Filaggrin null mutations are associated with increased asthma severity in children and young adults

doi:10.1016/j.jaci.2007.04.001

Journal of Allergy and Clinical Immunology

Volume 120, Issue 1, July 2007, Pages 64-68

https://doi.org/10.1016/j.jaci.2007.04.001 Get rights and content

Background

Filaggrin is a key protein involved in skin barrier function. Filaggrin (FLG) null mutations are important genetic predisposing factors for atopic disease.

Objective

To study the role of FLG null alleles in the clinical phenotype in children and young adults with asthma.

Methods

FLG mutations R501X and 2282del4 were assayed in 874 subjects 3 to 22 years old with asthma from Tayside. Lung function and disease severity were also studied.

Results

The filaggrin mutations were significantly associated with greater disease severity for asthma. Independent of eczema, mean FEV₁/forced vital capacity of FLG wild-type individuals differed from those carrying either FLG null allele (0.89 vs 0.86; P = .012). Individuals bearing FLG null alleles were more likely to be prescribed increased medication (χ² = 10.3; P = .001), with the homozygote null individuals having an odds ratio of 6.68 (95% CI, 1.7-27.0; P = .008) for being prescribed long-acting β-agonists in addition to inhaled steroids. FLG null alleles were also associated with increased rescue medication use (P = .004). Individuals with asthma and with FLG null alleles were more likely to have eczema, and individuals with eczema tended to have more severe asthma; however, the association of FLG null alleles with all markers of asthma disease severity was similar in children with and without eczema.

Conclusion

FLG mutations are associated not only with eczema-associated asthma susceptibility but also with asthma severity independent of eczema status.

Clinical implications

FLG status influences controller and reliever medication requirements in children and young adults with asthma.

Section snippets

Methods

The BREATHE study of childhood asthma has been extended from the time of publication of our initial results.² The current data set includes information on demographic, anthropometric, and clinical details from 874 individuals with physician-diagnosed asthma attending primary and secondary clinics in 18 primary care practices and a secondary care asthma clinic in Tayside, Scotland, from 2004 to 2006 (age 3-22 years). The study was approved by the Tayside Committee on Medical Research Ethics.

Results

The population characteristics are fairly typical of young individuals with well controlled asthma derived from both primary and secondary care²⁰ (Table I). The allele frequencies of the FLG mutations R501X and 2282del4 in the children with asthma were increased relative to the Tayside population, and this increase in allele frequency was limited to the children with asthma with a self-reported history of eczema as previously reported.² Mean FEV₁ and FVC measurements were 96% to 97% predicted,

Discussion

Both common FLG mutations R501X and 2282del4 were overrepresented in the Scottish asthma cohort compared with local population controls, and the FLG alleles were overrepresented in a significant fraction of the cohort that had eczema.² Since the completion of data collection for our initial study,² we have continued recruiting patients with asthma for the Scottish cohort primarily ascertained for asthma to generate the statistical power to investigate further the possible role of filaggrin gene

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Incident Asthma, Asthma Exacerbations, and Asthma-Related Hospitalizations in Patients With Atopic Dermatitis
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Atopic dermatitis (AD) is thought to induce asthma via the “atopic march,” but the effects of AD on incident asthma and asthma severity have not been fully characterized.
To determine risk of asthma, asthma exacerbations, and asthma-related hospitalizations among patients fwith AD.
A cohort study was conducted using electronic health records data from UK general practices from 1994 to 2015. Children (<18 years old) and adults (≥18 years) with AD were matched on age, practice, and index date to patients without AD. AD severity was categorized using treatments and dermatologist referrals. Outcomes were incident asthma among all patients and asthma exacerbation or hospitalization among patients with asthma.
On comparing 409,341 children with AD (93.2% mild, 5.5% moderate, 1.3% severe) with 1,809,029 unaffected children, those with AD were found to be associated with a 2-fold greater risk of asthma compared with those without AD (hazard ratio, 1.96; 95% CI, 1.93-1.98). On comparing 625,083 adults with AD (65.7% mild, 31.4% moderate, and 2.9% severe) with 2,678,888 unaffected adults, AD was found to be associated with a 38% higher risk of asthma (hazard ratio, 1.38; 95% CI, 1.36-1.40). Asthmatic patients with AD also had a 21% to 63% greater risk of asthma exacerbations and a 20% to 64% greater risk of asthma-related hospitalizations compared with asthmatic patients without AD. Risk of asthma, asthma exacerbation, or asthma-related hospitalization increased with AD severity in a dose-dependent manner in both the pediatric and adult cohorts.
AD, especially in children and when more severe, is associated with greater risk of asthma as well as greater risk of asthma exacerbations and hospitalizations among asthmatic patients.
Type 2 Inflammation Contributes to Skin Barrier Dysfunction in Atopic Dermatitis
2022, JID Innovations
Skin barrier dysfunction, a defining feature of atopic dermatitis (AD), arises from multiple interacting systems. In AD, skin inflammation is caused by host–environment interactions involving keratinocytes as well as tissue-resident immune cells such as type 2 innate lymphoid cells, basophils, mast cells, and T helper type 2 cells, which produce type 2 cytokines, including IL-4, IL-5, IL-13, and IL-31. Type 2 inflammation broadly impacts the expression of genes relevant for barrier function, such as intracellular structural proteins, extracellular lipids, and junctional proteins, and enhances Staphylococcus aureus skin colonization. Systemic anti‒type 2 inflammation therapies may improve dysfunctional skin barrier in AD.
Atopy as Immune Dysregulation: Offender Genes and Targets
2022, Journal of Allergy and Clinical Immunology: In Practice
Allergic diseases are a heterogeneous group of disorders resulting from exaggerated type 2 inflammation. Although typically viewed as polygenic multifactorial disorders caused by the interaction of several genes with the environment, we have come to appreciate that allergic diseases can also be caused by monogenic variants affecting the immune system and the skin epithelial barrier. Through a myriad of genetic association studies and high-throughput sequencing tools, many monogenic and polygenic culprits of allergic diseases have been described. Identifying the genetic causes of atopy has shaped our understanding of how these conditions occur and how they may be treated and even prevented. Precision diagnostic tools and therapies that address the specific molecular pathways implicated in allergic inflammation provide exciting opportunities to improve our care for patients across the field of allergy and immunology. Here, we highlight offender genes implicated in polygenic and monogenic allergic diseases and list targeted therapeutic approaches that address these disrupted pathways.
Cellular and molecular mechanisms of allergic asthma
2022, Molecular Aspects of Medicine
Asthma is a chronic disease of the airways, which affects more than 350 million people worldwide. It is the most common chronic disease in children, affecting at least 30 million children and young adults in Europe. Asthma is a complex, partially heritable disease with a marked heterogeneity. Its development is influenced both by genetic and environmental factors. The most common, as well as the most well characterized subtype of asthma is allergic eosinophilic asthma, which is characterized by a type 2 airway inflammation. The prevalence of asthma has substantially increased in industrialized countries during the last 60 years. The mechanisms underpinning this phenomenon are incompletely understood, however increased exposure to various environmental pollutants probably plays a role. Disease inception is thought to be enabled by a disadvantageous shift in the balance between protective and harmful lifestyle and environmental factors, including exposure to protective commensal microbes versus infection with pathogens, collectively leading to airway epithelial cell damage and disrupted barrier integrity. Epithelial cell-derived cytokines are one of the main drivers of the type 2 immune response against innocuous allergens, ultimately leading to infiltration of lung tissue with type 2 T helper (T_H2) cells, type 2 innate lymphoid cells (ILC2s), M2 macrophages and eosinophils. This review outlines the mechanisms responsible for the orchestration of type 2 inflammation and summarizes the novel findings, including but not limited to dysregulated epithelial barrier integrity, alarmin release and innate lymphoid cell stimulation.
Association of epidermal differentiation complex (EDC) genetic variants with House Dust Mite sensitization in Atopic Dermatitis Patients
2022, Immunobiology
Citation Excerpt :
Studies on the association of genes in AD suggest clusters of the EDC (Epidermal differentiation complex) (Weidinger et al., 2013; Toulza et al., 2007) and other barrier candidates (Liang et al., 2016), but the most important associations were related to two null mutations (R510X and 2282del4) in the filaggrin gene. The FLG gene encoding filaggrin is located in the EDC and many studies reveal that FLG mutations predispose significantly to an increased risk to develop atopic eczema (O'Regan et al., 2009; Jungersted et al., 2010; Palmer et al., 2006; Palmer et al., 2007). Besides FLG, changes in other cornified envelope proteins may also impact the skin barrier function.
The etiopathogenesis of AD is multifactorial and defects of the skin barrier, which physiologically constitutes the natural protection, are associated with the disease phenotype. The identification of the genetic and environmental factors paving the way for impaired barrier function is therefore important in developing new therapeutic and prevention strategies.
Confirmed 100 cases were tested against 106 controls for filaggrin mutation and LELP-1 polymorphism by PCR-RFLP and chain termination sequencing. Total IgE and Vitamin D were estimated by ELISA. House dust mite sensitization was assessed by an in-vivo skin prick test.
FLG deletion (2282del4) was present in 4% of the patients and all these were heterozygous carriers, whereas FLG null mutation (R501X) was not present in any of the cases. In the control group, both the mutations were not found. CT genotype and T allele of LELP-1 (rs7534334) were significantly associated with elevated IgE levels, early-onset, HDM sensitization, and disease severity (P < 0.05). However, the genotypic and allelic distribution of LELP-1 among the cases and controls was found to be insignificant.
The low frequency of 2282del4 deletion and the absence of R501X mutation suggest that filaggrin deficiency does not confer a major risk for AD in the Indian population. However, significant association of LELP-1 (rs7534334) variant allele with clinical variables may serve as a novel biomarker for the severity of Atopic Dermatitis as well as an indicator for the allergen-specific immunotherapy and hence bears important clinical implications and needs to study on larger sample size and diverse populations.
Republication de : Filagrin and allergy
2022, Revue Francaise d'Allergologie

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Supported by Scottish Enterprise Tayside, Perth and Kinross City Council, and the Gannochy Trust. C.N.A.P. is supported by the Scottish Executive Chief Scientist's Office Generation Scotland Initiative. The McLean/Smith group is supported by grants from the Dystrophic Epidermolysis Bullosa Research Association, the Pachyonychia Congenita Project, and the British Skin Foundation/National Eczema Society (W.H.I.M. and F.J.D.S.).

Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

View full text

Mechanisms of asthma and allergic inflammationFilaggrin null mutations are associated with increased asthma severity in children and young adults

Background

Objective

Methods

Results

Conclusion

Clinical implications

Section snippets

Methods

Results

Discussion

The cornified envelope: a model of cell death in the skin

Nat Rev Mol Cell Biol

Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

Nat Genet

Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris

Nat Genet

Loss-of-function variants within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations

J Allergy Clin Immunol

Null mutations in the filaggrin gene (FLG) determine major susceptibility to early-onset atopic dermatitis that persists into adulthood

J Invest Dermatol

Filaggrin loss-of-function variant contributes to atopic dermatitis risk in the population of Northern Germany

Br J Dermatol

Two common loss-of-function mutations within the filaggrin gene predispose for early onset of atopic dermatitis

J Invest Dermatol

Filaggrin mutations in children with severe atopic dermatitis

J Invest Dermatol

Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march

J Allergy Clin Immunol

Fleshing out filaggrin phenotypes

J Invest Dermatol

Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis

J Allergy Clin Immunol

Atopic dermatitis and the atopic march

J Allergy Clin Immunol

Mechanisms of asthma and allergic inflammation
Filaggrin null mutations are associated with increased asthma severity in children and young adults