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HLA Class I and II study in a mestizo family with high incidence of autoimmune disease
Estudio de HLA Clase I y II en una familia mestiza con alta incidencia de enfermedades autoinmunes
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Perrando Hospital, Resistencia, Chaco, Argentina" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Medical Clinic Department, Julio C. Perrando Hospital, Resistencia, Chaco, Argentina" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Estudio de HLA Clase I y II en una familia mestiza con alta incidencia de enfermedades autoinmunes" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1359 "Ancho" => 3120 "Tamanyo" => 277599 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of the HLA Class I and II haplotype in a family with high burden of autoimmune disease. Note that the maternal haplotype called (b) share the Class II alleles (DRB1*0407-DQB1*03) with the paternal haplotype called (d). This paternal haplotype is present in all patients with SLE.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Pathogenesis of autoimmune disease (AID) is associated with functional deficiency of multiples immunologic component including innate immune system. The failure of mechanisms regulatory could be due to the influence of multiple genetic factors to contribute to disease susceptibility.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The search for genes in systemic lupus erythematosus (SLE) have focused, on the highly polymorphic HLA Class I and II genes as well as genes within the HLA Class III region, particularly tumor necrosis factor (TNF) and complement component C4 gene loci.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Work by Graham et al.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> involving an analysis of approximately 50 microsatellite genetic markers across the HLA region among a set of 780 SLE families, the importance of HLA Class II haplotypes involving the HLA-DRB1 and -DQB1 loci, particularly those corresponding to serologic types HLA-DR2 and DR3.</p><p id="par0020" class="elsevierStylePara elsevierViewall">GWAS (genomic-wide association studies) in both European and Asian populations have shown that the strongest contribution to risk for SLE resides in the HLA region have identified more than 30 associated including genetic variants of HLA and Fcγ receptor genes, IRF5, STAT4, PTPN22, TNFAIP3, BLK, BANK1, TNFSF4 and ITGAM. However, these loci account for less than 10% of the genetic heritability.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3–5</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Population studies reveal that the susceptibility to SLE involves human leukocytes antigen (HLA) Class II. An association of HLA DR2 and DR3 with SLE is a common finding in patients of different ethnicities, some related to the presence of certain autoantibodies.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,6</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Some authors, find relationship of HLA Class I on progression of autoimmune diseases primarily mediated by CD8<span class="elsevierStyleSup">+</span> T lymphocytes that recognize HLA Class I peptides and determine the antigen specificity of the CTL-mediated immune response aganist pathogens and self-antigens.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7,8</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">On the other hand it is established that certain KIR receptors interact with Class I HLA molecules involved in the activation and inhibition of NK cells. The polymorphism of both molecules (HLA Class I and KIR receptors) lead to different cellular recognition and in some cases could cause imbalances that trigger diseases.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9,10</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">The aim of this study was to investigate the genes HLA Class I and II in a family with a high incidence of AID to establish whether they can contribute to the development of these diseases.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Materials and methods</span><p id="par0045" class="elsevierStylePara elsevierViewall">A mestizo family from Chaco Northeast Argentina with Hispanic Amerindian genetic background was select for the present study due to the high incidence of autoimmune diseases that present members of this family. Of eight members – father, mother and six children – five have developing an autoimmune disease, four with Systemic Lupus Erythematosus (SLE) according to the Immunologic and Clinical criteria of the American College of Rheumatology for a diagnosis of SLE,<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> and one with Autoimmune Hemolytic Anaemia (AIHA) whose diagnosis was based on the presence of anaemia, signs of haemolysis with reticulocytosis, low haptoglobin, increased lactate dehydrogenase, elevated indirect bilirubin, and positive direct antiglobulin test (Coombs test). In all patients diagnosed with Lupus we observed that skin was highly compromised but not other organs. The skin lesions were characterized by ulcerative papules, nodules, rash on face, torso and hands, in addition: arthritis, hair loss, fatigue. At diagnosis, one of the patients had pericarditis and other vasculitis also had low levels of anticardiolipin antibodies. Antinuclear antibodies (ANA) with speckled pattern with titers between 160 and 320 in all patients with SLE and two of them also presented anti-DNA antibodies.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Peripheral blood sample was extracted from all these patients according to the ethical standards of the responsible committee on human experimentation and to the Helsinki Declaration of 1975; DNA was extracted from mononuclear cells by using the Salting-out method. HLA-A*, B*, DRB1* and DQB1* genotyping were performed by men's of PCR followed by sequence-specific oligonucleotide probe reverse hybridization (SSO-Dynal). For the analysis of results the DYNAL strip software was used. The hybridization pattern hybridizations are updated twice a year for the manufacturer according to WHO Nomenclature Committee and IMGT/HLA Database. The lasted hit table can be found at <a class="elsevierStyleInterRef" href="http://www.tissue-typing.com/">www.tissue-typing.com</a>.</p><p id="par0055" class="elsevierStylePara elsevierViewall">LIPA-Key typing system and LIPA Software (INNOGENETICS) was used to define the subtypes of alleles in all patients that present the DRB1*04.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Statistical methods</span><p id="par0060" class="elsevierStylePara elsevierViewall">We performed the statistical analysis of HLA genes in the family following the Mendel's law of segregation. The association degree between observed and expected frequency was expressed in the odds radio (OR), which was calculated according to Woolf's formula. Significance of the observed association was determined using the Chi-square test and corrected by Yates or Fisher's exact test two-tailed with 95% confidence intervals (Cis), <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05 was considered significant.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Results</span><p id="par0065" class="elsevierStylePara elsevierViewall">The results of HLA Class I and II typing are shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">In four of the members of the family diagnosed with SLE we observed the presence of the HLA A*02 B*40 DRB1*04:07 DQB1*03:02 haplotype – of paternal line (with SLE). Three of the healthy members and the female patient with AIHA did not carry this haplotype. We analyze the observed and expected frequency of this haplotype, a highly significant result was observed, <span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>55.38 according to Mantel–Haenzel and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.0000000 using Yates correction.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Instead the patient diagnosed with AIHA and one of his siblings who had Class II haplotype DRB1*04:07, DQB1*03:02, which belongs to the maternal line (both parents have this haplotype Class II, but with different Class I haplotypes). Analyzing the observed and expected frequency of this haplotype, the results were not statistically significant, OR<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1.52, <span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2.65 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.103 (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0080" class="elsevierStylePara elsevierViewall">In four of the members of the family diagnosed with SLE we observed the presence of the HLA A*02 B*40 DRB1*04:07 DQB1*03:02 haplotype – of paternal line (with SLE). Three of the healthy members and the female patient with AIHA did not carry this haplotype.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Our results show the presence of Class II haplotype DRB1*04:07, DQB1*03.02, however did not find a direct association as would be expected because DRB1*04:07 allele is found with high frequency in Amerindian population. However, several authors report this allele in association to different AID. Gonzalez-Treviño et al.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> found that Hashimoto tiroiditis was associated with homozygosity for HLA-DRB1*04, Asenjo et al.,<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> found association with DRB1*0407, DQB1*0302 in a Mapuche family with high incidence of Type I Diabetes. Lopez-Tello et al.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> found a significant increase in the frequency of the HLA-DR4 (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.16) and the HLA-DR16 (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.005) alleles in a Mexican population with SLE.</p><p id="par0090" class="elsevierStylePara elsevierViewall">In this family, we analyzed Class I and Class II haplotype, and all patients with SLE show HLA A*02 B*40 DRB1*0407 DQB1*0302 with high statistical significance. Referring to ours findings, we must consider how HLA Class I in linkage disequilibrium with HLA Class II may be involved in susceptibility or in the development of SLE.</p><p id="par0095" class="elsevierStylePara elsevierViewall">There are some reports showing association in autoimmune disease with HLA Class I alleles, such as Diabetes Mellitus Type I with HLA-A24, B18, -B39-B62-B60.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> The HLA-B60 antigen corresponds to HLA-B*40 which was found in the mestizo family studied associated to SLE. Uchanska-Ziegler B et al.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> found HLA-B*27:05, HLA-A*03:01 or HLA-A*11:01 associated with diseases suspected to have an autoimmune etiology, and postulate that the products of these alleles, due to their unusual ability to bind with high affinity to a particular peptide set during positive selection in the thymus, and involved in shaping an abnormal T cell repertoire which predisposes to acquisition of autoimmune diseases.</p><p id="par0100" class="elsevierStylePara elsevierViewall">HLA-B27 increases the risk of developing ankylosing spondylitis. It is uncertain how HLA-B27 causes this increased risk. Researchers speculate that HLA-B27 may abnormally display peptides that trigger an immune reaction, resulting in the inflammatory process that causes arthritis.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">On the other hand, this forces us to think about the mechanisms by which HLA Class I could contribute to the pathogenesis of this disease, probably the interaction HLA Class I and KIR receptors, play an important role, as has been demonstrated in some autoimmune pathologies.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">SLE shows a strong familial aggregation, with high frequency among first degree relatives of patients. Moreover, in extended families, SLE may coexist with other organ specific autoimmune diseases such as hemolytic anemia, autoimmune thrombocytopenic purpura and thyroiditis.</p><p id="par0115" class="elsevierStylePara elsevierViewall">The primary function of HLA Class I molecules is to present peptide from cleavage of native antigens in the cytosol to CD8<span class="elsevierStyleSup">+</span> cells. The conformational differences between alleles of HLA Class I may create variability in the peptide binding properties for presentation to CD8<span class="elsevierStyleSup">+</span> cells resulting in the induction of tolerance or self-reactivity. While this could be one of the mechanisms in the HLA Class I intervention in autoimmune diseases, we can not establish whether the same may be one of the factors in the development of lupus and not Class II itself as found in some autoimmune diseases in mestizo population. In reference to the mestizo family studied, an extensive study in this population should be conducted to establish the true participation of HLA Class I region.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Ethical disclosures</span><p id="par0120" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Protection of human and animal subjects</span>. The authors declare that the procedures followed were in accordance with the regulations of the responsible Clinical Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration.<span class="elsevierStyleVsp" style="height:0.5px"></span><span class="elsevierStyleBold">Confidentiality of data</span>. The authors declare that no patient data appears in this article.<span class="elsevierStyleVsp" style="height:0.5px"></span><span class="elsevierStyleBold">Right to privacy and informed consent</span>. The authors declare that no patient data appears in this article.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of interest</span><p id="par0125" class="elsevierStylePara elsevierViewall">Authors declare that they have no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:2 [ "identificador" => "xres371060" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec350246" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres371059" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec350247" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Materials and methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Statistical methods" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Results" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Ethical disclosures" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Conflict of interest" ] 11 => array:2 [ "identificador" => "xack93322" "titulo" => "Acknowledgments" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-07-23" "fechaAceptado" => "2012-11-29" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec350246" "palabras" => array:5 [ 0 => "Human leukocyte antigen Class I and II" 1 => "Genetics" 2 => "Systemic lupus erithematous" 3 => "Mestizo family" 4 => "Autoimmune disease" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec350247" "palabras" => array:5 [ 0 => "Antígenos leucocitarios humanos Clase I y II" 1 => "Genética" 2 => "Lupus eritematoso sistémico" 3 => "Familia mestiza" 4 => "Enfermedad autoinmunitaria" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">There are many factors that influence the pathogenesis of autoimmune disease of which host genetic factors play an important role. The aim of this study was to investigate the HLA Class I and II genes in a family with a high incidence of AID to establish whether they contribute to the development of these disease.</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Four of them had been diagnosed with SLE and one with AHA. The patients with SLE showed the presence of HLA-A*02 B*40 DRB1*04:07 DQB1*03:02 haplotype with a high statistical significance. This haplotype was not present in the healthy individuals and in the patient with AHA, although the DRB1*04:07 DQB1*03:02 haplotype (carried by both parents) was found in the AHA patients and one of the healthy individuals.</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We must consider how HLA Class I in linkage disequilibrium with HLA Class II may be involved in susceptibility or in the development of SLE. An extensive study in this population should be conducted to establish the true participation of the HLA Class I region.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Muchos factores se han involucrado en la patogénesis de las enfermedades autoinmunitarias, entre los cuales el fondo genético desempeña un papel importante. El objetivo fue investigar los genes de HLA Clase I y II en una familia con alta incidencia de enfermedades autoinmunitarias para establecer si estos podrían contribuir al desarrollo de estas enfermedades.</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Los pacientes diagnosticados de lupus mostraron la presencia del haplotipo HLA A*02, B*40, DRB1*04:07, DQB1*03:02 con alta significación estadística. En los individuos sanos y en el paciente con AHA este haplotipo no estuvo presente; en cambio, el haplotipo Clase II DRB1*04:07, DQB1*03:02, estuvo también en el paciente con AHA y en uno de los individuos sanos.</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Deberíamos considerar cómo HLA Clase I en desequilibrio de ligamiento con HLA Clase II podría estar involucrado en la susceptibilidad o el desarrollo de lupus eritematoso sistémico. Un estudio más extenso de esta población debería llevarse a cabo a fin de establecer la verdadera participación de la región de HLA Clase I.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">This research was presented at First French-Argentine Immunology Congress (FAIC 2010), November 2–5, 2010, Buenos Aires, Argentina.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1359 "Ancho" => 3120 "Tamanyo" => 277599 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of the HLA Class I and II haplotype in a family with high burden of autoimmune disease. Note that the maternal haplotype called (b) share the Class II alleles (DRB1*0407-DQB1*03) with the paternal haplotype called (d). This paternal haplotype is present in all patients with SLE.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">The statistical analysis, between what was observed and what was expected: OR<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>4.0, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.0000091.</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">We did not observe any statistical significance when it was analyzed DRB1*0407: DQB1*03 haplotype OR<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1.52, <span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2.65 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.103.</p>" "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"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Individuals (<span class="elsevierStyleItalic">n</span>) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Positive (n/t) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Negative (n/t) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Total \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Haplotypes: HLA A*02 B*40 DRB1*0407 DQB1*03 Class I and II</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Affected individuals \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4/5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Not affected individuals \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0/3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3/3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="4" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleItalic">Haplotypes: DRB1*0407 DQB1*03 haplotype Class II</span></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Affected individuals \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5/5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0/5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Not affected individuals \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2/3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1/3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab560078.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Haplotypes Class I and II in affected and not affected individuals.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => 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Translation: This document was translated by Carla Rolón Martínez.</p>" ] ] ] "idiomaDefecto" => "en" "url" => "/1699258X/0000000900000006/v3_201409200209/S1699258X13000235/v3_201409200209/en/main.assets" "Apartado" => array:4 [ "identificador" => "17499" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Originales" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/1699258X/0000000900000006/v3_201409200209/S1699258X13000235/v3_201409200209/en/main.pdf?idApp=UINPBA00004M&text.app=https://reumatologiaclinica.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1699258X13000235?idApp=UINPBA00004M" ]
| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 13 | 14 | 27 |
| 2024 Octubre | 52 | 30 | 82 |
| 2024 Septiembre | 67 | 28 | 95 |
| 2024 Agosto | 72 | 44 | 116 |
| 2024 Julio | 68 | 35 | 103 |
| 2024 Junio | 94 | 49 | 143 |
| 2024 Mayo | 102 | 30 | 132 |
| 2024 Abril | 65 | 33 | 98 |
| 2024 Marzo | 63 | 44 | 107 |
| 2024 Febrero | 53 | 33 | 86 |
| 2024 Enero | 66 | 28 | 94 |
| 2023 Diciembre | 31 | 19 | 50 |
| 2023 Noviembre | 49 | 32 | 81 |
| 2023 Octubre | 52 | 32 | 84 |
| 2023 Septiembre | 101 | 37 | 138 |
| 2023 Agosto | 42 | 7 | 49 |
| 2023 Julio | 58 | 25 | 83 |
| 2023 Junio | 40 | 23 | 63 |
| 2023 Mayo | 44 | 21 | 65 |
| 2023 Abril | 30 | 16 | 46 |
| 2023 Marzo | 62 | 27 | 89 |
| 2023 Febrero | 51 | 38 | 89 |
| 2023 Enero | 28 | 29 | 57 |
| 2022 Diciembre | 67 | 49 | 116 |
| 2022 Noviembre | 63 | 33 | 96 |
| 2022 Octubre | 61 | 27 | 88 |
| 2022 Septiembre | 47 | 32 | 79 |
| 2022 Agosto | 42 | 51 | 93 |
| 2022 Julio | 37 | 44 | 81 |
| 2022 Junio | 54 | 47 | 101 |
| 2022 Mayo | 62 | 55 | 117 |
| 2022 Abril | 44 | 47 | 91 |
| 2022 Marzo | 46 | 51 | 97 |
| 2022 Febrero | 59 | 33 | 92 |
| 2022 Enero | 79 | 34 | 113 |
| 2021 Diciembre | 51 | 45 | 96 |
| 2021 Noviembre | 69 | 50 | 119 |
| 2021 Octubre | 64 | 50 | 114 |
| 2021 Septiembre | 37 | 55 | 92 |
| 2021 Agosto | 43 | 45 | 88 |
| 2021 Julio | 30 | 35 | 65 |
| 2021 Junio | 35 | 49 | 84 |
| 2021 Mayo | 49 | 37 | 86 |
| 2021 Abril | 103 | 65 | 168 |
| 2021 Marzo | 52 | 20 | 72 |
| 2021 Febrero | 48 | 24 | 72 |
| 2021 Enero | 45 | 19 | 64 |
| 2020 Diciembre | 41 | 25 | 66 |
| 2020 Noviembre | 42 | 21 | 63 |
| 2020 Octubre | 23 | 10 | 33 |
| 2020 Septiembre | 37 | 18 | 55 |
| 2020 Agosto | 36 | 14 | 50 |
| 2020 Julio | 33 | 13 | 46 |
| 2020 Junio | 41 | 17 | 58 |
| 2020 Mayo | 45 | 18 | 63 |
| 2020 Abril | 25 | 13 | 38 |
| 2020 Marzo | 41 | 21 | 62 |
| 2020 Febrero | 32 | 23 | 55 |
| 2020 Enero | 50 | 18 | 68 |
| 2019 Diciembre | 52 | 27 | 79 |
| 2019 Noviembre | 51 | 16 | 67 |
| 2019 Octubre | 35 | 12 | 47 |
| 2019 Septiembre | 46 | 22 | 68 |
| 2019 Agosto | 45 | 32 | 77 |
| 2019 Julio | 38 | 16 | 54 |
| 2019 Junio | 30 | 29 | 59 |
| 2019 Mayo | 43 | 56 | 99 |
| 2019 Abril | 65 | 30 | 95 |
| 2019 Marzo | 37 | 30 | 67 |
| 2019 Febrero | 27 | 20 | 47 |
| 2019 Enero | 32 | 30 | 62 |
| 2018 Diciembre | 106 | 60 | 166 |
| 2018 Noviembre | 147 | 20 | 167 |
| 2018 Octubre | 130 | 10 | 140 |
| 2018 Septiembre | 33 | 7 | 40 |
| 2018 Agosto | 18 | 11 | 29 |
| 2018 Julio | 14 | 5 | 19 |
| 2018 Mayo | 5 | 1 | 6 |
| 2018 Abril | 69 | 7 | 76 |
| 2018 Marzo | 49 | 6 | 55 |
| 2018 Febrero | 25 | 5 | 30 |
| 2018 Enero | 13 | 3 | 16 |
| 2017 Diciembre | 26 | 13 | 39 |
| 2017 Noviembre | 23 | 13 | 36 |
| 2017 Octubre | 26 | 4 | 30 |
| 2017 Septiembre | 22 | 13 | 35 |
| 2017 Agosto | 34 | 31 | 65 |
| 2017 Julio | 26 | 6 | 32 |
| 2017 Junio | 45 | 12 | 57 |
| 2017 Mayo | 43 | 3 | 46 |
| 2017 Abril | 35 | 4 | 39 |
| 2017 Marzo | 27 | 35 | 62 |
| 2017 Febrero | 29 | 8 | 37 |
| 2017 Enero | 29 | 5 | 34 |
| 2016 Diciembre | 43 | 17 | 60 |
| 2016 Noviembre | 46 | 16 | 62 |
| 2016 Octubre | 62 | 21 | 83 |
| 2016 Septiembre | 51 | 22 | 73 |
| 2016 Agosto | 47 | 24 | 71 |
| 2016 Julio | 15 | 11 | 26 |
| 2016 Mayo | 1 | 0 | 1 |
| 2016 Febrero | 1 | 0 | 1 |
| 2016 Enero | 2 | 0 | 2 |
| 2015 Diciembre | 2 | 0 | 2 |
| 2015 Octubre | 0 | 24 | 24 |
| 2015 Septiembre | 2 | 21 | 23 |
| 2015 Agosto | 4 | 0 | 4 |
| 2015 Julio | 25 | 4 | 29 |
| 2015 Junio | 29 | 13 | 42 |
| 2015 Mayo | 76 | 15 | 91 |
| 2015 Abril | 60 | 12 | 72 |
| 2015 Marzo | 63 | 12 | 75 |
| 2015 Febrero | 42 | 0 | 42 |
| 2015 Enero | 44 | 0 | 44 |
| 2014 Diciembre | 37 | 0 | 37 |
| 2014 Noviembre | 32 | 0 | 32 |
| 2014 Octubre | 42 | 0 | 42 |
| 2014 Septiembre | 41 | 0 | 41 |
| 2014 Agosto | 35 | 0 | 35 |
| 2014 Julio | 34 | 0 | 34 |
| 2014 Junio | 67 | 0 | 67 |
| 2014 Mayo | 48 | 0 | 48 |
| 2014 Abril | 59 | 0 | 59 |
| 2014 Marzo | 63 | 20 | 83 |
| 2014 Febrero | 68 | 19 | 87 |
| 2014 Enero | 92 | 42 | 134 |
| 2013 Diciembre | 101 | 48 | 149 |
| 2013 Noviembre | 79 | 62 | 141 |
| 2013 Octubre | 7 | 1 | 8 |
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