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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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,

Corresponding author

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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Article information

ISSN: 15782190
Original language: English

DOI:10.1016/j.adengl.2011.03.017

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

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