Gene-Environment Interaction in the Onset of Eczema in Infancy: Filaggrin Loss-of-Function Mutations Enhanced by Neonatal Cat Exposure
et al. (2008) Gene-environment
interaction in the onset of eczema in
infancy: Filaggrin loss-of-function
mutations enhanced by neonatal cat
exposure. PLoS Med 5(6): e131.
Gene-Environment Interaction in the Onset of Eczema in Infancy: Filaggrin Loss-of-Function Mutations Enhanced by Neonatal Cat Exposure
Hans Bisgaard 0 1
Angela Simpson 0 1
Colin N.A. Palmer 0 1
Klaus Bnnelykke 0 1
Irwin Mclean 0 1
Somnath Mukhopadhyay 0 1
Christian B. Pipper 0 1
Liselotte B. Halkjaer 0 1
Brian Lipworth 0 1
Jenny Hankinson 0 1
Ashley Woodcock 0 1
Adnan Custovic 0 1
Competing Interests: See section at end of manuscript. 0 1
0 Academic Editor: Matthias Wjst, National Research Center for Environment and Health GSF , Germany
1 1 Copenhagen Prospective Studies on Asthma in Childhood, Danish Paediatric Asthma Centre , Copenhagen , University Hospital Gentofte, Copenhagen, Denmark, 2 School of Translational Medicine, University of Manchester, University Hospital of South Manchester National Health Service Foundation Trust, Manchester, United Kingdom, 3 Population Pharmacogenetics Group, Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee , Dundee , United Kingdom , 4 Royal Alexandra Children's Hospital, Brighton and Sussex Medical School , Brighton , United Kingdom , 5 Asthma and Allergy Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee , Scotland , United Kingdom
A B S T R A C T
Loss-of-function variants in the gene encoding filaggrin (FLG) are major determinants of
eczema. We hypothesized that weakening of the physical barrier in FLG-deficient individuals
may potentiate the effect of environmental exposures. Therefore, we investigated whether
there is an interaction between FLG loss-of-function mutations with environmental exposures
(pets and dust mites) in relation to the development of eczema.
Methods and Findings
We used data obtained in early life in a high-risk birth cohort in Denmark and replicated the
findings in an unselected birth cohort in the United Kingdom. Primary outcome was age of
onset of eczema; environmental exposures included pet ownership and mite and pet allergen
levels. In Copenhagen (n 379), FLG mutation increased the risk of eczema during the first year
of life (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.274.00, p 0.005), with a further
increase in risk related to cat exposure at birth amongst children with FLG mutation (HR 11.11,
95% CI 3.7932.60, p , 0.0001); dog exposure was moderately protective (HR 0.49, 95% CI
0.241.01, p 0.05), but not related to FLG genotype. In Manchester (n 503) an independent
and significant association of the development of eczema by age 12 mo with FLG genotype
was confirmed (HR 1.95, 95% CI 1.133.36, p 0.02). In addition, the risk increased because of
the interaction of cat ownership at birth and FLG genotype (HR 3.82, 95% CI 1.3510.81, p
0.01), with no significant effect of the interaction with dog ownership (HR 0.59, 95% CI 0.16
2.20, p 0.43). Mite-allergen had no effects in either cohort. The observed effects were
independent of sensitisation.
We have demonstrated a significant interaction between FLG loss-of-function main
mutations (501x and 2282del4) and cat ownership at birth on the development of early-life
eczema in two independent birth cohorts. Our data suggest that cat but not dog ownership
substantially increases the risk of eczema within the first year of life in children with FLG
loss-offunction variants, but not amongst those without. FLG-deficient individuals may need to avoid
cats but not dogs in early life.
The Editors Summary of this article follows the references.
We recently discovered in the Copenhagen Prospective
Study on Asthma in Childhood (COPSAC) that
loss-offunction variants in the gene encoding filaggrin (FLG) are
major determinants of eczema . This finding has since been
replicated in other populations , and the population
attributable risk for eczema estimated at 11% .
FLG is situated in the Epidermal Differentiation Complex,
a dense cluster of genes on Chromosome 1q21. It codes for
the 500-kDa protein profilaggrin, which is the main protein
component of the keratohyalin granules within the outermost
living cell layers of the epidermis. During terminal
differentiation of keratinocytes, profilaggrin is dephosphorylated
into filaggrin peptides (37-kDa proteins), which form highly
compacted, chemically cross-linked layers that provide a
physical barrier that reduces water loss and protects the body
from potentially harmful environmental exposures.
Nonsense mutation R501X and frame-shift mutation 2282del4
lead to complete loss of filaggrin expression , which causes
excessively dry skin and impaired skin barrier function.
We hypothesized that weakening of skin barrier function in
filaggrin-deficient individuals may modulate the effect of
environmental exposures, thus modifying the expression of
eczema. Since most eczema in individuals with FLG mutations
occurs within the first year of life, the important environment
exposures that may affect the penetrance of FLG mutations
are likely to occur in the first months of life. We therefore
investigated whether there is an interaction between FLG
lossof-function mutations with early-life environmental
exposures (pets and dust mites) in relation to the development of
eczema. We used data obtained in a high-risk birth cohort in
Denmark, and in an unselected birth cohort in the UK.
COPSAC enrolled 411 high-risk neonates (mother with
verified asthma) at age 1 mo; the recruitment was previously
described in detail . The study was approved by the
Ethics Committee for Copenhagen (KF 01289/96) and The
Danish Data Protection Agency (2008-41-1754). Before
enrolment, informed consent was obtained from parents. Data
were collected on-line and locked after external monitoring.
An audit trail was run routinely.
Primary outcome. Eczema was diagnosed on clinical
examination in participants who were assessed at the
COPSAC Clinical Research Unit at age 1 mo, and at 6-mo
intervals thereafter; additional visits were arranged
immediately upon the onset of any skin or respiratory symptoms.
Skin examinations, diagnoses, and treatment of eczema were
carried out by trained study physicians. Skin lesions were
described on-line according to predefined morphology and
localization; eczema was defined based on the Hanifin-Rajka
criteria as previously detailed [9,10].
Secondary outcome. Allergic sensitisation was defined as
specific IgE . 0.35 kU/l to a range of common inhalant and
food allergens at age 6 and 18 mo (ImmunoCAP, Phadia) .
Environmental exposures. Pet exposure in early life was
determined at the interview at the 1-mo visit and defined as
cat or dog living in the house at birth.
Allergen exposure was measured in the dust samples
collected from the childs bed at age 1 y. Parents vacuumed
the bedding (the pillow and mattress) for 5 min with a dust
trap attached (ALK-Abello ). Mite, cat, and dog allergen
concentration was measured using the Sandwich ELISA .
Allergen exposure was dichotomized as high and low levels
(above and below the 75% quartile).
Charcoal cotton swabs were taken from the perineum of
the newborn and transported in Stuart transport media for
routine test for Staphylococcus aureus.
Manchester Asthma and Allergy Study
Manchester Asthma and Allergy Study (MAAS) is an
unselected population-based birth cohort described in detail
elsewhere [13,14]. The study is registered as ISRCTN72673620.
Participants were recruited prenatally, and followed
prospectively, attending the first review clinic at ages 1, 3, and 5 y (6 4
wk). The study was approved by the Local Research Ethics
Committee (SOU/00/258; SOU/00/259). Written informed
consent was obtained from all parents.
Primary outcome. Information on the age of onset of
parentally reported eczema was collected by age 1 y using an
interviewer-administered validated International Study on
Asthma and Allergies in Childhood (ISAAC) questionnaire.
Secondary outcome. To assess allergic sensitisation
children were skin prick tested at age 1 y (dust mite, cat, dog,
grasses, milk, egg), and sensitisation was defined as a weal
diameter 3 mm greater than the negative control.
Environmental exposures. Pet exposure in early life was
assessed by questionnaires administered during the home
visit carried out within 4 wk after birth and defined as the
presence of a cat or a dog in the house at birth.
Allergen exposure was measured in dust samples collected
at age 1 y by vacuuming 1 m2 of living-room floor for 2 min.
Mite, cat, and dog allergen was quantitated using
enzymelinked immunoassays; results were expressed as allergen
Genotyping for R501X was performed using a
TAQMANbased allelic discrimination assay (Applied Biosystems).
Allelic discrimination was assessed using Applied Biosystems
7700 sequence detection system. Probes and primers were as
described . Mutation 2282del4 was genotyped by sizing of a
fluorescent-labeled PCR fragment on an Applied Biosystems
3100 or 3730 DNA sequencer .
Children were classified according to a two level dominant
genetic model (i.e., children were assigned as having a FLG
mutation if they were heterozygous or homozygous for the
null allele in at least one of the two SNPs).
Effects of environmental factors and their possible
modification by genetic mutation were assessed by Kaplan-Meier
curves and Cox regression. The children were retained in the
analysis from birth until age at diagnosis of eczema, drop-out,
or age 1 y, whichever came first. Simultaneous quantification
of gene/environment effects was done by multiple Cox
regression. Pet exposure at birth and pet allergen exposure
were analysed separately. All analyses were carried out using
SAS 9.1.3, SPSS 13.0, and the free-ware statistical package R
(R Development Core Team, 2006). All estimates are reported
with 95% confidence intervals [CI] in brackets.
The effects from FLG mutations in both cohorts occurred
early in life as demonstrated by the Kaplan Meier curves
(Figures 1 and 2), with hazard ratios (HR) of 2.90 (1.804.68)
and 2.06 (1.403.05) in the first year and 0.71 (0.222.27) and
1.01 (0.482.51) after age 1 y (COPSAC and MAAS,
respectively). We therefore focused the analysis on the
interaction between FLG status and environmental exposures
during the first year of life. Exposure variables in both
cohorts were independent of FLG mutations.
Of 411 infants, 379 of mixed European ancestry were
genotyped for 501x and 2282del4  as well as R2448X and
S3247X . The main mutated alleles 501x and 2282del4
were present in 40 children and exhibited a very strong
association to the development of eczema as previously
Eczema was diagnosed in 28% (105 children) before age 1 y;
265 (75%) did not have pets in their home at birth, 38 (11%)
had a cat, 37 (11%) had a dog, and 11 (3%) had both;
information on pet ownership was not available in 28
children. Among the 38 children with main mutations and
information on pet ownership, 26 (68%) did not have pets,
seven (18%) had a dog only, four (11%) had a cat only, and
one (3%) had both. Objective measure of allergen exposure
was available in 339 children; 205 (60%) had low cat and dog
allergen levels, 54 (16%) high cat allergen level, 54 (16%) high
dog allergen level, 26 (8%) high cat and dog allergen levels,
and 78 (23%) high mite allergen level. Among the 38 children
with mutation, 22 (58%) had low cat and dog allergen levels,
five (13%) high cat allergen level, nine (24%) high dog
allergen level, two (5%) had high cat and dog allergen levels,
and ten (26%) high mite allergen level. Six children were lost
to follow-up during the first year but were included in the
analyses for the available follow-up period.
Kaplan-Meier plots suggested an increased risk of eczema
due to FLG mutation, and a further increased risk of eczema
due to cat exposure but only in the presence of FLG mutation
(Figure 3). Backwards elimination in a multiple Cox
regression including FLG status, cat exposure, dog exposure, mite
allergen exposure, and interactions between FLG status and
cat exposure, dog exposure, and mite allergen exposure
showed a significant interaction between cat exposure and
FLG status (p 0.0008) and a significant effect of dog
exposure (p 0.05). An additional exploration of the cat
exposure-FLG status interaction demonstrated an increased
risk of developing eczema due to mutation (HR 2.26 [95% CI
1.274.00], p 0.005), with an additional increased risk if also
exposed to cat (HR 11.11 [3.7932.60], p , 0.0001). The
overall decrease in risk due to exposure to dog was quantified
in an HR of 0.49 [0.241.01]. Analysis including only children
carrying mutant alleles demonstrated a significant effect of
cat ownership on development of eczema (HR 7.49 [2.37
23.67], p 0.0006).
For allergen exposure a similar analysis was made with cat,
dog, and mite allergen levels. The model confirmed an
increased risk of developing eczema due to mutation (HR
2.53 [1.454.41], p 0.001) with an additional increase in risk
if exposed to high cat allergen level (HR 3.77 [1.459.81], p
0.006). In this analysis there was no significant effect of dog or
mite allergens. Analysis including only children carrying
mutant alleles demonstrated a significant effect of cat
allergen exposure on development of eczema (HR 3.09
[1.178.19], p 0.023).
Cat allergen exposure shows high agreement with reported
cat exposure at 4 wk (simple Kappa coefficient 0.62 [0.51
0.73]). Similarly dog allergen exposure shows high agreement
with reported dog exposure at 4 wk (simple Kappa coefficient
S. aureus was identified from the perineum in one newborn
before the age of 3 mo.
Of 940 children with questionnaire data on the age of onset
of eczema, 513 provided a blood sample for DNA extraction.
Children who provided DNA did not differ from those who
did not in terms of family history, maternal age,
socioeconomic status, history of eczema, allergic sensitisation, and
pet ownership (data available on request).
A total of 503 children of mixed European ancestry had
information on FLG main mutations (501x and 2282del4), pet
ownership at birth, and the age of onset of eczema. By age 1 y,
eczema was reported by 187/503 parents (37%). Mutated
alleles were present in 50 children (10%); 324 (64%) did not
own any pets at birth, 88 (18%) had a cat at home, 66 (13%)
had a dog, and 25 (5%) had both. The frequency of pet
ownership did not differ between children with or without
FLG mutation (no pets 293/453 [64.7%] and 31/50 [62%], cat
77/453 [17%] and 11/50 [22%], dog 60/453 [13.2%] and 6/50
[12%], and both cat and dog 23/453 [5.1%] and 2/50 [4%], no
FLG mutation versus FLG mutation, respectively, p 0.84).
Cat allergen exposure was available in 461 children, mite
allergen in 458, and dog allergen in 460.
Kaplan-Meier plots demonstrating the age of onset of
eczema in the first year of life related to cat and dog
ownership amongst children with and without FLG mutation
are presented in Figure 4. The results of a multiple Cox
regression that included FLG genotype, cat and dog
ownership at birth, the interaction between FLG genotype with cat
and dog ownership, and mite exposure and its interaction
with FLG genotype indicated an increased risk of developing
eczema in the first 12 mo due to FLG mutation (HR 1.95 [95%
CI 1.133.36], p 0.017). Furthermore, in the presence of FLG
mutation, the risk increased further because of cat ownership
at birth, with no significant effect of cat ownership being
observed amongst children without FLG mutation
(interaction of cat ownership at birth and FLG mutation, HR 3.82
[1.3510.81], p 0.011). There was a trend for dog ownership
to increase the risk (HR 1.51 [0.962.37], p 0.075), with no
significant interaction of FLG genotype with dog ownership
(HR 0.59 [0.16-2.20], p 0.43) or mite allergen exposure (HR
1.15 [0.931.43], p 0.21). There was no significant effect of
having both cats and dogs (HR 1.57 [0.823.03]), or their
interaction with FLG genotype (p 0.96). Analysis including
only children carrying mutant alleles demonstrated a
significant effect of cat ownership on development of eczema
(HR 2.47 [1.095.62], p 0.03).
In terms of allergen exposure there was no significant
correlation between mite, cat, and dog allergen levels.
Multiple Cox regression that included FLG genotype, cat,
dog, and mite allergen levels, and the interaction between
genotype and allergen levels confirmed an increased risk of
developing eczema due to mutation (HR 2.22 [1.273.89], p
0.005) and the interaction between cat allergen and FLG
genotype (with risk increasing risk with increasing allergen
level among children with FLG mutation; HR for interaction
1.31 [1.031.67], p 0.026). Nonsignificant trends were
observed for dog allergen exposure (HR 1.07 [1.001.15], p
0.06), the direction of which appeared to inverse in the
interaction with FLG mutation (0.84 [0.681.05, p 0.1]).
Secondary outcomes. Allergic sensitisation was uncommon
in early life in both cohorts (in COPSAC, cat sensitisation was
detected in one infant with FLG mutation at 6 mo but none at
18 mo; in MAAS, two children were skin test positive to mite,
four to cat, and three to dog at age 1 y). We therefore did not
analyse sensitisation further.
We have demonstrated a significant interaction between
FLG loss-of-function main mutations (501x and 2282del4) and
cat ownership at birth on the development of early-life
eczema in two independent birth cohorts. Our data suggest
that cat but not dog ownership substantially increases the risk
of eczema within the first year of life in children with FLG
loss-of-function variants, but not amongst those without. The
observed effects were independent of allergic sensitisation.
For the primary outcome we selected age of onset of early
eczema. The rationale for this is that in both cohorts the
increased risk of eczema amongst FLG mutation carriers
occurred only in the first year of life and not thereafter
(Figures 1 and 2). Therefore development of eczema during
the first year of life is the relevant outcome when studying
this gene-environment interaction. This also means that the
important environmental exposures that may interact with
FLG in the development of eczema must occur in the first
months of life. This limits the number of relevant exposures,
as neonates typically live in a very sheltered environment.
Limitations and Strengths
This was a hypothesis-driven analysis. We hypothesized that
weakening of physical barrier of skin in FLG deficient
individuals may potentiate the effect of relevant
environmental exposures. Therefore we investigated whether there is
an interaction between FLG loss-of-function mutations with a
range of environmental exposures for which the skin could be
the relevant route of exposure. Since FLG is not expressed in
either lungs or GI tract, we did not test exposures through
such routes. We focused on the exposure that was associated
with eczema in previous epidemiological studies and that was
common for the two populations tested (domestic pets and
indoor allergens). In addition, in COPSAC we explored the
possibility of testing the effect of skin colonization with S.
aureus, but only one child in the mutated group was colonized
on the skin.
The different designs of the two cohorts prevented data
pooling in favour of replication, and necessitated some
differences in data analysis. Clinical outcomes were not
identical, resulting in a higher prevalence of infant eczema in
MAAS (parentally reported, 37%) compared to COPSAC
(investigator-diagnosed, 28%). This suggests that MAAS was
capturing milder cases and overreporting of eczema by
parents. COPSAC provided closely monitored prospective
data on eczema progression. The specificity of diagnosis was
high, since the detailed phenotyping and management was
carried out solely by the investigators, reducing the risk of
misclassification , which is of particular importance in the
clinical evaluation of eczema where interobserver variation is
a problem . Despite the differences in definition of
primary outcome, we achieved replication.
We acknowledge the fact that the initial finding is based on
only five children with eczema with a cat at home and
carrying FLG mutation in COPSAC, but the power of the
statistics (p , 0.0001) derives from the longitudinal dataset
with the time of onset clearly distinguishing these
populations. Cross-sectional analyses would not have such statistical
power. Furthermore, it is worth noting that the findings were
confirmed in the analysis of allergen levels, that pet
ownership did not differ between those with and without the
variant, and that the interaction between FLG variants and
cat ownership was replicated in an independent cohort that
included a larger number of cat exposed FLG mutation
Allergens levels were measured at age 1 y representing
allergen exposure during the first year of life. Dust samples
were taken from the childs mattress in COPSAC and from
the lounge floor in MAAS, which resulted in different
distribution of results (10-fold increase from third to fourth
quartile in COPSAC with only 3-fold difference in MAAS,
indicating that quartile analysis would not be appropriate in
MAAS). Although we used different indices of allergen
exposure, we obtained similar results.
In the original discovery in COPSAC of the loss-of-function
variants 501x and 2282del4 in the gene encoding filaggrin, we
demonstrated a strong association to the development of
eczema in the first years of life. Two new SNPs within the
filaggrin gene (R2447X and S3247X) have since been reported
 and were found in eight children in COPSAC. However,
these new SNPs are qualitatively different from the old
mutations with some residual function as demonstrated by a
significantly lower penetrance of eczema. Inclusion of the
novel SNPs would therefore weaken our analyses by mixing a
well-known strong risk factor with a weak risk factor, which
furthermore is qualitatively different and therefore may have
a different effect on the geneenvironmental interactions
studied. As a consequence we did not find it reasonable to
formulate a dominant genetic model based on all four SNPs.
Meaning of the Study
Several studies have suggested an effect of early-life pet
exposure on the development of atopic disease. However, the
data are inconsistent, with some studies showing increased
risk , and others decreased risk , or no effect .
These inconsistencies may be due in part to epidemiological
artifacts. Recall bias is an obvious risk when exposure
assessments are retrospective. Selection for keeping pets is
another potential bias. The time from exposure to assessment
of the health outcome has been long in some studies, which
may lead to confounding by early modification of the
exposure and therefore affect the long-term outcome. The
causal-effect direction may be uncertain in retrospective
assessments, as the pets may have been acquired after the
disease onset. Furthermore, cross-sectional studies may
report protective effects from pet exposure, when in fact
individuals have removed the pet from the household because
of the disease or the factors associated with a predisposition
to disease. Importantly, in both our studies we documented
pet exposure at birth (i.e., before eczema occurrence), thus
eliminating uncertainty of the direction of association
between exposure and disease. The findings were further
supported by objective measures of allergen exposure.
We only assessed animals living in the household, though
other exposures outside the home may be relevant, but this
would only have biased the risk estimates toward the null,
potentially underestimating the true risk. Having pets has
been reported to be biased from socioeconomic status,
smoking habits, and parental allergic rhinitis , but it is
unlikely to affect the genetic distribution in the study
population and could therefore not act as confounder.
The mechanism by which cat exposure drives the
development of eczema is unknown. Our data suggest that it does not
act through cat-specific immunoglobulin E (IgE). This is in
keeping with previous studies showing that the effect of FLG
loss-of-function mutations was equally strong on allergic and
nonallergic eczema, demonstrating that the development of
eczema is not dependent on allergic sensitisation . Cat
exposure may act through other nonallergic mechanisms
such as endotoxins. COPSAC recently reported that bacterial
colonization of the airways in neonates was associated with
later development of recurrent wheeze, asthma, and
increased total immunoglobulin E (IgE) . It may be possible
that cat exposure mediates its effect in the FLG mutated
genotypes via altered bacterial exposure, or that cat exposure
may be a surrogate marker for other unknown environmental
influences penetrating the imperfect skin barrier because of
defective profilaggrin synthesis.
Although there are many new susceptibility genes for
complex disorders following genome-wide association
studies, there are very few geneenvironment studies. Our
findings of a consistent effect from early-life cat ownership
on the phenotypic expression of eczema in infants with FLG
loss-of-function mutations in two independent birth cohorts
is an example of geneenvironment interaction in a common
complex disease, demonstrating that such geneenvironment
interactions exist and are detectable given appropriately
detailed studies of environmental exposures.
Alternative Language Abstract S1. Spanish Translation of the
Abstract by Antonio Nieto
Found at doi:10.1371/journal.pmed.0050131.sd001 (21 KB DOC).
Alternative Language Abstract S2. French Translation of the Abstract
by Florent Baty
Found at doi:10.1371/journal.pmed.0050131.sd002 (29 KB DOC).
Alternative Language Abstract S3. German Translation of the
Abstract by Anna Molter
Found at doi:10.1371/journal.pmed.0050131.sd003 (25 KB DOC).
The authors wish to thank the children and parents participating in
the COPSAC cohort as well as the COPSAC study team. The authors
would like to thank the MAAS children and their parents for their
continued support and enthusiasm. We acknowledge the dedication
of MAAS study team; we thank Julie Morris (MSc) for statistical
Author contributions. HB, CNAP, and AC conceived and designed
the study and obtained funding. KB and LBH collected and
assembled the data. HB and AC analysed and interpreted the data.
CBP provided statistical expertise. HB drafted the article. AS, CNAP,
KB, IM, SM, CBP, LBH, BL, JH, AW, and AC contributed to the
critical revision of the article for important intellectual content. HB,
AS, CNAP, KB, IM, SM, CBP, LBH, BL, JH, AW, and AC contributed
to the final approval of the article and provision of study materials or
Competing Interests: HB has been a consultant to, paid lecturer
for, and holds sponsored grants from AstraZeneca, GSK, Merck,
MedImmune, NeoLab, and Pfizer. He does not hold stock or options
in any pharmaceutical company in the respiratory field. IM has filed
two patents relating to genetic testing and therapy development
aimed at the filaggrin gene. AC receives grant and research support
from GlaxoSmithKline and is a consultant for GlaxoSmithKline and
UCB Pharma, ALK; and at the speakers bureau of Astra-Zeneca,
GlaxoSmithKline, and UCB Pharma, ALK.
Background. Eczema is a skin condition characterized by dry, red, and
itchy patches on the skin. Eczema is associated with asthma and allergy,
though allergy rarely plays a role in development or severity of eczema.
Eczema usually begins during infancy, typically on the face, scalp, neck,
extensor sides of the forearms, and legs. Up to one in five infants
develops eczema, but in more than half of them, the condition improves
or disappears completely before they are 15 years old. If eczema persists
into adulthood, it usually affects the face and the skin inside the knees
and elbows. There is no cure for eczema but it can be controlled by
avoiding anything that makes its symptoms worse. These triggers
include irritants such as wool, strong soaps, perfumes, and dry
environments. A good skin-care routine and frequent moisturizing can
also help to keep eczema under control, but in many cases,
corticosteroid creams and ointments may be necessary to reduce inflammation.
Why Was This Study Done? Eczema tends to run in families. This
suggests that eczema is caused by genetic factors as well as by
environmental factors. Recently, researchers discovered that two
common loss-of-function variants in the gene encoding filaggrin
(FLG) predispose people to eczema. People who inherit one or two
defective genes make no filaggrin, a protein that normally forms a
physical barrier in the skin that protects the body from potentially
harmful substances in the environment. Might the weakening of this
barrier in filaggrin-deficient individuals affect their responses to
environmental substances to which the skin is exposed? In this study, the
researchers test this potential explanation for how genetic and
environmental factors (in particular, exposure to pets) might interact to
determine an individuals chances of developing eczema.
What Did the Researchers Do and Find? To test their hypothesis, the
researchers studied two independent groups of infants during their first
year of lifea high-risk group consisting of infants born in Copenhagen,
Denmark to mothers with asthma and a group of infants born to women
from the general population in Manchester, United Kingdom. The
researchers determined which FLG variants each child had inherited and
classified those with either one or two defective copies of FLG as having
an FLG mutation. They determined pet exposure in early life by asking
whether a dog or a cat was living in the parental home when the child
was born (pet ownership) and then analyzed how these genetic and
environmental factors affected the age of onset of eczema. In both
groups, children with FLG mutations were twice as likely to develop
eczema during the first year of life as children without FLG mutations. For
children without FLG mutations, cat ownership at birth had no effect on
eczema risk but for children with FLG mutations, cat ownership at birth
(but not dog ownership) further increased the risk of developing eczema.
What Do These Findings Mean? These findings show that FLG
mutations and cat ownership at birth interact to determine the chances
of a child developing eczema during the first year of life. They provide
support, therefore, for the researchers suggestion that the weakening of
the skins protective barrier that is caused by filaggrin deficiency
increases the childs susceptibility to factors associated with cat
exposure. Only a small number of children in this study carried FLG
mutations and were exposed to cats from birth, so these findings need
confirming in independent studies. In addition, it is still not clear how
exposure to cats drives the development of eczema. Allergy was not the
mechanism as the FLG-deficient children exposed to cat and who
developed eczema did not develop cat-specific immunoglobin E
antibodies. Nevertheless, these findings suggest that, to reduce their
risk of developing eczema, filaggrin-deficient individuals should avoid
cats (but not dogs) during the first few months of life.
Additional Information. Please access these Web sites via the online
version of this summary at http://dx.doi.org/10.1371/journal.pmed.
The MedlinePlus Encyclopedia has a page on eczema (in English and
Spanish); links to further information are provided by MedlinePlus
EczemaNet is a comprehensive online information resource about
eczema provided by the American Academy of Dermatologists
The US National Institute of Arthritis and Musculoskeletal and Skin
Diseases provides information on eczema
The UK National Health Service Direct health encyclopedia provides
information for patients on eczema (in several languages)
The Copenhagen Studies on Asthma in Childhood (COPSAC) and
Manchester Asthma and Allergy Study (MAAS) Web sites provide more
information about the children involved in this research
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