The burden of disease associated with filaggrin mutations: A population-based, longitudinal birth cohort study

Henderson, John; Northstone, Kate; Lee, Simon P.; Liao, Hong; Zhao, Yiwei; Pembrey, Marcus; Mukhopadhyay, Somnath; Smith, George Davey; Palmer, Colin N.A.; McLean, W.H. Irwin; Irvine, Alan D.

doi:10.1016/j.jaci.2008.01.026

Cited by 314 publications

(312 citation statements)

References 21 publications

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“…Subsequently an impressive series of replication studies [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] confirmed that these polymorphisms confer an exceptionally strong risk for eczema and subsequent allergen sensitization and that FLG is one of the strongest known genes for complex diseases in general [22][23][24][25] .…”

Section: Resultsmentioning

confidence: 99%

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Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk

Weidinger

Baurecht

Wagenpfeil

et al. 2008

Journal of Allergy and Clinical Immunology

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Section: Resultsmentioning

confidence: 99%

“…Genotyping calls were made For the ALSPAC cohort the 2 commonest FLG mutations were typed as previously described 25 and the SPINK5 Lys420Ser polymorphism was typed by Taqman assay.…”

Section: Genotypingmentioning

confidence: 99%

Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk

Weidinger

Baurecht

Wagenpfeil

et al. 2008

Journal of Allergy and Clinical Immunology

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“…17 What is interesting is that patients with genetic differences tend to be susceptible to both this condition and other related allergic diseases. 24,25 Such large-scale genome profiling and genetic experiments have confirmed that the disruption of lipid rafts can lead to inflammatory disease under certain circumstances.…”

Section: Discussionmentioning

confidence: 96%

Effect of Cholesterol Depletion On Interleukin-8 Production in Human Respiratory Epithelial Cells

Kim

Hong

Lee

et al. 2013

Journal of Allergy and Clinical Immunology

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rate from their surroundings. Cholesterol, the most abundant lipid component of animal cell membranes, regulates membrane fluidity and plays a crucial role in the formation and stabilization of membrane microdomains. It is also an important contributor to cell-cell adhesion, migration, and even endocytosis. [4][5][6][7] However, despite increasing interest in the bronchial epithelium, the possible role of cholesterol in inflammation of the airway or the development of asthma has not been investigated. Among the numerous cytokines and chemokines released from human airways, interleukin-8 (IL-8) is a representative Original ArticleAllergy Asthma Immunol Res. 2013 November;5(6):402-408. http://dx.doi.org/10. 4168/aair.2013.5.6.402 pISSN 2092-7355 • eISSN 2092 Purpose: The lipid entities of cell membranes are components of the immune system and important mediators of inflammation. Despite increasing interest in the function of epithelial cells in inflammation, the role of cholesterol in this process has not been described. Here, we investigated the effect of cholesterol depletion on the inflammatory process in airway epithelial cells via the expression of interleukin (IL)-8 as a marker of inflammation. Methods: A 549 cells were treated with 0.5% methyl-β-cyclodextrin as a selective cholesterol extractor. The IL-8 level was assessed by enzyme-linked immunosorbent assay and reassessed after cholesterol repletion. Mitogen-activated protein kinase (MAPK) inhibitors were used to determine the upstream signaling pathway for IL-8 production in cholesterol-depleted cells. Results: We found a relationship between the amount of cholesterol in A 549 cells and inflammation of the airway. IL-8 production was increased in cholesterol-depleted A 549 cells and restored by cholesterol repletion. IL-8 production was decreased by pretreatment with the extracellular signal-regulated kinase (ERK) inhibitor U0126 but not with JNK inhibitor II or the p38 MAPK inhibitor SB202190. Conclusions: Our findings suggest that inflammatory responses are increased in cholesterol-depleted epithelial cells via the MAPK signaling system, predominantly by the ERK pathway. We conclude that the lipid components of airwayepithelial cells may play a role in the inflammatory process.

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“…Remarkably, FLG null alleles are rather common with carrier frequencies of ~8% in the general population and around 20% in AD cases [61,63,64]. In two large population-based studies [65,66] it was demonstrated that, assuming causality, filaggrin mutations account for up to 15% of the total causality of all AD in these populations. Thus, FLG mutations are the strongest and best replicated genetic risk for AD to date.…”

Section: Filaggrinmentioning

confidence: 99%

Clinical Impact of Current Genetics Findings

Weidinger¹,

Kabesch²

2011

Pediatric and Adolescent Medicine

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Atopic dermatitis (AD) is the one of the most common chronic skin diseases with prevalence rates of up to 20% in young infants and children and up to 5% in adults. The majority of patients show an onset of disease in early childhood and a spontaneous remission until adolescence, but there might be relapses, and the disease can also start in or persist into adulthood. AD presents a wide spectrum of clinical patterns and a variety of trigger factors with variable importance in the individual patient. It is frequently accompanied by elevated levels of total serum IgE antibodies and IgEmediated responses to common allergens, and often co-occurs with other allergic disorders such as food allergy, asthma and rhinitis, giving further rise to possible subpopulations of patients [1].Since there is no objective laboratory test or histologic finding specific for AD, diagnosis is usually made on the basis of a dermatologic examination of skin lesions considering their age-specific morphology and distribution. Further signs leading to the diagnosis of AD are the chronicity of symptoms and their association with pruritus [2]. For large epidemiologic studies, numerous diagnostic criteria have been developed in order to establish a definition for AD by using reliable discriminators resulting in increased validity and reproducibility of the diagnosis of AD. At present, the UK diagnostic criteria are most widely validated and appear to be applicable and repeatable across all ages and many ethnicities. However, as shown in a recent review, the ideal set of diagnostic criteria still has to be established [3].The pathophysiology of AD is complex and involves a disturbance of the epidermal barrier as well as abnormal immunological and inflammatory pathways leading to a Th2-dominated immune response with a Th17 component in acute AD lesions and the progressive conversion to a Th1-dominated response in chronic AD lesions [1].

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The burden of disease associated with filaggrin mutations: A population-based, longitudinal birth cohort study

Cited by 314 publications

References 21 publications

Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk

Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk

Effect of Cholesterol Depletion On Interleukin-8 Production in Human Respiratory Epithelial Cells

Clinical Impact of Current Genetics Findings

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