no significant differences are noted in the various polymorphic variants or among the protein expression data among arrested pregnancies due to chromosomal and unknown causes&#46;</p><p id="par0335" class="elsevierStylePara elsevierViewall">Given the immunocompetent machinery in the human uterus that facilitates pregnancy being accepted&#44; we are inclined to believe that pregnancy loss must depend on other regulation defects that are not necessarily triggered by the HLA-G molecule&#44; such as genetic anomalies in NK cells or their inhibitory receptors&#44; to such an extent that they do not properly perform their beneficial functions to maintain pregnancy or a specific maternal immunological situation at this specific gestational time&#46; Therefore&#44; we consider that a study in the deciduas using our study model could contribute new data in future studies to clarify causes of pregnancy loss&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Funding</span><p id="par0340" class="elsevierStylePara elsevierViewall">This project was supported by R&#43;D programme from the Centre for Industrial Technological Development &#40;CDTI&#44; ID 2007003&#41;&#44; a public corporation of the Spanish Ministry of Economy and Competitiveness and the IMPIVA R&#43;D &#40;IM IDTF&#47;2007&#47;166&#41; programme of the Generalitat Valenciana &#40;Regional Valencian Government&#41;&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Conflict of interest</span><p id="par1350" class="elsevierStylePara elsevierViewall">None of the authors declared a conflict of interest&#46;</p></span></span>"
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                  "titulo" => "&#42; Exon 3 polymorphism"
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              "titulo" => "Generation of haplotypes and distribution in our population"
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              "titulo" => "Generated haplotypes"
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              "titulo" => "Association between the studied polymorphisms&#44; and their corresponding haplotypes&#44; and the HLA-G protein expression"
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    "fechaRecibido" => "2015-04-29"
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            1 => "Human cytotrophoblast"
            2 => "Polymorphism"
            3 => "Protein expression"
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            1 => "Citotrofoblasto humano"
            2 => "Polimorfismo y Expresi&#243;n proteica"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">HLA-G and HLA-E are claimed to play a role in establishing maternal&#8211;fetal immune tolerance and in maintaining pregnancy&#46; The presence of polymorphism in the HLA-G gene could cause a deficient or excessive expression of the HLA-G and HLA-E molecules&#46; These anomalies could eventually cause pregnancy losses&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Clinical study&#46; A total of 90 patients were included in this study&#46; These patients suffered spontaneous abortions between weeks 6 and 11 of pregnancy&#46; We have analysed the most important polymorphisms of the HLA-G gene through different genetic studies and HLA-G and HLA-E expression through immunostaining in human cytotrophoblast cells from first trimester spontaneous abortions obtained by hystero-embryoscopy&#46; Placental biopsies obtained with this technique have minimal risk of maternal contamination and provide a reliable embryo karyotype&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Result</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We found that the expression of HLA-G and HLA-E is similar between samples of normal and abnormal karyotype&#46; In addition&#44; we found no evidence of association between the HLA-G polymorphisms and altered expression in both abortion groups&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Discussion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">This is the first study to analyse embryonic tissue which was unable to complete its implantation successfully&#46; We used a new technique with a minimal risk of maternal contamination which provided a reliable karyotype&#46; Our results suggest that&#44; neither HLA-G nor HLA-E protein expression seem responsible for spontaneous pregnancy losses in the first trimester&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducci&#243;n</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Las mol&#233;culas del HLA-G y HLA-E desempe&#241;an un papel muy importante en el establecimiento de la tolerancia inmune materno-fetal y en el mantenimiento del embarazo&#46; La presencia de polimorfismos en el gen HLA-G podr&#237;a causar una excesiva o deficiente expresi&#243;n del HLA-G&#44; y esto&#44; afectar a la expresi&#243;n del HLA-E&#46; Estas anomal&#237;as de expresi&#243;n podr&#237;an causar la p&#233;rdida del embarazo&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Materiales y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Estudio cl&#237;nico&#46; Un total de 90 pacientes fueron incluidas en este estudio&#46; Estas pacientes sufrieron abortos espont&#225;neos notificados entre la semana 6 y 11 de gestaci&#243;n&#46; Analizamos los polimorfismos m&#225;s importantes del gen del HLA-G mediante diferentes estudios gen&#233;ticos y la expresi&#243;n del HLA-G y HLA-E mediante inmunohistoqu&#237;mica en las c&#233;lulas del citotrofoblasto humano de abortos espont&#225;neos de primer trimestre obtenidos mediante histero-embrioscopia&#46; Con esta novedosa t&#233;cnica obtenemos biopsias placentarias con el m&#237;nimo riesgo de contaminaci&#243;n materna y as&#237; podemos proporcionar un cariotipo embrionario con alta fiabilidad&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">En este estudio encontramos que la expresi&#243;n proteica de HLA-G y HLA-E es similar entre muestras de cariotipo normal y anormal&#46; Adem&#225;s&#44; no encontramos asociaci&#243;n entre los polimorfismos de HLA-G y la alteraci&#243;n de su expresi&#243;n en ambos tipos de aborto&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Discusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Somos los primeros en analizar el propio tejido embrionario incapaz de terminar de forma exitosa su implantaci&#243;n&#46; Nuestros resultados sugieren que&#44; ni la expresi&#243;n de la prote&#237;na del HLA-G ni del HLA-E parecen responsables de las p&#233;rdidas del embarazo espont&#225;neo de primer trimestre&#46;</p></span>"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Intensity of HLA-G and HLA-E expression&#46; &#40;a&#41; Mesenchyma&#44; &#40;b&#41; syncytiotrophoblast and &#40;c&#41; extravillous cytotrophoblast&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Promotor &#40;&#8722;725C&#62;G&#41;</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Fragment generated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Forward&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#8242; GAAAGTGAAACTTAAGAGCTTTGTGAG<span class="elsevierStyleBold">GC</span> 3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="middle">117 bp</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Reverse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#8242; TTGGTAACCCCTGAATGATCAG 3&#8242; VIC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Exon 3</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Forward&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#8242; GGCGCCTTTACCAAAATCC 3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="middle">438 bp</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Reverse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#8242; GCACAAGGAGAGGAGGAAAATG 3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="3" align="left" valign="top">Exon 8 &#40;INDEL 14pb&#41;</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Forward&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#8242;GTGATGGGCTGTTTAAAGTGTCACC 3&#8242;&#46; 6-FAM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="middle"><span class="elsevierStyleItalic">227 bp</span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Reverse&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">5&#8242;GGAAGGAATGCAGTTCAGCATGA 3&#8242;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab946593.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Primers used in the genetic analysis of the HLA-G&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Presence of polymorphism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">&#8722;725C&#62;G&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Codon 93CAC&#62;CAT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Codon 110CTC&#62;ATC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Codon 130del1597C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">INDEL 14pb&#40;&#43;&#47;&#43; and &#43;&#47;&#8722;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Abnormal karyotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#47;30 &#40;20&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">8&#47;29 &#40;27&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">6&#47;29 &#40;20&#46;65&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#47;29 &#40;3&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">18&#47;30 &#40;60&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Normal karyotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">5&#47;27 &#40;18&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#47;25 &#40;16&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#47;25 &#40;16&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">4&#47;25 &#40;16&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">16&#47;27 &#40;59&#46;2&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab946598.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Presence of polymorphism in the HLA-G gen&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Haplotypes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Normal karyotypes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Abnormal karyotypes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Wt&#44; Wt&#44; Wt&#44; Wt&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#47;25 &#40;24&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#47;29 &#40;20&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Wt&#44; Wt&#44; Wt&#44; Wt&#44; INDEL 14pb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">7&#47;25 &#40;28&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6&#47;29 &#40;20&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;75&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;725C&#62;G&#44; Wt&#44; Wt&#44; Wt&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#47;25 &#40;12&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#47;29 &#40;10&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Wt&#44; Wt&#44; Wt&#44; del1597C&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Wt&#44; codon 93&#44; Wt&#44; Wt&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Wt&#44; Wt&#44; codon 110&#44; Wt&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#47;25 &#40;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#47;29 &#40;10&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;61&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;725C&#62;G&#44; Wt&#44; Wt&#44; Wt&#44; INDEL 14pb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#47;25 &#40;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#47;29 &#40;6&#46;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Wt&#44; Wt&#44; Wt&#44; del1597C&#44; INDEL 14pb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#47;25 &#40;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#47;29 &#40;3&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Wt&#44; codon 93&#44; Wt&#44; Wt&#44; INDEL 14pb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4&#47;29 &#40;13&#46;7&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Wt&#44; Wt&#44; codon 110&#44; Wt&#44; INDEL 14pb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Wt&#44; Wt&#44; cod&#243;n 110&#44; del1597C&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Wt&#44; cod&#243;n 93&#44; Wt&#44; del1597C&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;725G&#62;C&#44; Wt&#44; Wt&#44; del1597C&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;725G&#62;C&#44; codon 93&#44; Wt&#44; Wt&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;725G&#62;C&#44; Wt&#44; codon 110&#44; Wt&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#47;25 &#40;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Wt&#44; Cod&#243;n 93&#44; cod&#243;n 110&#44; Wt&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Wt&#44; cod&#243;n 93&#44; Wt&#44; del1597C&#44; INDEL 14pb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#47;25 &#40;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Wt&#44; cod&#243;n 93&#44; cod&#243;n 110&#44; Wt&#44; INDEL 14pb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#47;25 &#40;8&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#47;29 &#40;10&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="char" valign="top">19&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;725G&#62;C&#44; cod&#243;n 93&#44; Wt&#44; Wt&#44; INDEL 14pb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">1&#47;29 &#40;3&#46;4&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">1&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab946595.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Haplotypes generated of HLA-G&#46;</p>"
        ]
      ]
      4 => array:7 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Haplotypes</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Normal karyotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Abnormal karyotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="7" align="left" valign="middle">Low secretion of HLA-G</td><td class="td" title="table-entry  " align="left" valign="top">2&#95;Wt&#44; Wt&#44; Wt&#44; Wt&#44; INDEL 14pb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="7" align="left" valign="middle">13&#47;25 &#40;52&#37;&#41;</td><td class="td" title="table-entry  " rowspan="7" align="left" valign="middle">15&#47;29 &#40;51&#46;7&#37;&#41;</td><td class="td" title="table-entry  " rowspan="16" align="left" valign="middle">0&#46;99</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">4&#95;Wt&#44; Wt&#44; Wt&#44; del1597C&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">8&#95;Wt&#44; Wt&#44; Wt&#44; del1597C&#44; INDEL 14pb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">9&#95;Wt&#44; codon 93&#44; Wt&#44; Wt&#44; INDEL 14pb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">12&#95;Wt&#44; codon 93&#44; Wt&#44; del1597C&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">17&#95;Wt&#44; codon 93&#44; Wt&#44; del1597C&#44; INDEL 14pb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">18&#95;Wt&#44; codon 93&#44; codon 110&#44; Wt&#44; INDEL 14pb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="middle">High secretion of HLA-G</td><td class="td" title="table-entry  " align="left" valign="top">3&#95;&#8722;725C&#62;G&#44; Wt&#44; Wt&#44; Wt&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="4" align="left" valign="middle">5&#47;25 &#40;20&#37;&#41;</td><td class="td" title="table-entry  " rowspan="4" align="left" valign="middle">6&#47;29 &#40;20&#46;7&#37;&#41;</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">6&#95;Wt&#44; Wt&#44; codon 110&#44; Wt&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">14&#95;725G&#62;C&#44; codon 93&#44; Wt&#44; Wt&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">16&#95;Wt&#44; codon 93&#44; codon 110&#44; Wt&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="5" align="left" valign="middle">It does not affect the expression</td><td class="td" title="table-entry  " align="left" valign="top">1&#95;Wt&#44; Wt&#44; Wt&#44; Wt&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="5" align="left" valign="middle">7&#47;25 &#40;28&#37;&#41;</td><td class="td" title="table-entry  " rowspan="5" align="left" valign="middle">8&#47;29 &#40;27&#46;6&#37;&#41;</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">7&#95;&#8722;725C&#62;G&#44; Wt&#44; Wt&#44; Wt&#44; INDEL 14pb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">10&#95;Wt&#44; Wt&#44; codon 110&#44; Wt&#44; INDEL 14pb&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">11&#95;Wt&#44; Wt&#44; codon 110&#44; del1597C&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">13&#95;&#8722;725G&#62;C&#44; Wt&#44; Wt&#44; del1597C&#44; Wt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab946597.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Group of the haplotypes depending on his supposed HLA-G protein secretion&#46;</p>"
        ]
      ]
      5 => array:7 [
        "identificador" => "tbl0025"
        "etiqueta" => "Table 5"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " rowspan="3" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">HLA-G expression</th><th class="td" title="table-head  " colspan="11" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Polymorphisms</th></tr><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">No Polymorphisms&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">&#8722;725C&#62;G</th><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Codon 93</th><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Codon 110</th><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Codon 130 Del1597C</th><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">INDEL 14pb</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Average expression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;98&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;77&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;85&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;79&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;76&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab946594.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Association between polymorphisms and protein expression of HLA-G&#46;</p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "tbl0030"
        "etiqueta" => "Table 6"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">HLA-G expression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Normal karyotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Abnormal karyotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Average&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black"><span class="elsevierStyleItalic">p</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HLA-G low secretory&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;98&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">2&#46;75</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">0&#46;59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">HLA-G high secretory&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No date&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">3&#46;25&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">3&#46;25</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Not affect the HLA-G secretion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">3&#46;35&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top">2&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="char" valign="top"><span class="elsevierStyleBold">2&#46;92</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab946596.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Association between haplotypes and protein expression of HLA-G&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:62 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "Abbas et al&#46;&#44; 2004"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Analysis of human leukocyte antigen &#40;HLA&#41;-G polymorphism in normal women and in women with recurrent spontaneous abortions"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46; Abbas"
                            1 => "P&#46; Tripathi"
                            2 => "S&#46; Naik"
                            3 => "S&#46; Agrawal"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/j.1365-2370.2004.00487.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur&#46; J&#46; Immunogenet&#46;"
                        "fecha" => "2004"
                        "volumen" => "31"
                        "paginaInicial" => "275"
                        "paginaFinal" => "278"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15548266"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "Aldrich et al&#46;&#44; 2001"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "HLA-G genotypes and pregnancy outcome in couples with unexplained recurrent miscarriage"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:8 [
                            0 => "C&#46;L&#46; Aldrich"
                            1 => "M&#46;D&#46; Stephenson"
                            2 => "T&#46; Karrison"
                            3 => "R&#46;R&#46; Odem"
                            4 => "D&#46;W&#46; Branch"
                            5 => "J&#46;R&#46; Scott"
                            6 => "J&#46;R&#46; Schreiber"
                            7 => "C&#46; Ober"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Mol&#46; Hum&#46; Reprod&#46;"
                        "fecha" => "2001"
                        "volumen" => "7"
                        "paginaInicial" => "1167"
                        "paginaFinal" => "1172"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11719594"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "Alegre et al&#46;&#44; 2007"
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ISSN: 23409320
Original language: English
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