Analysis of Genetic Polymorphism of the HLA-B and HLA-DR Loci in Patients with Dermatophytic Onychomycosis and in Their First-Degree Relatives

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García-Romero, J. Granados, M.E. Vega-Memije, R. Arenas" "autores" => array:4 [ 0 => array:3 [ "nombre" => "M.T." "apellidos" => "García-Romero" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "J." "apellidos" => "Granados" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "M.E." "apellidos" => "Vega-Memije" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 3 => array:4 [ "nombre" => "R." "apellidos" => "Arenas" "email" => array:1 [ 0 => "rarenas98@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "¿" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Departamento de Dermatología, Servicio de Micología, Hospital General Dr. Manuel Gea González, México D.F., Mexico" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "División de Inmunogenética, Departamento de Trasplantes del Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México D.F., Mexico" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Análisis del polimorfismo genético de los loci HLA-B y HLA-DR en pacientes con onicomicosis dermatofítica y familiares en primer grado" ] ] "textoCompleto" => "IntroductionOnychomycosis is one of the most common nail disorders and is caused by the dermatophyte Trichophyton rubrum in 70% to 85% of cases.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a> Among the main predisposing factors are humidity, maceration, occlusion, trauma, diabetes, and immunosuppression.<a class="elsevierStyleCrossRefs" href="#bib0005">1–3</a> The host's immune response against dermatophyte infections is poorly understood, but it is likely that epidermal Langerhans cells process the metabolites produced by the fungus and present them to neutrophils and lymphocytes. It has, however, been postulated that patients with onychomycosis, apart from having reduced delayed-type hypersensitivity reactions, may not mount a sufficient immune response to eliminate the dermatophyte responsible for the infection.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> This selective, and possibly induced, immune deficiency, may be relatively common, as up to 20% of the general population have chronic dermatophytosis.<a class="elsevierStyleCrossRefs" href="#bib0015">3,5,6</a> On the other hand, there have been reports of onychomycosis due to T. rubrum in members of the same family, suggesting the presence of a genetic component.<a class="elsevierStyleCrossRefs" href="#bib0025">5–8</a> One group of authors, using pedigree analysis, even showed an autosomal dominant pattern of inheritance.<a class="elsevierStyleCrossRef" href="#bib0035">7</a> The presence of onychomycosis in members of the same family cannot be explained by intrafamilial transmission as the prevalence of this disease is very low in people who are married to or have been living with an infected person for years.<a class="elsevierStyleCrossRefs" href="#bib0030">6,7</a> In any case, depressed cellular immunity is a known risk factor for onychomycosis, and intact cellular immunity is critical for eliminating dermatophytes from the skin. The highly polymorphic major histocompatibility complex (MHC) genes are involved in regulating the immune response and are therefore useful for identifying genes associated with susceptibility to certain diseases and, in particular, infections. Thus, the polymorphic human leukocyte antigen (HLA) genes code for molecules involved in the inflammatory response (e.g., components of the complement system and the tumor necrosis factor),<a class="elsevierStyleCrossRefs" href="#bib0020">4,9,10</a> and they also exhibit a strong linkage disequilibrium. Consequently, any allele associated with a particular disease may be a marker of susceptibility to that disease, but it must be determined which is the primary susceptibility allele and which is indirectly associated with the disease.<a class="elsevierStyleCrossRefs" href="#bib0055">11–13</a> HLA-DR4 is the most common allele (23%) in mestizo Mexicans,<a class="elsevierStyleCrossRefs" href="#bib0045">9,10,13</a> and open-population studies have found alleles that confer resistance to onychomycosis in this population.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> We have designed a family-based study to expand current knowledge about the genetic component involved in susceptibility to onychomycosis.Case DescriptionsA segregation analysis of families in which at least 1 member had onychomycosis was performed by the dermatology department of Hospital General Dr. Manuel Gea González in Mexico DF, Mexico, between January and July 2010. The study design and methods complied with the principles of the Declaration of Helsinki. We included 47 mestizo Mexicans with a clinical diagnosis of onychomycosis confirmed by direct examination and/or by a positive dermatophyte culture. Twenty-five of the patients were blood relatives. We also included a healthy control group consisting of 31 first-degree blood and non-blood relatives of the patients. Once informed consent had been obtained, genomic DNA was extracted from peripheral blood mononuclear leukocytes for subsequent amplification of specific regions of the HLA-B and HLA-DR loci by polymerase chain reaction at the transplant department of the National Institute of Medical Sciences and Nutrition Salvador Zubirán. Alleles at each locus were identified by low-resolution HLA typing using sequence-specific oligonucleotide probes. Statistical analyses were performed using the StatCalc program in the Epi Info software package.We compared HLA-B and HLA-DR haplotype frequencies with those of a historical control group consisting of 381 unrelated healthy individuals with 762 distinct haplotypes.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> All of the people in the control groups were born in Mexico, as were their parents and grandparents. They were part of a healthy cohort of organ donors and had no history of autoimmune or HLA-related disease. The prevalence of onychomycosis in this group is unknown.Blood samples were obtained from 78 individuals (47 patients and 31 healthy relatives) from 25 families. HLA-B and HLA-DR haplotype frequencies were calculated for both patients and controls, but the very small number of haplotypes (n=28) in the control group made it impossible to compare the 2 groups. Given the high diversity of HLA-B haplotypes in relation to HLA-DR haplotypes, we decided to limit the comparison to alleles at the HLA-DR locus, which showed a clearer pattern of clustering. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the allele frequencies for individuals with onychomycosis and healthy individuals from the same ethnic group. The most common allele in both groups is HLA-DR4, possibly suggesting that both groups have the same ethnic origin. Most other allele frequencies were similar between patients and controls, with the exception of HLA-DR8, which was significantly more frequent in the patient group than in the control group (P=.03; OR, 1.92; 95% CI, 1.04–3.54).<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>DiscussionWe have identified an allele associated with susceptibility to developing onychomycosis in mestizo Mexicans at the HLA-DR locus, and in particular at HLA-DR8. Interestingly, the frequencies of all of the other alleles at both the HLA-DR and HLA-B loci were similar in individuals with onychomycosis and healthy controls. These findings differ from the results of a recent study by Asz-Sigall et al.,<a class="elsevierStyleCrossRef" href="#bib0070">14</a> in which a significantly lower frequency of HLA-DR6 was found in a similar group of patients compared to controls, suggesting that this allele confers protection against developing onychomycosis. These differences are probably due to variations in the study designs, as Asz-Sigall et al. researched families with multiple cases of the disease. Our findings also differ from those of Ahmed et al.,<a class="elsevierStyleCrossRef" href="#bib0075">15</a> who found a high frequency of HLA-A26, HLA-AW33, and HLA-DR4 in a group of 29 patients with chronic dermatophyte infections. As would be expected, our findings also differ from those reported in 2 studies of Ashkenazi Jews,<a class="elsevierStyleCrossRefs" href="#bib0020">4,5</a> a genetically homogenous population with a well-characterized HLA profile. While Zaitz et al.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> reported that HLA-DR53 exerted a protective effect in susceptibility to developing chronic onychomycosis due to T. rubrum, Sadahiro et al.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> found an association between HLA-B14 and resistance to infection, as well as a possible association between HLA-DQB1*06 and susceptibility to chronic dermatophytosis. Nonetheless, these studies agree that these antigens play a critical role in immune response modulation and in the development of chronic fungal infections, such as onychomycosis. The mechanism by which HLA-DR8 increases susceptibility to onychomycosis is complex and probably involves multiple factors, including a genetic component. However, our study provides particularly useful insights, since we included non-blood relatives of the patients with onychomycosis and found that the role of HLA-DR8 was maintained. This genetic factor is polygenic, and the genes analyzed here regulate immune responses and, in particular, adaptive responses. It is important thus that future studies include molecular markers of innate immune responses such as Toll-like receptors on phagocytes.ConclusionsWe have confirmed that the HLA system plays a role in the T-cell immune response against fungal antigens, and have identified the HLA-DR8 allele to be a likely susceptibility factor for development of onychomycosis in a group of mestizo Mexicans. While we did not identify an HLA allele that conferred resistance to onychomycosis in our group of patients, we should note that the number of HLA haplotypes in healthy individuals was very low.In future studies analyzing gene frequencies, it would be of interest to increase the number of families in order to obtain a sufficient number of healthy individuals for the control group and not have to resort to a historical control group.Conflict of InterestsThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:2 [ "identificador" => "xres95583" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec82742" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres95582" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec82741" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Case Descriptions" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Conclusions" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conflict of Interests" ] 9 => array:2 [ "identificador" => "xack35203" "titulo" => "Acknowledgments" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec82742" "palabras" => array:4 [ 0 => "Onychomycosis" 1 => "Dermatophytes" 2 => "HLA-DR" 3 => "Class II MHC genes" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec82741" "palabras" => array:4 [ 0 => "Onicomicosis" 1 => "Dermatofitos" 2 => "HLA-DR" 3 => "Genes del MHC II" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Onychomycosis is known to have predisposing factors and a high prevalence within families that cannot be explained by within-family transmission. We determined the frequency of HLA-B and HLA-DR haplotypes in 25 families of Mexican patients with onychomycosis in order to define the role of the class II major histocompatibility complex (MHC) in genetic susceptibility to this infection. Seventy-eight subjects participated in the study, 47 with onychomycosis and 31 healthy individuals. The frequencies of the HLA-B and HLA-DR haplotypes were compared with those found in first-degree relatives without onychomycosis and in a historic control group of healthy individuals. The frequencies in the controls were similar to those of the healthy relatives of the patients. However, on comparison of the patients with historic controls, we detected a higher frequency of the HLA-DR8 haplotype (P=.03; odds ratio, 1.89; 95% confidence interval, 0.98–36). These findings suggest that there are polymorphisms in genes of the MHC that increase susceptibility to onychomycosis, particularly haplotype HLA-DR8." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "En la onicomicosis hay factores predisponentes conocidos y una alta prevalencia en familiares no explicada por transmisión intrafamiliar. Analizamos la frecuencia génica de alelos de los genes HLA-B y HLA-DR en 25 familias de pacientes mexicanos con onicomicosis para conocer el papel del complejo mayor de histocompatibilidad (MHC) clase II en la susceptibilidad genética a esta enfermedad. Se estudiaron 78 individuos, 47 de ellos con onicomicosis y 31 sanos. Se determinaron las frecuencias génicas de los alelos de los loci HLA-B y HLA-DR y se compararon con las presentes en familiares de primer grado sin onicomicosis y con un grupo de individuos sanos. Estas fueron semejantes a las de familiares sanos; sin embargo, al comparar pacientes con controles históricos se encontró un aumento de la frecuencia del alelo HLA-DR8 (p=0,03; OR=1,89; IC 95%: 0,98–36). Estos datos sugieren que dentro del MHC existen genes de susceptibilidad al desarrollo de onicomicosis; en particular con el alelo HLA-DR8." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: García-Romero M. T, Granados J, Vega-Memije ME, Arenas R. Análisis del polimorfismo genético de los loci HLA-B Y HLA-DR en pacientes con onicomicosis dermatofítica y familiares en primer grado. Actas Dermosifiliogr. 2012;103:59–62." ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:3 [ "leyenda" => "Abbreviations: HLA, human leukocyte antigen, OR, odds ratio." "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">HLA-DR Locus \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 " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Patients (n=71<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a>)</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Controls (n=762<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a>)</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">P \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">OR \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">95% CI \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-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">No.<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Frequency \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">No.<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a> \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="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Frequency \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \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 " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DR4 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.281 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">196 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.257 \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">NS \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">DR8 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.211 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">93 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.122 \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">.03 \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">1.92 \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">(1.04–3.54) \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">DR14 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.140 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">67 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.087 \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">NS \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">DR7 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.084 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">69 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.090 \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">NS \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">DR13 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.084 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">66 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.086 \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">NS \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">DR1 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">4 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.056 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">62 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.081 \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">NS \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">DR11 \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="char" 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><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.042 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.090 \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">NS \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">DR3 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.028 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">54 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.070 \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">NS \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">DR15 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.028 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">45 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.059 \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 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Terasaki" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Clin Exp Dermatol" "fecha" => "1985" "volumen" => "10" "paginaInicial" => "45" "paginaFinal" => "50" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3857131" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S000293940900316X" "estado" => "S300" "issn" => "00029394" ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:3 [ "identificador" => "xack35203" "titulo" => "Acknowledgments" "texto" => "We are grateful to the Fundación Nacional para la Enseñanza y la investigación and the Fundación Mexicana para la Dermatología, A.C. for providing the funds required for the DNA and HLA analyses in this study." ] ] ] "idiomaDefecto" => "en" "url" => "/15782190/0000010300000001/v1_201304241248/S1578219012000431/v1_201304241248/en/main.assets" "Apartado" => array:4 [ "identificador" => "6156" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Case Report" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/15782190/0000010300000001/v1_201304241248/S1578219012000431/v1_201304241248/en/main.pdf?idApp=UINPBA000044&text.app=https://actasdermo.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1578219012000431?idApp=UINPBA000044"]

Estadísticas

Case Report

Analysis of Genetic Polymorphism of the HLA-B and HLA-DR Loci in Patients with Dermatophytic Onychomycosis and in Their First-Degree Relatives

Análisis del polimorfismo genético de los loci HLA-B y HLA-DR en pacientes con onicomicosis dermatofítica y familiares en primer grado

M.T. García-Romeroa, J. Granadosb, M.E. Vega-Memijea, R. Arenasa,

Autor para correspondencia

rarenas98@hotmail.com

Corresponding author.

a Departamento de Dermatología, Servicio de Micología, Hospital General Dr. Manuel Gea González, México D.F., Mexico

b División de Inmunogenética, Departamento de Trasplantes del Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México D.F., Mexico

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Onychomycosis is one of the most common nail disorders and is caused by the dermatophyte <span class="elsevierStyleItalic">Trichophyton rubrum</span> in 70&#37; to 85&#37; of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> Among the main predisposing factors are humidity&#44; maceration&#44; occlusion&#44; trauma&#44; diabetes&#44; and immunosuppression&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a> The host&#39;s immune response against dermatophyte infections is poorly understood&#44; but it is likely that epidermal Langerhans cells process the metabolites produced by the fungus and present them to neutrophils and lymphocytes&#46; It has&#44; however&#44; been postulated that patients with onychomycosis&#44; apart from having reduced delayed-type hypersensitivity reactions&#44; may not mount a sufficient immune response to eliminate the dermatophyte responsible for the infection&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> This selective&#44; and possibly induced&#44; immune deficiency&#44; may be relatively common&#44; as up to 20&#37; of the general population have chronic dermatophytosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;5&#44;6</span></a> On the other hand&#44; there have been reports of onychomycosis due to <span class="elsevierStyleItalic">T&#46; rubrum</span> in members of the same family&#44; suggesting the presence of a genetic component&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#8211;8</span></a> One group of authors&#44; using pedigree analysis&#44; even showed an autosomal dominant pattern of inheritance&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> The presence of onychomycosis in members of the same family cannot be explained by intrafamilial transmission as the prevalence of this disease is very low in people who are married to or have been living with an infected person for years&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> In any case&#44; depressed cellular immunity is a known risk factor for onychomycosis&#44; and intact cellular immunity is critical for eliminating dermatophytes from the skin&#46; The highly polymorphic major histocompatibility complex &#40;MHC&#41; genes are involved in regulating the immune response and are therefore useful for identifying genes associated with susceptibility to certain diseases and&#44; in particular&#44; infections&#46; Thus&#44; the polymorphic human leukocyte antigen &#40;HLA&#41; genes code for molecules involved in the inflammatory response &#40;e&#46;g&#46;&#44; components of the complement system and the tumor necrosis factor&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;9&#44;10</span></a> and they also exhibit a strong linkage disequilibrium&#46; Consequently&#44; any allele associated with a particular disease may be a marker of susceptibility to that disease&#44; but it must be determined which is the primary susceptibility allele and which is indirectly associated with the disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#8211;13</span></a> HLA-DR4 is the most common allele &#40;23&#37;&#41; in mestizo Mexicans&#44;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;10&#44;13</span></a> and open-population studies have found alleles that confer resistance to onychomycosis in this population&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> We have designed a family-based study to expand current knowledge about the genetic component involved in susceptibility to onychomycosis&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Case Descriptions</span><p id="par0010" class="elsevierStylePara elsevierViewall">A segregation analysis of families in which at least 1 member had onychomycosis was performed by the dermatology department of Hospital General Dr&#46; Manuel Gea Gonz&#225;lez in Mexico DF&#44; Mexico&#44; between January and July 2010&#46; The study design and methods complied with the principles of the Declaration of Helsinki&#46; We included 47 mestizo Mexicans with a clinical diagnosis of onychomycosis confirmed by direct examination and&#47;or by a positive dermatophyte culture&#46; Twenty-five of the patients were blood relatives&#46; We also included a healthy control group consisting of 31 first-degree blood and non-blood relatives of the patients&#46; Once informed consent had been obtained&#44; genomic DNA was extracted from peripheral blood mononuclear leukocytes for subsequent amplification of specific regions of the HLA-B and HLA-DR loci by polymerase chain reaction at the transplant department of the National Institute of Medical Sciences and Nutrition Salvador Zubir&#225;n&#46; Alleles at each locus were identified by low-resolution HLA typing using sequence-specific oligonucleotide probes&#46; Statistical analyses were performed using the StatCalc program in the Epi Info software package&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">We compared HLA-B and HLA-DR haplotype frequencies with those of a historical control group consisting of 381 unrelated healthy individuals with 762 distinct haplotypes&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> All of the people in the control groups were born in Mexico&#44; as were their parents and grandparents&#46; They were part of a healthy cohort of organ donors and had no history of autoimmune or HLA-related disease&#46; The prevalence of onychomycosis in this group is unknown&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Blood samples were obtained from 78 individuals &#40;47 patients and 31 healthy relatives&#41; from 25 families&#46; HLA-B and HLA-DR haplotype frequencies were calculated for both patients and controls&#44; but the very small number of haplotypes &#40;n&#61;28&#41; in the control group made it impossible to compare the 2 groups&#46; Given the high diversity of HLA-B haplotypes in relation to HLA-DR haplotypes&#44; we decided to limit the comparison to alleles at the HLA-DR locus&#44; which showed a clearer pattern of clustering&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> shows the allele frequencies for individuals with onychomycosis and healthy individuals from the same ethnic group&#46; The most common allele in both groups is HLA-DR4&#44; possibly suggesting that both groups have the same ethnic origin&#46; Most other allele frequencies were similar between patients and controls&#44; with the exception of HLA-DR8&#44; which was significantly more frequent in the patient group than in the control group &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;03&#59; OR&#44; 1&#46;92&#59; 95&#37; CI&#44; 1&#46;04&#8211;3&#46;54&#41;&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Discussion</span><p id="par0025" class="elsevierStylePara elsevierViewall">We have identified an allele associated with susceptibility to developing onychomycosis in mestizo Mexicans at the HLA-DR locus&#44; and in particular at HLA-DR8&#46; Interestingly&#44; the frequencies of all of the other alleles at both the HLA-DR and HLA-B loci were similar in individuals with onychomycosis and healthy controls&#46; These findings differ from the results of a recent study by Asz-Sigall et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> in which a significantly lower frequency of HLA-DR6 was found in a similar group of patients compared to controls&#44; suggesting that this allele confers protection against developing onychomycosis&#46; These differences are probably due to variations in the study designs&#44; as Asz-Sigall et al&#46; researched families with multiple cases of the disease&#46; Our findings also differ from those of Ahmed et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> who found a high frequency of HLA-A26&#44; HLA-AW33&#44; and HLA-DR4 in a group of 29 patients with chronic dermatophyte infections&#46; As would be expected&#44; our findings also differ from those reported in 2 studies of Ashkenazi Jews&#44;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;5</span></a> a genetically homogenous population with a well-characterized HLA profile&#46; While Zaitz et al&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> reported that HLA-DR53 exerted a protective effect in susceptibility to developing chronic onychomycosis due to <span class="elsevierStyleItalic">T&#46; rubrum</span>&#44; Sadahiro et al&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> found an association between HLA-B14 and resistance to infection&#44; as well as a possible association between HLA-DQB1&#42;06 and susceptibility to chronic dermatophytosis&#46; Nonetheless&#44; these studies agree that these antigens play a critical role in immune response modulation and in the development of chronic fungal infections&#44; such as onychomycosis&#46; The mechanism by which HLA-DR8 increases susceptibility to onychomycosis is complex and probably involves multiple factors&#44; including a genetic component&#46; However&#44; our study provides particularly useful insights&#44; since we included non-blood relatives of the patients with onychomycosis and found that the role of HLA-DR8 was maintained&#46; This genetic factor is polygenic&#44; and the genes analyzed here regulate immune responses and&#44; in particular&#44; adaptive responses&#46; It is important thus that future studies include molecular markers of innate immune responses such as Toll-like receptors on phagocytes&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conclusions</span><p id="par0030" class="elsevierStylePara elsevierViewall">We have confirmed that the HLA system plays a role in the T-cell immune response against fungal antigens&#44; and have identified the HLA-DR8 allele to be a likely susceptibility factor for development of onychomycosis in a group of mestizo Mexicans&#46; While we did not identify an HLA allele that conferred resistance to onychomycosis in our group of patients&#44; we should note that the number of HLA haplotypes in healthy individuals was very low&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">In future studies analyzing gene frequencies&#44; it would be of interest to increase the number of families in order to obtain a sufficient number of healthy individuals for the control group and not have to resort to a historical control group&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Conflict of Interests</span><p id="par0040" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "identificador" => "xpalclavsec82742"
          "titulo" => "Keywords"
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        2 => array:2 [
          "identificador" => "xres95582"
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          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
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        5 => array:2 [
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          "titulo" => "Case Descriptions"
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        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Discussion"
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        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Conclusions"
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        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Conflict of Interests"
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        9 => array:2 [
          "identificador" => "xack35203"
          "titulo" => "Acknowledgments"
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        10 => array:1 [
          "titulo" => "References"
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          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec82742"
          "palabras" => array:4 [
            0 => "Onychomycosis"
            1 => "Dermatophytes"
            2 => "HLA-DR"
            3 => "Class II MHC genes"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec82741"
          "palabras" => array:4 [
            0 => "Onicomicosis"
            1 => "Dermatofitos"
            2 => "HLA-DR"
            3 => "Genes del MHC II"
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        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Onychomycosis is known to have predisposing factors and a high prevalence within families that cannot be explained by within-family transmission&#46; We determined the frequency of HLA-B and HLA-DR haplotypes in 25 families of Mexican patients with onychomycosis in order to define the role of the class II major histocompatibility complex &#40;MHC&#41; in genetic susceptibility to this infection&#46; Seventy-eight subjects participated in the study&#44; 47 with onychomycosis and 31 healthy individuals&#46; The frequencies of the HLA-B and HLA-DR haplotypes were compared with those found in first-degree relatives without onychomycosis and in a historic control group of healthy individuals&#46; The frequencies in the controls were similar to those of the healthy relatives of the patients&#46; However&#44; on comparison of the patients with historic controls&#44; we detected a higher frequency of the HLA-DR8 haplotype &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;03&#59; odds ratio&#44; 1&#46;89&#59; 95&#37; confidence interval&#44; 0&#46;98&#8211;36&#41;&#46; These findings suggest that there are polymorphisms in genes of the MHC that increase susceptibility to onychomycosis&#44; particularly haplotype HLA-DR8&#46;</p>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">En la onicomicosis hay factores predisponentes conocidos y una alta prevalencia en familiares no explicada por transmisi&#243;n intrafamiliar&#46; Analizamos la frecuencia g&#233;nica de alelos de los genes HLA-B y HLA-DR en 25 familias de pacientes mexicanos con onicomicosis para conocer el papel del complejo mayor de histocompatibilidad &#40;MHC&#41; clase II en la susceptibilidad gen&#233;tica a esta enfermedad&#46; Se estudiaron 78 individuos&#44; 47 de ellos con onicomicosis y 31 sanos&#46; Se determinaron las frecuencias g&#233;nicas de los alelos de los <span class="elsevierStyleItalic">loci</span> HLA-B y HLA-DR y se compararon con las presentes en familiares de primer grado sin onicomicosis y con un grupo de individuos sanos&#46; Estas fueron semejantes a las de familiares sanos&#59; sin embargo&#44; al comparar pacientes con controles hist&#243;ricos se encontr&#243; un aumento de la frecuencia del alelo HLA-DR8 &#40;p&#61;0&#44;03&#59; OR&#61;1&#44;89&#59; IC 95&#37;&#58; 0&#44;98&#8211;36&#41;&#46; Estos datos sugieren que dentro del MHC existen genes de susceptibilidad al desarrollo de onicomicosis&#59; en particular con el alelo HLA-DR8&#46;</p>"
      ]
    ]
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara">Please cite this article as&#58; Garc&#237;a-Romero M&#46; T&#44; Granados J&#44; Vega-Memije ME&#44; Arenas R&#46; An&#225;lisis del polimorfismo gen&#233;tico de los <span class="elsevierStyleItalic">loci</span> HLA-B Y HLA-DR en pacientes con onicomicosis dermatof&#237;tica y familiares en primer grado&#46; Actas Dermosifiliogr&#46; 2012&#59;103&#58;59&#8211;62&#46;</p>"
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        "tabla" => array:3 [
          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; HLA&#44; human leukocyte antigen&#44; OR&#44; odds ratio&#46;</p>"
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">HLA-DR Locus&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="2" align="center" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Patients &#40;n&#61;71<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&#41;</td><td class="td" title="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Controls &#40;n&#61;762<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&#41;</td><td class="td" title="\n
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                  \t\t\t\t">95&#37; CI&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">No&#46;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">No&#46;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Frequency&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\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
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                  \t\t\t\t">DR4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">NS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">DR8&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">93&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;122&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&#46;03&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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Información del artículo

ISSN: 15782190
Idioma original: Inglés

DOI:10.1016/j.adengl.2011.03.017

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2023 Marzo	26	20	46
2023 Febrero	40	23	63
2023 Enero	32	33	65
2022 Diciembre	43	41	84
2022 Noviembre	26	22	48
2022 Octubre	34	24	58
2022 Septiembre	28	35	63
2022 Agosto	28	36	64
2022 Julio	31	37	68
2022 Junio	33	25	58
2022 Mayo	40	48	88
2022 Abril	45	40	85
2022 Marzo	40	52	92
2022 Febrero	39	38	77
2022 Enero	48	39	87
2021 Diciembre	40	36	76
2021 Noviembre	46	41	87
2021 Octubre	47	53	100
2021 Septiembre	43	45	88
2021 Agosto	29	41	70
2021 Julio	27	22	49
2021 Junio	25	43	68
2021 Mayo	39	38	77
2021 Abril	90	72	162
2021 Marzo	94	39	133
2021 Febrero	42	34	76
2021 Enero	34	17	51
2020 Diciembre	24	22	46
2020 Noviembre	20	21	41
2020 Octubre	20	15	35
2020 Septiembre	28	22	50
2020 Agosto	20	18	38
2020 Julio	26	18	44
2020 Junio	22	21	43
2020 Mayo	31	18	49
2020 Abril	27	21	48
2020 Marzo	36	29	65
2020 Febrero	5	10	15
2020 Enero	8	9	17
2019 Diciembre	4	1	5
2019 Noviembre	4	2	6
2019 Octubre	0	2	2
2019 Septiembre	0	5	5
2019 Agosto	4	8	12
2019 Julio	4	18	22
2019 Junio	4	0	4
2019 Mayo	6	5	11
2019 Abril	5	19	24
2019 Marzo	2	7	9
2019 Febrero	0	5	5
2019 Enero	3	0	3
2018 Noviembre	1	0	1
2018 Octubre	2	0	2
2018 Septiembre	2	0	2
2018 Agosto	0	3	3
2018 Julio	0	2	2
2018 Junio	0	1	1
2018 Mayo	0	9	9
2018 Marzo	3	0	3
2018 Febrero	20	14	34
2018 Enero	45	14	59
2017 Diciembre	46	8	54
2017 Noviembre	37	15	52
2017 Octubre	37	11	48
2017 Septiembre	38	9	47
2017 Agosto	69	13	82
2017 Julio	63	5	68
2017 Junio	60	9	69
2017 Mayo	45	5	50
2017 Abril	41	16	57
2017 Marzo	25	32	57
2017 Febrero	30	13	43
2017 Enero	23	18	41
2016 Diciembre	40	14	54
2016 Noviembre	51	7	58
2016 Octubre	47	17	64
2016 Septiembre	56	9	65
2016 Agosto	75	8	83
2016 Julio	54	14	68
2016 Junio	8	12	20
2016 Mayo	5	16	21
2016 Abril	6	6	12
2016 Marzo	8	0	8
2016 Febrero	10	1	11
2016 Enero	10	1	11
2015 Diciembre	6	3	9
2015 Noviembre	16	7	23
2015 Octubre	13	1	14
2015 Septiembre	12	10	22
2015 Agosto	22	4	26
2015 Julio	67	1	68
2015 Junio	48	13	61
2015 Mayo	107	18	125
2015 Abril	65	20	85
2015 Marzo	56	7	63
2015 Febrero	47	13	60
2015 Enero	60	15	75
2014 Diciembre	83	8	91
2014 Noviembre	41	7	48
2014 Octubre	51	14	65
2014 Septiembre	48	9	57
2014 Agosto	63	17	80
2014 Julio	64	20	84
2014 Junio	76	9	85
2014 Mayo	74	13	87
2014 Abril	63	10	73
2014 Marzo	84	22	106
2014 Febrero	47	8	55
2014 Enero	63	23	86
2013 Diciembre	33	9	42
2013 Noviembre	23	14	37
2013 Octubre	25	10	35
2013 Septiembre	11	6	17
2013 Agosto	23	11	34
2013 Julio	8	25	33
2013 Junio	14	27	41
2013 Mayo	17	20	37
2013 Abril	8	8	16
2013 Marzo	17	11	28
2013 Febrero	34	4	38
2013 Enero	30	8	38
2012 Diciembre	18	5	23
2012 Noviembre	1	1	2
2012 Octubre	0	3	3
2012 Septiembre	0	1	1

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