Exome sequencing of filaggrin and related genes in African-American children with atopic dermatitis.
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ABSTRACT:
SUBMITTER: Margolis DJ
PROVIDER: S-EPMC4102628 | biostudies-literature | 2014 Aug
REPOSITORIES: biostudies-literature
Publications
Exome sequencing of filaggrin and related genes in African-American children with atopic dermatitis.
Margolis David J DJ Gupta Jayanta J Apter Andrea J AJ Hoffstad Ole O Papadopoulos Maryte M Rebbeck Tim R TR Wubbenhorst Bradley B Mitra Nandita N
The Journal of investigative dermatology 20140307 8
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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-EPMC4659403 | 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: Not available
| S-EPMC8778950 | biostudies-literature
Project description:PurposeAtopic 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.Materials and methodsSeventy Korean patients with AD were enrolled in this study. Fourteen FLG mutations previously detected in Korean, Japanese, and Chinese patients were screened by genotyping.ResultsFour 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).ConclusionThis 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:ImportanceAtopic dermatitis (AD) is a common chronic illness that has been associated with variation in the filaggrin gene (FLG). Four variants are most often evaluated.ObjectivesTo comprehensively describe and compare results from targeted sequencing of FLG loss-of-function (LoF) variants in children of African and European ancestry and the association of these variants with onset and persistence of AD.Design, setting, and participantsThis prospective US cohort study assessed the genetic subcohort of the Pediatric Eczema Elective Registry (PEER). Children with mild to moderate AD were included in the analysis. Massively parallel sequencing (MPS) was used to focus on FLG LoF variation in white and African American children. Patients were enrolled from June 2005 through July 2017. Data were analyzed from January 25 through May 10, 2019.Main outcomes and measuresAssociations of FLG LoF variation with white and African American ancestry and with the risk and persistence of AD.ResultsA total of 741 children were included in the analysis (394 [53.2%] female and 347 [46.8%] male; mean [SD] age at onset, 1.97 [2.72] years); of these, 394 (53.2%) were white, 326 (44.0%) were African American, and 21 (2.8%) were of other ancestries. Using MPS technology, 23 FLG LoF variants were found in children with AD. The prevalence of FLG LoF variants was 177 participants (23.9%) in the full cohort, 124 white participants (31.5%), and 50 African American participants (15.3%). The odds ratio for carrying any FLG LoF variant in a white child compared with an African American child with AD was 2.44 (95% CI, 1.76-3.39). Some FLG LoF variants are only found in children of a specific ancestry (eg, p.S3316* and p.R826* were not seen in white patients). Children with an FLG LoF were more likely to have persistent AD (odds ratio, 0.67; 95% CI, 0.56-0.80).Conclusions and relevanceThe FLG LoF variants in a US cohort of children with mild to moderate AD differ significantly by race and their association with the persistence of AD. Conventional testing of the 4 frequently evaluated variants is inadequate. Any planned genetic diagnostic test for AD based on FLG LoF variants must be inclusive and not rely on the most frequently studied variants.
| S-EPMC6669787 | biostudies-literature
Project description:BackgroundWhile numerous genetic loci associated with atopic dermatitis (AD) have been discovered, to date, work leveraging the combined burden of AD risk variants across the genome to predict disease risk has been limited.ObjectivesThis study aims to determine whether polygenic risk scores (PRSs) relying on genetic determinants for AD provide useful predictions for disease occurrence and severity. It also explicitly tests the value of including genome-wide association studies of related allergic phenotypes and known FLG loss-of-function (LOF) variants.MethodsAD PRSs were constructed for 1619 European American individuals from the Atopic Dermatitis Research Network using an AD training dataset and an atopic training dataset including AD, childhood onset asthma, and general allergy. Additionally, whole genome sequencing data were used to explore genetic scoring specific to FLG LOF mutations.ResultsGenetic scores derived from the AD-only genome-wide association studies were predictive of AD cases (PRSAD: odds ratio [OR], 1.70; 95% CI, 1.49-1.93). Accuracy was first improved when PRSs were built off the larger atopy genome-wide association studies (PRSAD+: OR, 2.16; 95% CI, 1.89-2.47) and further improved when including FLG LOF mutations (PRSAD++: OR, 3.23; 95% CI, 2.57-4.07). Importantly, while all 3 PRSs correlated with AD severity, the best prediction was from PRSAD++, which distinguished individuals with severe AD from control subjects with OR of 3.86 (95% CI, 2.77-5.36).ConclusionsThis study demonstrates how PRSs for AD that include genetic determinants across atopic phenotypes and FLG LOF variants may be a promising tool for identifying individuals at high risk for developing disease and specifically severe disease.
| S-EPMC8973457 | biostudies-literature
Project description:BackgroundAtopic dermatitis (AD) is a common skin disorder with elevated prevalence. Cataract induced by AD rarely occurs in adolescent and young adult patients, which is also called atopic cataract. Using whole exome sequencing, we aimed to explore genetic alterations among AD and atopic cataract.ResultWe recruited a 19 year-old Chinese male with AD accompanied with cataracts, his father with AD and his mother without AD or cataract. Through analysis of the exomic sequence of the 3 individuals from the same family, we identified that with respect to AD, there were 162 genes mutated in both this patient and his father but not in his mother. In addition, we found 10 genes mutated in this patient only without in his parents according to cataract.ConclusionThis research suggests that coinheritance of mutations in these genes may correlate with AD, and the pathogenesis of AD complicated with cataracts was related to genetic factors.
| S-EPMC5601745 | biostudies-literature
Project description:TWEAK Upregulates atopic dermatitis related genes in human kearatinocytes
2023-11-28 | GSE214503 | GEO