Published 9 July 2009, doi:10.1136/bmj.b1203
Cite this as: BMJ 2009;339:b1203

Editorials

Gene defects and allergy

Identifying specific genotypes of allergy is a major breakthrough in patient care

Allergic diseases—such as asthma, rhinitis, and eczema—have been increasing worldwide over several decades, and the increase has largely been attributed to a Western lifestyle (the hygiene hypothesis). However, the exact causes of the increase are unknown. Several trigger mechanisms are probably involved, but it is still not clear whether similar triggers are responsible for the increases seen in different allergic diseases.¹ In the linked systematic review (doi: 10.1136/bmj.b2433), van den Oord and Sheikh assess the association between defects of the filaggrin gene (FLG) and the risk of developing allergic sensitisation and allergic disorders.²

Allergies form a heterogeneous group of diseases in which IgE mediated reactions are the key feature, and a wide variety of symptoms can occur. Diagnosis is largely based on the history, symptoms, and detection of IgE mediated hypersensitivity, usually through skin prick testing or specific IgE determination from blood. Symptoms of allergy are non-specific in most cases because they can all be present in the absence of allergy—for example, in viral induced asthma, vasomotor rhinitis, and constitutional eczema. Moreover, skin prick testing (still the first choice test for diagnosing allergy) and determination of specific IgE have limitations, such as false positivity and false negativity. Skin prick tests and specific IgE can also be positive in healthy people in the absence of allergic symptoms. The diagnosis of allergic disease is therefore still suboptimal (especially when based on questionnaires in large epidemiological surveys) because of the limitations of current diagnostic methods.

Different underlying mechanisms and pathways probably lead to the production of allergen specific IgE across the spectrum of allergic diseases. This suggests complex genetics and the contribution of multiple genes. For decades researchers have looked for genes that might contribute to allergic diseases. Most studies have suggested that many genes with small effects, rather than few genes with strong effects, contribute to the development of allergy. Until recently, no major associations had been described, and a real "allergy gene" was elusive. However, since 2006, several studies have consistently pointed to a strong influence of one particular gene—FLG.^{3 4 5 6 7 8}

The systemic review and meta-analysis by van den Oord and Sheikh,² is a comprehensive summary of research into the effects of filaggrin. The review finds that FLG gene mutations significantly increase the risk of allergic sensitisation, atopic eczema, allergic rhinitis, and asthma in children with coexisting eczema.

However, FLG mutations do not account for all cases, and atopic eczema is not a monogenic disease. Instead, several genetic factors probably contribute to the complex pathophysiology of the disease.⁹ Different subtypes of atopic eczema—such as eczema with early onset, childhood eczema, adulthood eczema, and eczema without underlying allergy—might be based on distinct genetic constellations.

Nevertheless, it is now clear that FLG mutations are the strongest and most widely replicated genetic risk factor for eczema identified to date. The discovery that null (loss of function) mutations in the FLG gene are associated with atopic eczema and with allergic sensitisation is the most important breakthrough in understanding the genetic basis of this complex disorder. Furthermore, the defects have been linked to a specific type of allergic disease: a type of eczema with allergic sensitisation and an increased risk of rhinitis and asthma. This association has been replicated in several studies using various methods, and in populations around the globe. The next challenge is to identify all the common FLG genotypes in different ethnic groups to allow better disease stratification and optimisation of treatment.

Allergic diseases are complex, and genome-environment interactions play a key part. Distinguishing different genotypes of allergy will be a major step forward, and it could revolutionise the prevention, diagnosis, and treatment of allergy in children. Because different allergy genes and genotypes elicit the IgE mediated reaction via different underlying mechanism, with different clinical manifestations and prognoses, they are likely to need a different therapeutic approach. Pharmacogenetics could be used to tailor treatment to each patient. Large and well designed prognostic clinical studies, epidemiological studies, and interventional studies will need to be conducted to translate research about the mechanisms of disease into clinical practice.

Cite this as: BMJ 2009;339:b1203

¹ National University Singapore, Department of Paediatrics, 119074 Singapore , ² Institute of Medical Biology, Agency for Science and Technology and Research, 138648 Singapore

Research, doi:10.1136/bmj.b2433

---

Competing interests: None declared.

Provenance and peer review: Not commissioned; externally peer reviewed.

References

1. Platts-Mills TAE, Erwin E, Heymann P, Woodfolk J. Is the hygiene hypothesis still a viable explanation for the increased prevalence of asthma? Allergy 2005;60(suppl 79):25-31.[CrossRef][Web of Science][Medline]
2. Van den Oord RAHM, Sheikh A. Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis. BMJ 2009;339:b2433.[Abstract/Free Full Text]
3. Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet 2006;38:441-6.[CrossRef][Web of Science][Medline]
4. Sandilands A, Terron-Kwiatkowski A, Hull PR, O’Regan GM, Clayton TH, Watson RM, et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet 2007;39:650-4.[CrossRef][Web of Science][Medline]
5. Marenholz I, Nickel R, Ruschendorf F, Schulz F, Esparza-Gordillo J, Kerscher T, et al. Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march. J Allergy Clin Immunol 2006;118:866-71.[CrossRef][Web of Science][Medline]
6. Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, Diaz-Lacava A, et al. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol 2006;118:214-9.[CrossRef][Web of Science][Medline]
7. Stemmler S, Parwez Q, Petrasch-Parwez E, Epplen JT, Hoffjan S. Two common loss-of-function mutations within the filaggrin gene predispose for early onset of atopic dermatitis. J Invest Dermatol 2007;127:722-4.[CrossRef][Web of Science][Medline]
8. Nomura T, Sandilands A, Akiyama M, Liao H, Evans AT, Sakai K, et al. Unique mutations in the filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic dermatitis. J Allergy Clin Immunol 2007;119:434-40.[CrossRef][Web of Science][Medline]
9. Novak N. New insights into the mechanism and management of allergic diseases: atopic dermatitis. Allergy 2009;64:265-75.[CrossRef][Web of Science][Medline]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    StumbleUpon    Technorati    What's this?

Relevant Article

Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis

Rosanne A H M van den Oord and Aziz Sheikh
BMJ 2009 339: b2433. [Abstract] [Full Text] [PDF]

Rapid Responses:

Read all Rapid Responses

Why have allergic diseases been increasing worldwide over several decades? The humidity hypothesis may be the answer

Christopher ME Rowland Payne
bmj.com, 23 Jul 2009 [Full text]

Online poll

Find out more here>> and here>>