Clinical Characteristics and Genetic Variations in Early-Onset Atopic Dermatitis Patients.
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ABSTRACT: Background
Hereditary factors contribute to atopic dermatitis (AD) development. We developed the reverse blot hybridization assay (REBA) kit to simultaneously detect variations in skin barrier- and immune response-related genes prevalent in Korean AD patients.Objective
To identify genetic variations and clinical characteristics that could predict early AD development.Methods
We compared AD-related genetic variations between early-onset AD subjects and non-AD controls, and clinical characteristics and genetic variations between early- and late-onset AD subjects. We compared 28 early-onset AD subjects and 57 non-AD controls from a birth cohort and 108 early- (age ≤3 years) and 90 late-onset AD subjects and 189 non-AD controls from a university hospital. Genetic variations were detected via REBA.Results
There were no differences in AD-related genetic variation between early-onset AD subjects and non-AD controls in the birth cohort. When the birth cohort and hospital populations were combined, early-onset AD subjects and non-AD controls showed different frequencies of genetic variations of KLK7, SPINK5 1156, DEFB1, IL5RA, IL12RB1a, and IL12RB1b. No differences in the frequency of genetic variations were observed between early- and late-onset AD subjects. Immunoglobulin E positivity for house dust mites was prevalent in late-onset AD subjects. A family history of atopic diseases was associated with early-onset AD.Conclusion
No AD-related genetic variations could predict early AD development in Koreans, even though neonates with a family history of atopic diseases are likely to develop AD at ≤3 years of age. Environmental exposure may be more important than genetic variation in determining the onset age of AD.
SUBMITTER: Kim BJ
PROVIDER: S-EPMC7992730 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAtopic dermatitis (AD) has increased in frequency to rates as high as 20% for children in developed countries. AD is one of the most common childhood diseases and has a complex etiology involving genetic and environmental factors. Thus, a broad understanding of genetic background is needed for early diagnosis of AD.ObjectiveIdentification of candidate functional genetic variants associated with early-onset AD in Koreans.MethodsWhole-exome sequencing (WES) was performed in three families. Sanger sequencing was used to validate detected variants in 112 AD patients and 61 controls.ResultsFunctional variants were filtered by WES, and then variants related to allergic immune diseases were selected through a literature search. Two candidate non-synonymous single-nucleotide polymorphisms of CDKAL1 (rs77152992) and ERBB2 (rs1058808) were identified, c.1226C>T, p.Pro409Leu, c.3463C>G, and p. Pro1170Ala respectively. A case-control study was performed to determine whether rs77152992 and rs1058808 are candidate risk factors for early-onset AD. rs77152992 was significantly associated with early-onset AD (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.21~0.83; p=0.0133) in allele frequencies. The CC genotype of CDKAL1 had significantly increased risk of AD (OR, 2.16; 95% CI, 1.0~4.6; p=0.0475). rs1058808 had no correlation with AD. Total eosinophil count was significantly increased in AD patients with the CC genotype of CDKAL1 (rs77152992).ConclusionCDKAL1 (rs77152992) and ERBB2 (rs1058808) were deemed functionally interesting based on WES. Our case-control study suggests that the CC genotype of rs77152992 may be associated with increased eosinophil counts. It may enhance the risk of early-onset AD.
| S-EPMC5929943 | biostudies-literature
Project description:Background: Atopic dermatitis (AD) predominantly affects young children, but our understanding of AD pathogenesis is based on skin and blood samples from longstanding adult AD. Genomic biopsy profiling from early pediatric AD showed significant Th2 and Th17/Th22-skewing, without the characteristic adult Th1 up-regulation. Since obtaining pediatric biopsies is difficult, blood gene expression profiling may provide a surrogate for the pediatric skin signature. Objective: To define the blood profile and associated biomarkers of early moderate-to-severe pediatric AD. Methods: We compared microarrays and RT-PCR of blood cells from 28 AD children (<5yrs and within 6 months of disease onset) to healthy control blood cells. Differentially expressed genes/DEGs in blood (fold change/FCH>1.2 and false discovery rate/FDR<0.05) were then compared with skin DEGs. Results: Eosinophil and Th2 markers (IL5RA, IL1RL1/ST2, HRH4, CCR3, SIGLEC8, PRSS33, CLC from gene arrays; IL13/IL4/CCL22 from RT-PCR) were upregulated in early pediatric AD blood, while IFNG/Th1 was decreased. Th1 markers were negatively correlated with clinical severity (EASI, pruritus, transepidermal water loss/TEWL), whereas Th2/Th17-induced IL19 was positively correlated with SCORAD. While a few RT-PCR-defined immune markers (IL13/CCL22) were increased in blood, as previously also reported for skin, there was minimal overlap based on gene array DEGs. Conclusion: The whole blood signature of early moderate-to-severe pediatric AD blood cells show predominantly a Th2/eosinophil profile, but markers largely differ from the skin profile. Given their complementarity, pooling of biomarkers from blood and skin may improve profiling and predictions, providing insight regarding disease course allergic comorbidity development, and response to systemic medications.
2018-12-06 | GSE116486 | GEO
Project description:PURPOSE:Variations in barrier- or immune response-related genes are closely related to the development of atopic dermatitis (AD). This study was designed to identify genetic variations and clinical features to predict 'recalcitrant AD.' METHODS:AD patients were classified as treatable and recalcitrant. Treatable AD patients showed satisfactory clinical improvement with basic and topical treatments. Recalcitrant AD patients used systemic immune-suppressants for over 4 weeks as they had not shown clinical improvement with basic and topical treatments. The frequency of gene variations in barrier- (FLG 3321delA, FLG K4022X, KLK7, SPINK 1156, SPINK 1188, SPINK 2475) and immune response- (DEFB1, KDR, IL-5RA, IL-9, and IL-12RB1a, b) related genes were compared between each AD group and the controls. RESULTS:Of all, 249 treatable AD and 32 recalcitrant AD were identified. Heterozygous mutations (Hetero) in KLK7 was more frequent in recalcitrant AD patients than treatable AD, without statistical significance. Hetero in DEFB1 was more frequent in treatable AD patients. However, no other significant genetic differences between treatable and recalcitrant AD was observed. Instead, higher initial Eczema Area Severity Index (EASI) score, serum immunoglobulin E (IgE) level, allergen specific IgE for house dust mites, and family history of atopic diseases were associated with recalcitrant AD with statistical significance. CONCLUSIONS:According to our study, no genetic variation to predict recalcitrant AD was identified, suggesting that clinical manifestation, rather than genetic variations of AD patients is more likely to be an important factor in predicting the prognosis of AD. Further large-scale studies on the correlation between genetic variation and recalcitrant AD are needed.
| S-EPMC5911443 | biostudies-literature
Project description:FLG encodes a large protein called profilaggrin, which plays a key role in maintaining an effective skin barrier against the environment. In this study, we identified FLG single nucleotide variations (FLG-SNVs) and evaluated the association of FLG-SNVs with clinical phenotypes including atopic dermatitis (AD)-associated minor clinical features, presence of specific allergic sensitization, and serum parameters.Eighty-one Korean patients with AD were enrolled. AD-associated minor clinical features as well as allergic rhinitis and asthma were diagnosed by specialists. FLG-SNVs were identified by Sanger sequencing of entire exons through long-range PCR. Allergic sensitization to a specific allergen was evaluated by multiple allergen simultaneous test. Serologic parameters such as serum eosinophil cationic protein (ECP) and eosinophil derived neurotoxin (EDN) were measured.A total of seventy-three SNVs and 4 LOF mutations were successfully genotyped. rs71626704 and rs76413899 were significantly associated with a history of asthma and cheilitis (P = 0.002 and P = 0.033, respectively), however, the associations were not found statistically significant after adjustment by multiple comparisons. In addition, we detected haplotype blocks which were correlated with non-specific hand or foot dermatitis and scalp scale. We identified FLG-SNVs which were associated with sensitization to environmental allergens; rs62623409 and rs71625199 (P = 0.038 and P = 0.008, respectively). Patients with FLG P478S TT and history of allergic rhinitis showed a higher EDN level, and among those patients, the ones with asthma showed a higher ECP level.This study revealed the association of FLG-SNVs with AD-associated minor clinical features. We firstly identified rs71625199 which was associated with higher environmental allergic sensitization. We also suggest that FLG P478S is a kind of disease modifier which affects serologic parameters such as EDN and ECP.
| S-EPMC5744964 | biostudies-literature
Project description:BackgroundSkin biopsies promote our understanding of atopic dermatitis/AD pathomechanisms in infants/toddlers with early-onset AD, but are not feasible in pediatric populations. Tape strips are an emerging, minimally invasive alternative, but global transcriptomic profiling in early pediatric AD is lacking. We aimed to provide global lesional and nonlesional skin profiles of infants/toddlers with recent-onset, moderate-to-severe AD using tape strips.MethodsSixteen tape strips were collected for RNA-seq profiling from 19 infants/toddlers (<5 years old; lesional and nonlesional) with early-onset moderate-to-severe AD (≤6 months) and 17 healthy controls.ResultsWe identified 1829 differentially expressed genes/DEGs in lesional AD and 662 DEGs in nonlesional AD, vs healthy skin (fold-change ≥2, FDR <0.05), with 100% sample recovery. Both lesional and nonlesional skin showed significant dysregulations of Th2 (CCL17 and IL4R) and Th22/Th17 (IL36G, CCL20, and S100As)-related genes, largely lacking significant Th1-skewing. Significant down-regulation of terminal differentiation (FLG and FLG2), lipid synthesis/metabolism (ELOVL3 and FA2H), and tight junction (CLDN8) genes were primarily seen in lesional AD. Significant negative correlations were identified between Th2 measures and epidermal barrier gene-subsets and individual genes (FLG with IL-4R and CCL17; r < -0.4, P < .05). Significant correlations were also identified between clinical measures (body surface area/BSA, pruritus ADQ, and transepidermal water loss/TEWL) with immune and barrier mRNAs in lesional and/or nonlesional AD (FLG/FLG2 with TEWL; r < -0.4, P < .05).ConclusionRNA-seq profiling using tape strips in early-onset pediatric AD captures immune and barrier alterations in both lesional and nonlesional skin. Tape strips provide insight into disease pathomechanisms and cutaneous disease activity.
| S-EPMC9285647 | biostudies-literature
Project description:Therapeutic regimens for the treatment and long-term management of AD traditionally had a two-fold objective of decreasing skin inflammation and repairing the defective skin barrier. Essential treatments for AD in children should include topical moisturizers for skin hydration and prevention of flares, topical anti-inflammatory medications (e.g. corticosteroids, calcineurin inhibitors, PDE4 inhibitor), allergen/irritant avoidance, and treatment of skin infections. Treatment regimens should be severity-based, and implemented in a stepwise approach tailored to the individual patient. This stepwise approach includes initial use of emollients, gentle skin care, and escalating to more potent anti-inflammatory treatments as the disease severity increases. Currently available systemic medications should be reserved for the presence of recalcitrance to topical therapies due to associated toxicities. We believe that early treatment of AD is not only essential in treating the skin disease, but also in preventing the development of additional atopic diseases, such as food allergy, asthma and allergic rhinitis. The defective skin barrier of AD permits a route of entry for food and environmental allergens, and upon exposure, keratinocytes secrete TSLP, which activates the TH2 pathway. This TH2 differentiation sets off the atopic march and the subsequent diseases that are seen. This review highlights treatment options and strategies in pediatric AD therapy with an emphasis on early therapy. Supporting evidence on the efficacy and safety of each intervention will be discussed.
| S-EPMC5983898 | biostudies-literature
Project description:ImportanceKnowledge about factors associated with persistence of atopic dermatitis (AD) during childhood is sparse.ObjectiveTo explore heritable, environmental, and clinical factors associated with persistent AD based on 13 years' follow-up of an at-risk birth cohort.Design, setting, and participantsIn the Copenhagen Prospective Study on Asthma in Childhood 2000 (COPSAC2000) clinical birth cohort study, 411 children born to mothers with asthma were followed up until the age of 13 years at a clinical research unit in Copenhagen, Denmark, from August 1998 to June 2015. Atopic dermatitis was diagnosed prospectively during close clinical follow-up according to the criteria of Hanifin and Rajka. Data were gathered on parental history, social circumstances, and environmental factors through parent interviews. The cohort was followed up with biannual visits to the clinic until the age of 7 years and were seen again at age 13 years. Data were analyzed from August 2015 to January 2018.Main outcomes and measuresAtopic dermatitis was diagnosed using Hanifin and Rajka major and minor criteria, and severity was determined by Scoring Atopic Dermatitis (SCORAD) index, with possible scores from 0 to 83, with higher scores indicating more severe AD.ResultsOf the 411 children in the cohort, 203 (49.4%) were male and 186 (45.3%) were diagnosed with AD before the age of 13 years; 40 of 166 children (24.1%) had persistent AD at the age of 13 years, and 126 (76.0%) experienced remission. Factors associated with persistent AD to age 13 years included heritability, environmental exposures, asthma and allergic sensitization, clinical presentation at the time of diagnosis, the composition of Hanifin and Rajka diagnostic minor criteria, and AD severity according to SCORAD. A higher AD genetic risk score was associated with an increased the risk for persistent AD (multivariable odds ratio [OR], 1.8; 95% CI, 1.1-2.9; P = .02), together with paternal asthma (multivariable OR, 3.7; 95% CI, 1.2-11.5; P = .02); paternal AD (multivariable OR, 6.2; 95% CI, 1.17-23.2; P = .007), and higher social circumstances (multivariable OR, 1.6; 95% CI, 1.0-2.5; P = .05). Particular clinical presentations at time of diagnosis were also associated with specific minor criteria of Hanifin and Rajka (Dennie-Morgan and anterior neck folds, white dermographism, intolerance to wool, itching when sweating, tendency to skin infection, food intolerance, and food allergy) (OR, 2.6; 95% CI, 1.1-6.2; P = .03) as well as increased severity at diagnosis (OR, 1.1; 95% CI, 1.0-1.1; P = .007).Conclusions and relevanceIn a birth cohort of children at risk for asthma who received close clinical follow-up to age 13 years, known genetic AD risk variants, paternal asthma and AD, high social circumstances, diagnostic minor criteria, and disease severity at onset were associated with persistent AD at age 13 years. These findings may be applied in clinical practice to evaluate the likely disease course for individual patients.
| S-EPMC6439574 | biostudies-literature
Project description:Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. Genetic predisposition, epidermal barrier disruption, and dysregulation of the immune system are some of the critical components of AD. An impaired skin barrier may be the initial step in the development of the atopic march as well as AD, which leads to further skin inflammation and allergic sensitization. Type 2 cytokines as well as interleukin 17 and interleukin 22 contribute to skin barrier dysfunction and the development of AD. New insights into the pathophysiology of AD have focused on epidermal lipid profiles, neuroimmune interactions, and microbial dysbiosis. Newer therapeutic strategies focus on improving skin barrier function and targeting polarized immune pathways found in AD. Further understanding of AD pathophysiology will allow us to achieve a more precision medicine approach to the prevention and the treatment of AD.
| S-EPMC6399565 | biostudies-literature
Project description:Moderate to severe atopic dermatitis (AD) has a high disease burden and a significant effect on quality of life. Observational studies are necessary to determine the patient disease burden and long-term disease control in the Japanese population. ADDRESS-J is a non-interventional, observational registry of adult Japanese patients with moderate to severe AD. Herein, we report baseline data from the ADDRESS-J study describing disease characteristics and current treatment practices. At baseline, 300 adult AD patients with Investigator's Global Assessment (IGA) scores (range, 0-4) of 3 (moderate) or 4 (severe) whose treatments for AD were intensified, were assessed for clinical and patient-reported outcomes and current AD treatments. The registry patients' median age was 34.0 years; 60.7% were male and 71.7% had had AD for more than 20 years. At baseline, 220 study patients had an IGA score of 3 and 80 had an IGA score of 4. The median Eczema Area and Severity Index score was 21.7 (range, 0-72), the median body surface area involvement was 46.25%, and the median pruritus numerical rating scale score was 7.0 (range, 0-10); for each of these measures, higher scores represent greater severity. Most registry patients (86.7%) had recently used topical corticosteroids or topical calcineurin inhibitors as treatment for AD. This registry cohort represents a population of Japanese patients with moderate to severe AD and provides an important resource for characterizing the disease burden and evaluating the safety and effectiveness of various AD treatments.
| S-EPMC6594225 | biostudies-literature
Project description:IntroductionDupilumab is the first biologic licensed to treat patients with moderate-to-severe atopic dermatitis (AD) who require systemic therapy. PROLEAD was designed to document the real-world effectiveness and safety of dupilumab in patients with moderate-to-severe AD. The present study aims to describe the baseline characteristics of patients treated with dupilumab in Germany.MethodsPROLEAD is a national, multicentre, prospective, non-interventional study, with a 2-year observation period. Adults with moderate-to-severe AD treated with dupilumab were included. Baseline characteristics, physician assessments, and patient-reported outcomes (PROs) were collected.ResultsThe study involved 126 sites throughout Germany. Of 839 patients assessed for eligibility, 828 were included, with baseline data available for 817 patients. Mean (standard deviation, SD) age of patients was 43.4 (15.8) years, with 396 (48.5%) patients being female. Overall, 66.6% of patients received their first diagnosis of AD during childhood. In total, 423 (51.8%) patients had co-existing atopic and type 2 inflammatory diseases, including allergic conjunctivitis (36.8%) and bronchial asthma (22.5%). Overall, 61.4% of patients had received systemic therapy, most commonly oral corticosteroids (49.9%). Approximately half of patients (51.3%) had received UV/phototherapy prior to baseline. Treatment with moderate-potent (Class 2) or potent (Class 3) topical corticosteroids was the most common concomitant treatment at baseline. However, 50.4% of patients had not received concomitant AD treatment with dupilumab at baseline. The most reported reason for initiating dupilumab was "Topical therapy alone was not sufficient" (95.1%). Mean (SD) physician assessments: EASI: 22.9 (14.5); SCORAD: 63.3 (16.2); IGA: 3.3 (0.7). Mean (SD) PROs: DLQI: 13.9 (7.1); peak pruritus NRS: 7.4 (2.3).ConclusionsPatients with moderate-to-severe AD present a long medical history, impaired quality of life, and high prevalence of co-existing type 2 inflammatory diseases. Dupilumab was used as a first-line systemic treatment in 38.6% of patients.
| S-EPMC9464282 | biostudies-literature