Filaggrin - the major predisposing gene for atopic disease and a target for stratified therapeutic intervention
Submitting InstitutionUniversity of Dundee
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Immunology
Summary of the impact
Atopic eczema and associated conditions — asthma, food allergy and hay
fever — affect ~40% of the population in developed nations. They cause
significant morbidity and create a multibillion-pound global healthcare
burden. The discovery that loss-of-function mutations in the gene encoding
filaggrin represent a strong risk factor for eczema, asthma and peanut
allergy has defined a key pathological mechanism in atopic disease. This
breakthrough in understanding has brought new focus on the skin barrier.
It has shown impact in treatment approaches to maintain barrier function,
translational research targeting epithelial dysfunction and improved
public and professional awareness of the role of skin in atopic disease.
Atopic eczema is a complex trait, in which multiple genetic risk factors
interact with environmental factors in disease pathogenesis. Historically,
research in atopic disease has focused on the immune response in the
investigation of disease pathogenesis and in therapy development.
The research underpinning our breakthrough in understanding atopy
pathogenesis dates back to 2006, when the group of Prof Irwin McLean
(Professor of Human Genetics and Head of the Division of Molecular
Medicine, University of Dundee) reported that the common monogenic skin
disease, ichthyosis vulgaris (characterised by dry, scaly skin), is caused
by loss-of-function mutations in the gene encoding filaggrin (FLG)
[i]. The gene product profilaggrin is cleaved to produce monomeric
filaggrin, playing a role in keratin filament aggregation, skin barrier
formation and cutaneous hydration.
The McLean group made a seminal discovery, demonstrating that up
to 50% of severe childhood eczema cases carry FLG loss-of-function
mutations [ii,iii]. This created a paradigm shift in the eczema/allergy
field by showing that one of the primary driving forces underlying common
atopic disorders is impaired skin barrier function. These findings support
a model for eczema aetiology whereby skin barrier dysfunction allows entry
of allergens and irritants resulting in skin and systemic inflammation.
Additional compelling evidence in support of this hypothesis was provided
in 2009 when the McLean group published the first mouse model of
filaggrin-related eczema and demonstrated that impaired skin barrier
function leads to skin and systemic inflammation triggered by percutaneous
allergen stimulation [iv].
The gene FLG is difficult to analyse due to its large size and
highly repetitive sequence [i-iii]. Techniques developed by Prof McLean
and colleagues to analyse other epidermal structural genes led to
ground-breaking discoveries in rare genodermatoses throughout the 1990s
and subsequently enabled the sequencing of FLG in advance of
international competitors. A complex pattern of prevalent and rare FLG
mutations in different population groups has now been identified.
Longitudinal population-based genetic studies have confirmed that FLG
is a major genetic factor in eczema, asthma and allergic rhinitis and that
FLG haploinsufficiency is particularly associated with severe,
early onset and persistent disease. Five recent genome-wide association
studies and one meta-analysis have confirmed that FLG is the
strongest genetic risk in atopic eczema, with an odds ratio >3.
Furthermore FLG remains the only locus in which a relationship has
been unequivocally demonstrated between gene and disease pathomechanism.
In 2011 Prof McLean and Dr Sara Brown (Wellcome Trust
Intermediate Clinical Fellow, Clinical Senior Lecturer and Honorary
Consultant Dermatologist, University of Dundee) led an international
collaboration to investigate the role of FLG mutations in
IgE-mediated peanut allergy. They reported a strong association with
replication in independent population groups [v], representing the first
established genetic risk factor in this severe food allergy. Dr Brown
also demonstrated in 2012 that copy number variation within FLG
contributes to eczema risk with a dose-dependent effect [vi], illustrating
the potential clinical utility of therapies aimed to increase filaggrin
The University of Dundee has filed two patents in developing FLG
genotyping as part of a personalised medicine approach for the
treatment/prevention of atopic disease and for enhancement of filaggrin
expression as a novel therapy. These patents underpin grant income to the
McLean group from MRC and MRC Developmental Pathway Funding Scheme
(totalling ~£1.6million) in collaboration with the Drug Discovery Unit,
University of Dundee.
References to the research
i. Smith FJD, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE,
Zhao Y, Liao H, Evans AT, Goudie DR, Lewis-Jones S, Arseculeratne G, Munro
CS, Sergeant A, O'Regan G, Bale SJ, Compton JG, Digiovanna JJ, Presland
RB, Fleckman P, McLean WHI (2006) Loss-of-function mutations in
the gene encoding filaggrin cause ichthyosis vulgaris. Nat. Genet.
38, 337-42 (DOI: 10.1038/ng1743).
ii. Palmer CNA, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP,
Goudie DR, Sandilands A, Campbell LE, Smith FJD, O'Regan GM, Watson RM,
Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S,
Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer
LB, Bisgaard H, Mukhopadhyay S and McLean WHI (2006) Common
loss-of-function variants of the epidermal barrier protein filaggrin are a
major predisposing factor for atopic dermatitis. Nat. Genet. 38,
441-6 (DOI: 10.1038/ng1767).
iii. Sandilands A, Terron-Kwiatkowski A, Hull PR, O'Regan GM, Clayton TH,
Watson RM, Carrick T, Evans AT, Liao H, Zhao Y, Campbell LE, Schmuth M,
Gruber R, Janecke AR, Elias PM, van Steensel MAM, Nagtzaam I, van Geel M,
Steijlen PM, Munro CS, Bradley DG, Palmer CNA, Smith FJD, McLean
WHI* and Irvine AD* (*joint senior authorship). (2007) Comprehensive
analysis of the gene encoding filaggrin uncovers prevalent and rare
mutations in ichthyosis vulgaris and atopic eczema. Nat. Genet. 39,
650-4 (DOI: 10.1038/ng2020).
iv. Fallon PG, Sasaki T, Sandilands A, Campbell LE, Saunders SP, Mangan
NE, Callanan JJ, Kawasaki H, Shiohama A, Kubo A, Sundberg J, Presland RB,
Fleckman P, Shimizu N, Kudoh J, Irvine AD, Amagai M and McLean
WHI. A homozygous frameshift mutation in the mouse Flg gene facilitates
enhanced percutaneous allergen priming. Nat. Genet. 41,
602-8 (DOI: 10.1038/ng.358).
v. Brown SJ, Asai Y, Cordell HJ, Campbell LE, Zhao Y, Liao H,
Northstone K, Henderson J, Alizadehfar R, Ben-Shoshan M, Morgan K, Roberts
G, Masthoff LJ, Pasmans SG, van den Akker PC, Wijmenga C, Hourihane JO,
Palmer CN, Lack G, Clarke A, Hull PR, Irvine AD, McLean WHI (2011)
Loss-of-function variants in the filaggrin gene are a significant risk
factor for peanut allergy. J. Allergy Clin. Immunol. 127,
661-7 (DOI: 10.1016/j.jaci.2011.01.031).
vi. Brown SJ, Kroboth K, Sandilands A, Campbell LE, Pohler E,
Kezic S, Cordell HJ, McLean WHI, Irvine AD (2012) Intragenic copy
number variation within filaggrin contributes to the risk of atopic
dermatitis with a dose-dependent effect. J. Invest. Dermatol. 132,
98-104 (DOI: 10.1038/jid.2011.342).
• McLean WHI and Smith FJD (2005). "Identification of
loss-of-function mutations in filaggrin causing ichthyosis vulgaris and
predisposing to other diseases" PCT/GB2006004707. Priority GB/15.2.05/ GBA
0525492. Date of filing 15.12.06. Date of publication 27.08.2008.
• McLean WHI and Smith FJD (2006). "Prevention/treatment of
ichthyosis vulgaris, atopy and other disorders." PCT/GB2007000109.
Priority GB/18.01.06/ GBA 0600948. Date of filing 17.01.07. Date of
Details of the impact
Change in the understanding of atopy pathogenesis has led to change
in clinical practice
A significant minority (9%) of the UK population carries one or more FLG
null alleles , therefore the increased risk of atopic disease affects
an estimated 5.7 million people, of whom approximately 2.4 million (42%)
 are likely to develop atopic eczema which is directly attributable to
FLG haploinsufficiency [3,4]. An additional 10.6% of the population
are homozygous for the lowest copy number variants of FLG,
associated with an increased risk of eczema (odds ratio ~1.67) [vi]. FLG
mutations increase the risk of disease at every stage of the so-called
`atopic march', from eczema early in life, to asthma, food allergy and
later allergic rhinitis [1,2].
The paradigm shift in understanding atopy has changed the focus of
clinical care to epidermal barrier function [5,6]. Since 2008, the
filaggrin/atopy link has been the subject of 90 review articles [PubMed
search: filaggrin AND atopic 31/10/2013]. The research has attracted six
major national/international research prizes, including the American Skin
Association Achievement Award 2009.
The research focus on barrier function has informed the development of
therapeutic guidelines. Thus, the NICE guidelines state: "Atopic eczema
often has a genetic component that leads to the breakdown of the skin
barrier. This makes the skin susceptible to trigger factors, including
irritants and allergens, which can make the eczema worse" (http://guidance.nice.org.uk/CG57/QuickRefGuide/pdf/English).
The NICE guideline on treatment emphasises the importance of emollient use
to improve skin barrier function, now a key quality statement: "Children
with atopic eczema are prescribed sufficient quantities (250-500 g weekly)
from a choice of unperfumed emollients for daily use." (http://publications.nice.org.uk/atopic-eczema-in-children-qs44/list-of-quality-statements).
new understanding has been conveyed in undergraduate and postgraduate
teaching. Examples include the UK Advanced Paediatric Dermatology Course,
a lecture at the British Association of Dermatologists' Annual meeting
2013 and the NHS educational web pages `NHS inform' and `NHS choices' .
National and international public interest has increased awareness
of atopic disease
The eczema genetic discovery has led to improved public understanding of
science: Irwin McLean and Sara Brown have spoken to
capacity audiences at Café Science Dundee ; on a wider scale, they have
achieved major worldwide publicity, including front-page coverage by every
major newspaper in the UK, BBC News website  and Newsnight, ITV, Sky
News and a total of >100 TV and radio interviews. Media exposure has
continued with the intense interest in peanut allergy.
The message of skin barrier impairment in eczema has increased public
understanding of atopic disease, which improves compliance with emollient
therapy . The National Eczema Society explains: "If you have eczema
...the protective barrier is therefore not as good as it should be...
skin with eczema is more liable to become red and inflamed on contact
with substances that are known to irritate or cause an allergic reaction."
The British Association of Dermatologists' patient information leaflet on
atopic eczema (http://www.bad.org.uk/site/792/default.aspx)
explains the genetically-determined skin barrier defect and use of
FLG genotype is used to stratify patients for clinical care and
The knowledge that FLG-null genotype is most strongly associated
with persistent, severe eczema and multiple atopic co-morbidities has
facilitated clinical sub-classification . In patients with signs of
filaggrin deficiency, specific attention may be paid to the possible
development of asthma and food allergy. Asthma management in particular is
optimised by early recognition in children (http://www.brit-thoracic.org.uk/guidelines/asthma-guidelines.aspx).
Clinical trials of barrier enhancement interventions are underway. The
Barrier Enhancement for Eczema Prevention study (2010-11) demonstrated a
50% reduction in eczema incidence in babies receiving daily emollients,
interacting with FLG genotype (http://www.controlled-trials.com/ISRCTN84854178).
A larger study is funded by the NIHR HTA Programme: `A randomised controlled
trial to determine whether skin barrier enhancement with emollients can
prevent eczema in high risk children' in which 1282 high-risk babies will
be screened for FLG mutations and monitored for development of
eczema, asthma and hay fever (http://www.nets.nihr.ac.uk/projects/hta/126712).
Collectively, these three allergic diseases rank sixth for annual
expenditures among chronic health conditions in the US, with a total
estimated bill of ~$24billion (http://www.epa.gov/ORD/gems/scinews_aeroallergens.htm).
A randomised controlled trial of silk therapeutic clothing for the
long-term management of eczema in children (http://www.hta.ac.uk/project/2984.asp)
also includes our FLG genotype-stratified analysis.
The finding that intragenic copy number variation determines eczema risk
with a dose-dependent effect [vi] indicates that an increase
in functional filaggrin of only 5-10% is sufficient to significantly
reduce eczema risk. This gives added impetus to the search for filaggrin
up-regulation therapies which would be applicable to 33% of the population
carrying low copy number [vi].
Sources to corroborate the impact
Reviews in medical and scientific journals:
- McAleer MA and Irvine AD (2011) The multifunctional role of filaggrin
in allergic skin disease. J. Allergy Clin. Immunol. 131,
208-91 (DOI: 10.1016/j.jaci.2012.12.668).
- Irvine AD, McLean WHI and Leung DY (2011) Filaggrin mutations
associated with skin and allergic diseases. New Engl. J. Med. 365,
1315-27 (DOI: 10.1056/NEJMra1011040).
Meta-analyses of FLG effect:
- Rodríguez E, Baurecht H, Herberich E, Wagenpfeil S, Brown SJ, Cordell
HJ, Irvine AD and Weidinger S (2009) Meta-analysis of filaggrin
polymorphisms in eczema and asthma: robust risk factors in atopic
disease. J. Allergy Clin. Immunol. 123, 1361-70 (DOI:
- van den Oord RA and Sheikh A (2009) Filaggrin gene defects and risk of
developing allergic sensitisation and allergic disorders: systematic
review and meta-analysis. Brit. Med. J. 339, b2433 (DOI:
Reviews in science media and the cosmetic industry:
- Ainsworth C (2011) SKIN into the breach. A focus on skin barrier
disorders has opened up new thinking about how allergies kick in. Nature
479, S12-14 (DOI: 10.1038/479S12a).
- Harding CR, Aho S and Bosko CA (Unilever) (2013) Filaggrin —
revisited. Int. J. Cosmetic Science 35, 412-423 (DOI:
NHS educational resources:
Examples of public engagement:
- Café Science Dundee http://www.cafesciencedundee.co.uk/?p=1235
- BBC news has given extensive coverage to the filaggrin story including
skin barrier and eczema (http://news.bbc.co.uk/1/hi/scotland/tayside_and_central/4817512.stm)
and genetic risk for peanut allergy (http://www.bbc.co.uk/news/uk-scotland-tayside-central-12698727)
which reached number 7 most-read on the BBC news webpage.
- Eczema Outreach Scotland (http://eczemaoutreachscotland.org.uk/.)
a support group for patients and their families, established in 2011. Dr
Sara Brown is a medical adviser and attends educational and