Low filaggrin monomer repeats in African American pediatric patients with moderate to severe atopic dermatitis.
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ABSTRACT:
SUBMITTER: Quiggle AM
PROVIDER: S-EPMC4659403 | biostudies-literature | 2015 May
REPOSITORIES: biostudies-literature
Publications
Low filaggrin monomer repeats in African American pediatric patients with moderate to severe atopic dermatitis.
Quiggle Ashley M AM Goodwin Zane A ZA Marfatia Twinkal R TR Kumar Monique G MG Ciliberto Heather H Bayliss Susan J SJ de Guzman Strong Cristina C
JAMA dermatology 20150501 5
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Project description:BackgroundAtopic dermatitis (AD) is a common skin disease characterized by recurrent episodes of itching. Genetic variation associated with the persistence of AD has not been described for African American subjects.ObjectiveWe sought to evaluate genetic variation of filaggrin-2 (FLG2) in African American subjects with AD.MethodsWe evaluated a multiyear prospective cohort study of African American children with AD with respect to FLG2 variation based on whole-exome sequencing, followed by a targeted analysis. We ultimately evaluated the association of rs12568784 and rs16833974 with respect to the persistence of AD symptoms over time.ResultsWhole-exome analysis was conducted on 60 subjects, revealing a premature stop codon in exon 3 at S2377X (rs12568784) and X2392S (rs150529054) and a large exon 3 deletion mutation, Q2053del224. On the basis of a priori criteria, we then studied rs12568784, rs16833974 (H1249R), and Q2053del224. We noted that patients with S2377X (odds ratio [OR], 0.44; 95% CI, 0.25-0.46) and H1249R (OR, 0.23; 05% CI, 0.12-0.46) were significantly less likely to be free of symptoms of AD, and Q2053del224 (OR, 0.54; 95% CI, 0.16-1.80) trended toward this outcome. S2377X and H1249R were in high linkage disequilibrium (D' = 0.95).ConclusionsIn an African American cohort with AD, FLG2 mutations were associated with more persistent AD. This is the first finding of genetic variation of a skin barrier protein in subjects of African ancestry with AD.
| S-EPMC3943564 | biostudies-literature
Project description: Not available
| S-EPMC4102628 | biostudies-literature
Project description:Atopic dermatitis (AD) is a chronic, pruritic skin disease often complicated by bacterial superinfection affecting 10.7% of American children. The pathogenesis involves a skin barrier breakdown in addition to dysfunctional innate and adaptive immune response, including an unbalanced increase in T-helper 2 cells and hyperimmunoglobulinemia E. The increased numbers of T-helper 2 cells are involved in stimulating the production of immunoglobulin E and eosinophilia by releasing interleukin-4, -5, and -13 as well as in decreasing protection against bacterial superinfection by releasing interleukin-10. The current Food and Drug Administration-approved symptomatic treatment for AD includes topical ointments, topical and systemic corticosteroids, topical immunomodulant therapy, antibiotics, and phototherapy, but there are not approved targeted therapies or cures. By presenting a case of an 8-year-old African-American boy, this case report supports novel therapy of moderate-to-severe AD with apremilast, a phosphodiesterase type 4 inhibitor. Apremilast has recently completed the phase 2 clinical trial (NCT02087943) for treatment of AD in adults. This case report illustrates the potential for apremilast as a treatment for AD in children, where there is a great need for safe and effective medications.
| S-EPMC4965536 | biostudies-literature
Project description:Filaggrin (FLG) loss-of-function (LOF) variants are a major risk factor for the common inflammatory skin disease, atopic dermatitis (AD) and are often population-specific. African-American (AA) children are disproportionately affected with AD, often later developing asthma and/or allergic rhinitis and comprise an atopy health disparity group for which the role of FLG LOF is not well known. Discovery of FLG LOF using exome sequencing is challenging given the known difficulties for accurate short-read alignment to FLG's high homology repeat variation. Here, we employed an array-based sequencing approach to tile across each FLG repeat and discover FLG LOF in a well-characterized cohort of AA children with moderate-to-severe AD. Five FLG LOF were identified in 23% of our cohort. Two novel FLG LOF singletons, c.488delG and p.S3101*, were discovered as well as p.R501*, p.R826* and p.S3316* previously reported for AD. p.S3316* (rs149484917) is likely an African ancestral FLG LOF, reported in African individuals in ExAC (Exome Aggregation Consortium), Exome Variant Server (ESP), and 4 African 1000G population databases (ESN, MSL, ASW, and ACB). The proportion of FLG LOF (11.5%) among the total FLG alleles in our cohort was significantly higher in comparisons with FLG LOF reported for African individuals in ExAC (2.5%; P = 4.3 × 10-4 ) and ESP (1.7%; P = 3.5 × 10-5 ) suggesting a disease-enrichment effect for FLG LOF. Our results demonstrate the utility of array-based sequencing in discovering FLG LOF, including novel and population-specific, which are of higher prevalence in our AA severe AD group than previously reported.
| S-EPMC6440476 | biostudies-literature
Project description:ObjectiveAsthma and atopic dermatitis (AD) are complex diseases with striking disparities across racial and ethnic groups, which may be partly attributable to genetic factors. Here we summarize current knowledge from asthma and AD genome-wide association studies (GWAS) and pharmacogenetic studies in African ancestry populations.Data sourcesGWAS catalog; PUBMed.Study selectionsGWAS catalog studies with trait annotations "asthma" and "atopic eczema" and African ancestry individuals in the discovery dataset; the recent CAAPA asthma GWAS; reports on pharmacogenetic studies in asthma and AD.ResultsAlthough GWASs have revolutionized gene discovery for multiple complex traits, African Americans continue to be severely underrepresented in sufficiently powered genetics studies. Indeed, of the 16 asthma and 21 AD loci that reached genomewide significance in Europeans, very few have replicated in African ancestry populations. Challenges in comparing results from European vs African ancestry cohorts include modest sample size, differences in risk allele frequency, effect size, correlation between genetic variants, and environmental exposure in evolutionary history. African Americans also constitute a small percentage of dermatological and respiratory-focused clinical trials. Pharmacogenetic studies have similarly been focused largely on non-Hispanic whites, despite compelling evidence that genetic variation from different ancestral backgrounds may alter therapeutic efficacy of asthma and AD drugs.ConclusionLarge-scale genetic studies of asthma and AD in African Americans are essential to reduce research and health disparities and empower scientific discoveries.
| S-EPMC6500742 | biostudies-literature
Project description:Baricitinib (Olumiant®) is an oral small molecule inhibitor of Janus kinase (JAK)1 and JAK2, which have been implicated in the pathogenesis of atopic dermatitis (AD). In phase III studies in adults with moderate to severe AD who were inadequately controlled with topical corticosteroids (TCS) or systemic treatments (e.g. ciclosporin), or for whom these therapies were not advisable, baricitinib, alone or in combination with TCS, achieved significant and/or clinically relevant improvements in multiple measures of disease severity, pruritus, skin pain, sleep disturbance and health-related quality of life (HR-QOL) over 16 weeks. Benefit onset was rapid, with efficacy generally sustained over the longer term (treatment duration ≤ 68 weeks). In this patient population, the safety profile of baricitinib was consistent with that established in the moderate to severe rheumatoid arthritis (RA) population. Although further longer-term data would be beneficial, current evidence indicates that baricitinib, alone or in combination with TCS, provides an oral alternative to subcutaneous biologics for the treatment of moderate to severe AD in adults who are candidates for systemic therapy.
| S-EPMC9061224 | biostudies-literature
Project description: Not available
| S-EPMC8778950 | biostudies-literature
Project description:Atopic dermatitis (AD) is a common, heterogeneous, inflammatory skin disorder characterized by chronic or relapsing eczematous lesions with intense pruritus and discomfort. Affected patients often experience significant impairment in their quality of life, and the treatment of moderate-to-severe AD forms remains challenging. In the past few decades, increasing knowledge on the AD pathogenesis has driven the development of novel targeted therapies. Interleukin (IL)-13 plays a central and pleiotropic role in AD pathogenesis, contributing directly or indirectly to epidermal barrier disfunction, type-2 inflammation, dysbiosis, fibrosis, and itch response. For this reason, agents selectively targeting IL-13, such as lebrikizumab, emerged as a potential therapy for AD. This article reviews the current evidence about lebrikizumab in the management of AD. The phase II and phase III trials seem to corroborate efficacy of lebrikizumab in the treatment of moderate-to-severe AD, as shown by significant improvement of Eczema Area and Severity Index, body surface area, and pruritus scores. Also, lebrikizumab demonstrated favorable safety and tolerability profiles, with the majority of patients experiencing no significant adverse events. Lebrikizumab seems to be a promising emerging targeted biological agent for patients with moderate-to-severe AD. More data on the long-term efficacy and safety, head-to-head comparisons with other agents, and real-world evidence will help to clarify its place in therapy in AD.
| S-EPMC10460333 | biostudies-literature
Project description:Atopic dermatitis (AD) is a chronic, relapsing eczematous inflammatory skin disease. Mutations in the filaggrin gene (FLG) are major predisposing factors for AD. Ethnic differences exist between Asian and European populations in the frequency and spectrum of FLG mutations. Moreover, a distinct set of FLG mutations has been reported in Asian populations. The aim of this study was to examine the spectrum of FLG mutations in Koreans with AD. We also investigated the association of FLG mutations and clinical features of AD and compared the Korean FLG landscape with that of other East Asian countries.Seventy Korean patients with AD were enrolled in this study. Fourteen FLG mutations previously detected in Korean, Japanese, and Chinese patients were screened by genotyping.Four FLG null mutations (3321delA, K4022X, S3296X, and S2889X) were identified in eleven patients (15.7%). The most commonly detected mutations in Korean patients with AD were 3321delA (n=6, 9.1%) and K4022X (n=3, 4.5%). FLG mutations were significantly associated with elevated IgE (?200 KIU/L and/or MAST-CLA >3+, p=0.005), palmar hyperlinearity (p<0.001), and a family history of allergic disease (p=0.021).This study expanded our understanding of the landscape of FLG mutations in Koreans and revealed an association between FLG mutations and AD phenotype.
| S-EPMC5290020 | biostudies-literature
Project description:BackgroundAtopic 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.ObjectiveWe 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.MethodsWe 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.ResultsTwo 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.ConclusionThese 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.
| S-EPMC4090750 | biostudies-literature