RESUMEN
Atopic dermatitis and psoriasis are the two most common immune-mediated inflammatory disorders affecting the skin. Genome-wide studies demonstrate a high degree of genetic overlap, but these diseases have mutually exclusive clinical phenotypes and opposing immune mechanisms. Despite their prevalence, atopic dermatitis and psoriasis very rarely co-occur within one individual. By utilizing genome-wide association study and ImmunoChip data from >19,000 individuals and methodologies developed from meta-analysis, we have identified opposing risk alleles at shared loci as well as independent disease-specific loci within the epidermal differentiation complex (chromosome 1q21.3), the Th2 locus control region (chromosome 5q31.1), and the major histocompatibility complex (chromosome 6p21-22). We further identified previously unreported pleiotropic alleles with opposing effects on atopic dermatitis and psoriasis risk in PRKRA and ANXA6/TNIP1. In contrast, there was no evidence for shared loci with effects operating in the same direction on both diseases. Our results show that atopic dermatitis and psoriasis have distinct genetic mechanisms with opposing effects in shared pathways influencing epidermal differentiation and immune response. The statistical analysis methods developed in the conduct of this study have produced additional insight from previously published data sets. The approach is likely to be applicable to the investigation of the genetic basis of other complex traits with overlapping and distinct clinical features.
Asunto(s)
Hibridación Genómica Comparativa , Dermatitis Atópica/genética , Estudio de Asociación del Genoma Completo , Psoriasis/genética , Alelos , Estudios de Casos y Controles , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 5/genética , Cromosomas Humanos Par 6/genética , Estudios de Cohortes , Sitios Genéticos , Humanos , Modelos Logísticos , Complejo Mayor de Histocompatibilidad/genética , Polimorfismo de Nucleótido Simple , Control de Calidad , Reproducibilidad de los ResultadosRESUMEN
Generalized lymphatic anomaly is a rare, complex, lymphatic anomaly generally involving soft tissues, spleen, and bones. It can lead to focal skeletal fragility and pathologic effusions. A recent prospective trial of sirolimus for complicated vascular anomalies showed partial response in seven patients with generalized lymphatic anomaly treated with sirolimus with a target trough level of 10-15 ng/mL for 1 year (Adams et al). We describe successful treatment of generalized lymphatic anomaly with a lower-dose, long-term course of sirolimus.
Asunto(s)
Inmunosupresores/administración & dosificación , Anomalías Linfáticas/tratamiento farmacológico , Sirolimus/administración & dosificación , Preescolar , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
BACKGROUND/OBJECTIVES: Atopic dermatitis (AD) affects up to 20% of children. Although the majority of patients are adequately controlled using emollients, topical corticosteroids, topical calcineurin inhibitors, or phototherapy, children with moderate to severe AD may require systemic treatment for control. The objective of the current study was to evaluate the efficacy and safety of methotrexate in children with severe AD attending a tertiary referral center. METHODS: A retrospective chart review was undertaken of all children who received methotrexate for severe AD at our tertiary referral center from November 2010 to August 2015. RESULTS: Forty-seven children were started on methotrexate for AD during this period. The mean Investigator Global Assessment (IGA) at the 3- to 5-month follow-up improved from 4.25 to 2.8, with further improvement to 1.9 in the patients that continued therapy beyond 10 months. Changes in the Children's Dermatology Life Quality Index (CDLQI) mirrored changes in the IGA, with improvement in the mean CDLQI from 14.4 at the start of the treatment to 7.5 at the 3- to 5-month follow-up. Further improvement in the CDLQI to 6.6 in patients who continued methotrexate beyond 10 months confirmed continued improvement in disease control beyond medium-term therapy. The treatment was well tolerated. CONCLUSIONS: Methotrexate appears to be an effective, safe treatment for severe pediatric AD. Its therapeutic effects continue beyond the medium-term treatment period, as reflected by further improvement in IGA and CDLQI scores in patients who continued methotrexate therapy beyond 10 months.
Asunto(s)
Dermatitis Atópica/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Metotrexato/uso terapéutico , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Inmunosupresores/efectos adversos , Lactante , Masculino , Metotrexato/efectos adversos , Calidad de Vida , Estudios Retrospectivos , Centros de Atención Terciaria , Resultado del TratamientoRESUMEN
We recently reported two common filaggrin (FLG) null mutations that cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. We show here that these common European mutations are ancestral variants carried on conserved haplotypes. To facilitate comprehensive analysis of other populations, we report a strategy for full sequencing of this large, highly repetitive gene, and we describe 15 variants, including seven that are prevalent. All the variants are either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis. In an Irish case-control study, the five most common European mutations showed a strong association with moderate-to-severe childhood eczema (chi2 test: P = 2.12 x 10(-51); Fisher's exact test: heterozygote odds ratio (OR) = 7.44 (95% confidence interval (c.i.) = 4.9-11.3), and homozygote OR = 151 (95% c.i. = 20-1,136)). We found three additional rare null mutations in this case series, suggesting that the genetic architecture of filaggrin-related atopic dermatitis consists of both prevalent and rare risk alleles.
Asunto(s)
Dermatitis Atópica/genética , Predisposición Genética a la Enfermedad , Ictiosis Vulgar/genética , Proteínas de Filamentos Intermediarios/genética , Secuencia de Bases , Codón sin Sentido/genética , Epidermis/metabolismo , Proteínas Filagrina , Mutación del Sistema de Lectura/genética , Frecuencia de los Genes , Humanos , Proteínas de Filamentos Intermediarios/metabolismo , Irlanda , Datos de Secuencia Molecular , Análisis de Secuencia de ADN , Población BlancaRESUMEN
Atopic dermatitis (AD) is the most common dermatological disease of childhood. Many children with AD have asthma and AD shares regions of genetic linkage with psoriasis, another chronic inflammatory skin disease. We present here a genome-wide association study (GWAS) of childhood-onset AD in 1563 European cases with known asthma status and 4054 European controls. Using Illumina genotyping followed by imputation, we generated 268 034 consensus genotypes and in excess of 2 million single nucleotide polymorphisms (SNPs) for analysis. Association signals were assessed for replication in a second panel of 2286 European cases and 3160 European controls. Four loci achieved genome-wide significance for AD and replicated consistently across all cohorts. These included the epidermal differentiation complex (EDC) on chromosome 1, the genomic region proximal to LRRC32 on chromosome 11, the RAD50/IL13 locus on chromosome 5 and the major histocompatibility complex (MHC) on chromosome 6; reflecting action of classical HLA alleles. We observed variation in the contribution towards co-morbid asthma for these regions of association. We further explored the genetic relationship between AD, asthma and psoriasis by examining previously identified susceptibility SNPs for these diseases. We found considerable overlap between AD and psoriasis together with variable coincidence between allergic rhinitis (AR) and asthma. Our results indicate that the pathogenesis of AD incorporates immune and epidermal barrier defects with combinations of specific and overlapping effects at individual loci.
Asunto(s)
Asma/genética , Dermatitis Atópica/genética , Estudio de Asociación del Genoma Completo/métodos , Psoriasis/genética , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 5 , Cromosomas Humanos Par 6 , Ligamiento Genético , Sitios Genéticos , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Polimorfismo de Nucleótido Simple , Población Blanca/genética , Adulto JovenRESUMEN
Kasabach-Merritt Phenomenon (KMP) refers to the clinical constellation of thrombocytopenia, consumptive coagulopathy and purpura associated with Kaposiform haemangioedothelioma or tufted angioma, but not the more common infantile haemangioma. It shows a variable and unpredictable response to traditional pharmacological agents, such as steroids, vincristine or interferon alpha 2a or 2b. More recently, the interaction between platelets and endothelial cells and the proangiogenic phenotype that results has been recognized to underly the pathogenesis of this disorder. Recent efforts have attempted to target the platelet by using antiplatelet agents and by the withholding of platelet transfusions even in those patients who have significant thrombocytopenia and laboratory evidence of coagulopathy. Excellent response rates and prompt results have been achieved by combining antiplatelet therapy with vincristine, without the need for steroid use. This synergistic approach moves away from the conventional wisdom of treating the underlying lesion to control the coagulopathy. Sirolimus, which is directed against the PI3/AKT/mTOR downstream signalling pathway involved in lymphangiogenesis, has also shown promising results, although further study is needed.
Asunto(s)
Síndrome de Kasabach-Merritt/metabolismo , Síndrome de Kasabach-Merritt/fisiopatología , Síndrome de Kasabach-Merritt/terapia , Humanos , Transducción de Señal , Trombocitopenia/patología , Trombocitopenia/fisiopatología , Trombocitopenia/terapiaRESUMEN
BACKGROUND: Atopic dermatitis (AD; eczema) is characterized by a widespread abnormality in cutaneous barrier function and propensity to inflammation. Filaggrin is a multifunctional protein and plays a key role in skin barrier formation. Loss-of-function mutations in the gene encoding filaggrin (FLG) are a highly significant risk factor for atopic disease, but the molecular mechanisms leading to dermatitis remain unclear. OBJECTIVE: We sought to interrogate tissue-specific variations in the expressed genome in the skin of children with AD and to investigate underlying pathomechanisms in atopic skin. METHODS: We applied single-molecule direct RNA sequencing to analyze the whole transcriptome using minimal tissue samples. Uninvolved skin biopsy specimens from 26 pediatric patients with AD were compared with site-matched samples from 10 nonatopic teenage control subjects. Cases and control subjects were screened for FLG genotype to stratify the data set. RESULTS: Two thousand four hundred thirty differentially expressed genes (false discovery rate, P < .05) were identified, of which 211 were significantly upregulated and 490 downregulated by greater than 2-fold. Gene ontology terms for "extracellular space" and "defense response" were enriched, whereas "lipid metabolic processes" were downregulated. The subset of FLG wild-type cases showed dysregulation of genes involved with lipid metabolism, whereas filaggrin haploinsufficiency affected global gene expression and was characterized by a type 1 interferon-mediated stress response. CONCLUSION: These analyses demonstrate the importance of extracellular space and lipid metabolism in atopic skin pathology independent of FLG genotype, whereas an aberrant defense response is seen in subjects with FLG mutations. Genotype stratification of the large data set has facilitated functional interpretation and might guide future therapy development.
Asunto(s)
Dermatitis Atópica/genética , Proteínas de Filamentos Intermediarios/genética , Piel/metabolismo , Transcripción Genética/inmunología , Adolescente , Estudios de Casos y Controles , Niño , Dermatitis Atópica/inmunología , Dermatitis Atópica/metabolismo , Dermatitis Atópica/patología , Espacio Extracelular/inmunología , Femenino , Proteínas Filagrina , Regulación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Proteínas de Filamentos Intermediarios/inmunología , Metabolismo de los Lípidos/inmunología , Masculino , Piel/inmunología , Piel/patología , Adulto JovenRESUMEN
Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.
Asunto(s)
Dermatitis Atópica/genética , Proteínas de Filamentos Intermediarios/fisiología , Mutación , Fenómenos Fisiológicos de la Piel , Alelos , Asma/genética , Asma/inmunología , Niño , Estudios de Cohortes , Dermatitis Atópica/inmunología , Femenino , Proteínas Filagrina , Predisposición Genética a la Enfermedad , Humanos , Proteínas de Filamentos Intermediarios/genética , Proteínas de Filamentos Intermediarios/inmunología , Masculino , LinajeAsunto(s)
Hiperpigmentación/patología , Nevo Pigmentado/patología , Adolescente , Humanos , Masculino , Tórax/patologíaRESUMEN
BACKGROUND: Filaggrin (FLG) mutations result in reduced stratum corneum (SC) natural moisturizing factor (NMF) components and consequent increased SC pH. Because higher pH activates SC protease activity, we hypothesized an enhanced release of proinflammatory IL-1 cytokines from corneocytes in patients with atopic dermatitis (AD) with FLG mutations (AD(FLG)) compared with that seen in patients with AD without these mutations (AD(NON-FLG)). OBJECTIVES: We sought to investigate SC IL-1 cytokine profiles in the uninvolved skin of controls and patients with AD(FLG) versus patients with AD(NON-FLG). We also sought to examine the same profiles in a murine model of filaggrin deficiency (Flg(ft)/Flg(ft) [Flg(delAPfal)] mice). METHODS: One hundred thirty-seven patients were studied. NMF levels were ascertained using confocal Raman spectroscopy; transepidermal water loss and skin surface pH were measured. IL-1α, IL-1ß, IL-18, IL-1 receptor antagonist (IL-1RA), and IL-8 levels were determined in SC tape strips from 93 patients. All subjects were screened for 9 FLG mutations. Flg(ft)/Flg(ft) (Flg(delAPfal)) mice, separated from maFlg(ft)/maFlg(ft) (flaky tail) mice, were used for the preparation and culture of primary murine keratinocytes and as a source of murine skin. RT-PCR was performed using primers specific for murine IL-1α, IL-1ß, and IL-1RA. RESULTS: SC IL-1 levels were increased in patients with AD(FLG); these levels were inversely correlated with NMF levels. NMF values were also inversely correlated with skin surface pH. Skin and keratinocytes from Flg(ft)/Flg(ft) mice had upregulated expression of IL-1ß and IL-1RA mRNA. CONCLUSIONS: AD(FLG) is associated with an increased SC IL-1 cytokine profile; this profile is also seen in a murine homologue of filaggrin deficiency. These findings might have importance in understanding the influence of FLG mutations on the inflammasome in the pathogenesis of AD and help individualize therapeutic approaches.
Asunto(s)
Dermatitis Atópica/genética , Interleucina-1/genética , Proteínas de Filamentos Intermediarios/genética , Mutación , Adolescente , Alelos , Animales , Niño , Preescolar , Citocinas/metabolismo , Dermatitis Atópica/metabolismo , Femenino , Proteínas Filagrina , Genotipo , Humanos , Concentración de Iones de Hidrógeno , Lactante , Interleucina-1/metabolismo , Proteínas de Filamentos Intermediarios/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Piel/metabolismoRESUMEN
Delineating the extent of capillary malformations in the operating suite can be challenging because of a variety of physiologic modifiers, including vasodilatation induced by anesthesia, reactive erythema, and filtering of colors with protective laser eyewear. The use of traditional surgical pens to mark the treatment field has limitations; we have found the use of a white eyeliner pencil to delineate lesions a contemporary technique that assists in identifying the target tissue intraoperatively.
Asunto(s)
Capilares/anomalías , Cosméticos , Cuidados Intraoperatorios/métodos , Coloración y Etiquetado/métodos , Malformaciones Vasculares/diagnóstico , Femenino , Humanos , Lactante , Quirófanos , Malformaciones Vasculares/cirugíaRESUMEN
BACKGROUND: Atopic eczema is a common inflammatory skin disease with multifactorial etiology. The genetic basis is incompletely understood; however, loss of function mutations in the filaggrin gene (FLG) are the most significant and widely replicated genetic risk factor reported to date. The first genome-wide association study in atopic eczema recently identified 2 novel genetic variants in association with eczema susceptibility: a single nucleotide polymorphism on chromosome 11q13.5 (rs7927894) and a single nucleotide polymorphism (rs877776) within the gene encoding hornerin on chromosome 1q21. OBJECTIVE: To test the association of these 2 novel variants with pediatric eczema and to investigate their interaction with FLG null mutations. METHODS: Case-control study to investigate the association of rs7927894, rs877776 and the 4 most prevalent FLG null mutations with moderate-severe eczema in 511 Irish pediatric cases and 1000 Irish controls. Comprehensive testing for interaction between each of the loci was also performed. RESULTS: The association between rs7927894 and atopic eczema was replicated in this population (P = .0025, chi(2) test; odds ratio, 1.27; 95% CI, 1.09-1.49). The 4 most common FLG null variants were strongly associated with atopic eczema (P = 1.26 x 10(-50); combined odds ratio, 5.81; 95% CI, 4.51-7.49). Interestingly, the rs7927894 association was independent of the well-established FLG risk alleles and may be multiplicative in its effect. There was no significant association between rs877776 and pediatric eczema in this study. CONCLUSION: Single nucleotide polymorphism rs7927894 appears to mark a genuine eczema susceptibility locus that will require further elucidation through fine mapping and functional analysis.
Asunto(s)
Cromosomas Humanos Par 11/genética , Dermatitis Atópica/genética , Predisposición Genética a la Enfermedad , Variación Genética , Proteínas de Filamentos Intermediarios/genética , Mutación , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Proteínas Filagrina , Estudio de Asociación del Genoma Completo , Humanos , Irlanda , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
BACKGROUND: Filaggrin (FLG) has a central role in the pathogenesis of atopic dermatitis (AD). FLG is a complex repetitive gene; highly population-specific mutations and multiple rare mutations make routine genotyping complex. Furthermore, the mechanistic pathways through which mutations in FLG predispose to AD are unclear. OBJECTIVES: We sought to determine whether specific Raman microspectroscopic natural moisturizing factor (NMF) signatures of the stratum corneum could be used as markers of FLG genotype in patients with moderate-to-severe AD. METHODS: The composition and function of the stratum corneum in 132 well-characterized patients with moderate-to-severe AD were assessed by means of confocal Raman microspectroscopy and measurement of transepidermal water loss (TEWL). These parameters were compared with FLG genotype and clinical assessment. RESULTS: Three subpopulations closely corresponding with FLG genotype were identified by using Raman spectroscopy. The Raman signature of NMF discriminated between FLG-associated AD and non-FLG-associated AD (area under the curve, 0.94; 95% CI, 0.91-0.99). In addition, within the subset of FLG-associated AD, NMF distinguished between patients with 1 versus 2 mutations. Five novel FLG mutations were found on rescreening outlying patients with Raman signatures suggestive of undetected mutations (R3418X, G1138X, S1040X, 10085delC, and L2933X). TEWL did not associate with FLG genotype subgroups. CONCLUSIONS: Raman spectroscopy permits rapid and highly accurate stratification of FLG-associated AD. FLG mutations do not influence TEWL within established moderate-to-severe AD.
Asunto(s)
Dermatitis Atópica/genética , Predisposición Genética a la Enfermedad , Proteínas de Filamentos Intermediarios/genética , Fenotipo , Piel/metabolismo , Niño , Femenino , Proteínas Filagrina , Genotipo , Humanos , Irlanda , Masculino , Mutación , Espectrometría RamanAsunto(s)
Hemangioendotelioma/diagnóstico por imagen , Síndrome de Kasabach-Merritt/diagnóstico por imagen , Sarcoma de Kaposi/diagnóstico por imagen , Neoplasias Torácicas/diagnóstico por imagen , Trombocitopenia/diagnóstico por imagen , Hemangioendotelioma/tratamiento farmacológico , Humanos , Lactante , Síndrome de Kasabach-Merritt/tratamiento farmacológico , Masculino , Radiografía , Sarcoma de Kaposi/tratamiento farmacológico , Neoplasias Torácicas/tratamiento farmacológico , Trombocitopenia/tratamiento farmacológicoRESUMEN
The recent identification of loss-of-function mutations in the structural protein filaggrin as a widely replicated major risk factor for eczema sheds new light on disease mechanisms in eczema, a disease that had heretofore largely been considered to have a primarily immunologic etiopathogenesis. The filaggrin gene (FLG) mutation findings are consistent with a recently proposed unifying hypothesis that offers a mechanistic understanding of eczema pathogenesis synthesizing a heritable epithelial barrier defect and resultant diminished epidermal defense mechanisms to allergens and microbes, followed by polarized T(H)2 lymphocyte responses with resultant chronic inflammation, including autoimmune mechanisms. Although compelling evidence from genetic studies on FLG implicates perturbed barrier function as a key player in the pathogenesis of eczema in many patients, much is still unknown about the sequence of biologic, physicochemical, and aberrant regulatory events that constitute the transition from an inherited barrier defect to clinical manifestations of inflammatory eczematous lesions and susceptibility to related atopic disorders. The exact contribution of FLG to the wider atopic story, factors modifying FLG expression, and the role of other barrier proteins remain to be delineated. In this review we highlight recent advances in our understanding of the FLG genetics in the cause of eczema and related complex diseases.
Asunto(s)
Dermatitis Atópica/genética , Epidermis/metabolismo , Proteínas de Filamentos Intermediarios/genética , Adolescente , Adulto , Ácidos Carboxílicos/química , Ácidos Carboxílicos/metabolismo , Niño , Preescolar , Análisis Mutacional de ADN , Dermatitis Atópica/epidemiología , Femenino , Proteínas Filagrina , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Lactante , Proteínas de Filamentos Intermediarios/química , Masculino , Mutación Missense/genética , Polimorfismo Genético , Proteolisis , Pirrolidinonas/química , Pirrolidinonas/metabolismo , Riesgo , Sudáfrica , Ácido Urocánico/química , Ácido Urocánico/metabolismo , Adulto JovenRESUMEN
Kaposiform hemangioendothelioma is an aggressive vascular tumor, named for its striking histologic resemblance to Kaposi sarcoma and locally invasive growth. Mortality is high, and ranges from 10% to 24% for all kaposiform hemangioendothelioma lesions, with a significantly higher mortality for deep soft-tissue or visceral lesions occurring in infants less than 6 months. Mediastinal and neck kaposiform hemangioendothelioma in particular merit special discussion, as involvement of these critical anatomic locations results in significant site-specific therapeutic challenges due to invasion of vital structures, inherent delays in establishing histopathologic confirmation, and difficulties in monitoring disease status. We report our experience with three cases of mediastinal and neck kaposiform hemangioendothelioma, emphasizing the unique diagnostic and management challenges, variable response to treatment and outcome of this anatomic variant of kaposiform hemangioendothelioma.
Asunto(s)
Neoplasias de Cabeza y Cuello/congénito , Hemangioendotelioma/congénito , Neoplasias del Mediastino/congénito , Femenino , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/patología , Hemangioendotelioma/diagnóstico , Hemangioendotelioma/patología , Humanos , Lactante , Recién Nacido , Neoplasias del Mediastino/diagnóstico , Neoplasias del Mediastino/patología , Sarcoma de Kaposi/patologíaRESUMEN
The recent identification of loss-of-function mutations in the structural protein filaggrin as a widely replicated major risk factor for eczema sheds new light on disease mechanisms in eczema, a disease that had heretofore largely been considered to have a primarily immunologic etiopathogenesis. The filaggrin gene (FLG) mutation findings are consistent with a recently proposed unifying hypothesis that offers a mechanistic understanding of eczema pathogenesis synthesizing a heritable epithelial barrier defect and resultant diminished epidermal defense mechanisms to allergens and microbes, followed by polarized T(H)2 lymphocyte responses with resultant chronic inflammation, including autoimmune mechanisms. Although compelling evidence from genetic studies on FLG implicates perturbed barrier function as a key player in the pathogenesis of eczema in many patients, much is still unknown about the sequence of biologic, physicochemical, and aberrant regulatory events that constitute the transition from an inherited barrier defect to clinical manifestations of inflammatory eczematous lesions and susceptibility to related atopic disorders. The exact contribution of FLG to the wider atopic story, factors modifying FLG expression, and the role of other barrier proteins remain to be delineated. In this review we highlight recent advances in our understanding of the FLG genetics in the cause of eczema and related complex diseases.
Asunto(s)
Autoinmunidad , Dermatitis Atópica/inmunología , Eccema/inmunología , Flagelina/inmunología , Células Th2/inmunología , Animales , Enfermedad Crónica , Dermatitis Atópica/genética , Eccema/genética , Proteínas Filagrina , Flagelina/genética , Humanos , Inflamación/genética , Inflamación/inmunología , MutaciónRESUMEN
BACKGROUND: Polymorphisms in the serine protease inhibitor gene serine peptidase inhibitor Kazal type 5 (SPINK5) and the serine protease kallikrein-related peptidase 7 gene (KLK7) appear to confer risk to eczema in some cohorts, but these findings have not been widely replicated. These genes encode proteins thought to be involved in the regulation of posttranslation processing of filaggrin (FLG), the strongest identified genetic risk factor for eczema to date. OBJECTIVES: We sought to clarify the individual risk of eczema conferred by the SPINK5 polymorphism rs2303067 (Glu420Lys) and a previously described insertion in the 3' untranslated region of KLK7 and to examine potential epistatic effects between these variants and FLG mutations. METHODS: Initially, we examined the effects of these polymorphisms and FLG in 486 unrelated patients from a German family-based study, an additional 287 German patients, and 418 unrelated Irish/English patients with eczema (n for 3 genes studied = 1191 vs 4544 control subjects). We then additionally studied the SPINK5 polymorphism and FLG mutations in 1583 patients with eczema from the Avon Longitudinal Study of Parents and Children cohort (sample size for 2 genes studied = 2774 vs 10,607 control subjects). RESULTS: No association was seen with the SPINK5 or KLK7 variants in the case-control analysis; however, a weaker effect was observed for the SPINK5 variant with maternal transmission in the family-based study. No interactions were seen between the polymorphisms in KLK7, SPINK5, and FLG. CONCLUSION: The SPINK5 420LysSer mutation confers a risk of eczema when maternally inherited but is not a major eczema risk factor. The KLK7 insertion appears to confer no risk of eczema. We found no interaction between the SPINK5 risk allele or the putative KLK7 risk allele and FLG mutations.
Asunto(s)
Eccema/genética , Proteínas de Filamentos Intermediarios/genética , Calicreínas/genética , Polimorfismo de Nucleótido Simple , Proteínas Inhibidoras de Proteinasas Secretoras/genética , Adulto , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Proteínas Filagrina , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Mutación , Inhibidor de Serinpeptidasas Tipo Kazal-5RESUMEN
Mutations in the filament aggregating protein (filaggrin) gene have recently been identified as the cause of the common genetic skin disorder ichthyosis vulgaris (IV), the most prevalent inherited disorder of keratinization. The main characteristics of IV are fine-scale on the arms and legs, palmar hyperlinearity, and keratosis pilaris. Here, we have studied six Irish families with IV for mutations in filaggrin. We have identified a new mutation, 3702delG, in addition to further instances of the reported mutations R501X and 2282del4, which are common in people of European origin. A case of a 2282del4 homozygote was also identified. Mutation 3702delG terminates protein translation in filaggrin repeat domain 3, whereas both recurrent mutations occur in repeat 1. These mutations are semidominant: heterozygotes have an intermediate phenotype most readily identified by palmar hyperlinearity and in some cases fine-scale and/or keratosis pilaris, whereas homozygotes or compound heterozygotes generally have more marked ichthyosis. Interestingly, the phenotypes of individuals homozygous for R501X, 2282del4, or compound heterozygous for R501X and 3702delG, were comparable, suggesting that mutations located centrally in the filaggrin repeats are also pathogenic.