184

CHA PTER 1 4

Genetics and Aetiology of Atopic Dermatitis

Elke Rodriguez & Stephan Weidinger
Department of Dermatology, Allergology and Venereology, University Hospital Schleswig‐Holstein, Campus Kiel, Kiel, Germany

Introduction, 184 Conclusions and future directions, 190

Genes implicated in the aetiology of eczema, 187
ATOPIC DERMATITIS

Abstract by approximately 20% of patients, and they are neither necessary

SECTION 3:

nor sufficient to cause the disease. Most of the other loci harbour
candidate genes with functions related to immune regulation, in
Atopic dermatitis or eczema represents a typical multifactorial dis-
particular innate signalling and T‐cell specification and activation,
ease in that there is an individual hereditary predisposition that is
but the causative genes or gene products as well as the underlying
triggered by environmental and lifestyle factors. The heritability
molecular mechanisms remain to be identified and characterized.
of atopic dermatitis, i.e. the genetically determined proportion of
Together, the established susceptibility loci explain about 20% of
the total variance observed in a population, is estimated to be 70–
the total estimated heritability. This ‘missing heritability’ may be
80%. The possibilities for deciphering inherited risk factors have
explained by gene interactions, rare gene variants not yet discov-
impressively increased during the last years. As a result, more than
ered and epigenetic changes, but may also relate to an overestima-
30 susceptibility loci have been successfully identified. Null vari-
tion of the heritable disease component and the phenotypic com-
ants in the gene encoding the key epidermal barrier protein filag-
plexity of the disease.
grin are the strongest single risk factor, but they are carried only

Key points • Two notable exceptions are loss‐of‐function variants in the gene
FLG, which cause the dry skin condition ichthyosis vulgaris due
to a deficiency of the epidermal structural protein filaggrin, and
• Atopic dermatitis has a very strong heritable component.
infrequent variants in the gene encoding GARP, which lower the
• Genetic risk loci for atopic dermatitis are being discovered
expression of this receptor for latent transforming growth factor
through a range of strategies from linkage studies to genome‐
(TGF)‐β on the surface of regulatory T cells.
wide association studies.
• Known risk loci explain about 20% of the total estimated
• Thus far, more than 30 susceptibility loci for atopic dermatitis
heritability of atopic dermatitis.
have been identified. For most of these regions the causative
genes or gene products remain to be identified and characterized.

been suggested that eczema is part of a syndrome of

Introduction
Challenges in defining (atopic) dermatitis/
eczema
Eczema (atopic dermatitis, atopic eczema) is the most
common chronic skin disease in infants and children,
with prevalence rates of up to 30%. It is estimated that
approximately 60% of patients with childhood eczema
undergo spontaneous remission in early adolescence, but
up to 50% may have recurrences in adulthood, and the
disease can persist into or start in adulthood, making it
one of the most common skin disorders across all ages [1].
Eczema, asthma and rhinitis tend to cluster in the
same individuals and families [2], and are often accom­
panied by elevated levels of total serum IgE antibodies
and aberrant IgE‐mediated responses to otherwise
harmless environmental agents [3]. Therefore it has
‘atopic diseases’, in which patients may develop food
allergy, eczema, asthma and rhinitis in any order and in
any combination over time [4]. Atopy itself is defined as
‘personal or familial tendency to become sensitized and
produce IgE antibodies in response to low doses of
allergens, usually proteins’ and to ‘develop typical
symptoms such as asthma, rhinoconjunctivitis, or
eczema/dermatitis’ [5]. Based on the fact that eczema
symptoms often precede those of asthma and because
eczema represents a well‐established risk factor for
asthma, it has been further hypothesized that a suscepti­
ble child commonly passes through a sequential/over­
lapping series of phenotypes from eczema and food
allergy to asthma and subsequently allergic rhinitis
(‘atopic march”) [6–9]. While allergic sensitization
­represents one possible and plausible mechanistic link

Harper’s Textbook of Pediatric Dermatology, Fourth Edition. Edited by Peter Hoeger, Veronica Kinsler and Albert Yan.
© 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.
 Chapter 14
between asthma and eczema, it is notable that a signifi­
cant proportion of patients with eczema are not ‘atopic’,
i.e. they have normal total serum IgE concentrations and
no specific IgE responses [3,10]. Furthermore, epidemi­
ological research indicates that sensitization might sim­
ply be a shared epiphenomenon and suggests that the
association between asthma and eczema may occur
much earlier, i.e. early co‐occurrence of eczema and
wheeze progressing to asthma [10–12]. Thus, the role
and temporal significance of elevated IgE in eczema is
as yet unclear, and the concept of an ‘allergic march’
may represent an oversimplification of complex disease
co‐associations. Other discovered mechanisms such as
epidermally produced thymic stromal lymphopoietin
(TSLP)‐mediated lung inflammation may provide
­alternative explanations for an early co‐association of
eczema and asthma [13,14].
Eczema has a wide spectrum of clinical presentations
and it is unclear whether it is a single disorder with dif­
ferent clinical manifestations or a group of syndromes
with unique or overlapping pathophysiological path­
ways that open out into a rather uniform clinical pres­
entation. However, a rigorous definition of patient
subgroups is highly desirable in order to facilitate epi­
demiological, genetic and clinical investigations. In the
absence of a gold standard or adequate laboratory tests
to diagnose eczema, numerous lists of diagnostic crite­
ria have been developed in order to establish a defini­
tion. At present, the UK diagnostic criteria have been
the most widely validated and appear to be applicable
and repeatable across all ages and many ethnicities [15].
However, the ideal set of diagnostic criteria still has to
be established [16].
The confusing terminology for atopic diseases, with
terms such as atopic eczema, atopic dermatitis, childhood
eczema, atopiform dermatitis and flexural dermatitis fre­
quently used synonymously in the literature, reflects the
complexity of the diseases and the as yet insufficient
knowledge on their pathophysiology. It has previously
been suggested that ‘eczema’ be defined as the disease for­
merly called ‘atopic eczema’ or ‘atopic dermatitis’,
whereas the term ‘atopic eczema’ be reserved for those
patients with eczema and evidence for IgE involvement
[5,17]. However, as pointed out in a review, this division
might not adequately reflect the natural history of this dis­
ease [1], and it has to be considered that so far most, if not
all, studies on the genetics of eczema were performed
prior to these suggestions. Also, most existing DNA collec­
tions have been assembled using older definitions.
It is anticipated that difficulties in defining eczema and
its phenotypes may be overcome or at least improved by
studying the genetics, and that the results of molecular
studies will be of great nosological significance, enabling
a classification of atopic disorders based on the underly­
ing genetic effects rather than on hypothetical concepts
and clinical symptoms as is the case today. A similar
development has already taken place in other medical
fields such as in neurodegenerative diseases, many of
which are now defined by their mutated genes (e.g. spi­
nocerebellar ataxias).
Genetics and Aetiology of Atopic Dermatitis 185
Evidence for a genetic basis for eczema
There is a longstanding recognition that atopic diseases
cluster in families and are hereditary disorders [18–20].
Twin studies showed distinctly higher concordance rates
among monozygotic than dizygotic twin pairs (for
eczema 0.23–0.86 vs. 0.15–0.50), and segregation analyses
suggested that genetic factors account for more than 70%
of the variance in the susceptibility to eczema [21–24].
However, unlike monogenic disorders, which are caused
by mutations in a single gene, eczema and atopic disor­
ders are likely to be complex poly‐ or oligogenetic traits,
thought to be the result of a complicated network of
numerous susceptibility loci that exert additive or syner­
ATOPIC DERMATITIS
gistic effects but may have only a small role when considered
in isolation [25]. In addition, interacting environmental
SECTION 3:
factors are thought to precipitate the polygenic risk back­
ground into disease manifestation [26]. The importance
of environmental influences is emphasized by the wide
ranges in concordance rates, the incomplete concordance
among monozygotic twins and the changing and variable
prevalences of atopic symptoms both between countries
with similar ethnic groups and within countries [27,28].
The dissection of complex traits is further hampered by
phenocopy, incomplete penetrance and genetic heterogeneity
[26]. In addition, a set of studies suggested that, particu­
larly in atopic disorders such as eczema, inheritance of
certain polymorphisms from the mother is more likely to
be associated with allergic diseases in the child than
inheritance from the father [29]. This parent‐of‐origin
effect is supported by epidemiological studies that indi­
cate a crucial role of environmental exposures during
pregnancy [30] and a more close relationship of the
infant’s disease risk to maternal than paternal disease sta­
tus [31–33]. Genomic imprinting is one important epige­
netic mechanism that might explain such parent‐of‐origin
effects. Imprinting is a phenomenon in which disease‐
predisposing alleles only show their effects in a particular
epigenetic context, for example methylation induced by
the parental origin of the variant, leading to mono‐allelic
expression in the somatic cells of the offspring. Differential
expression can occur in all cells, or in specific tissues or
developmental stages [34].
Methods used in the genetic dissection
of eczema
For elucidation of the genetic background of complex dis­
eases, genetic association studies and linkage analyses
play an important role. The DNA sequence of human
beings is on average 99.9% identical. The remaining 0.1%
of DNA sequence differences between any two individu­
als are mainly based on common single nucleotide poly­
morphisms (SNPs), in which a single nucleotide within
the DNA sequence is replaced with an alternative one,
and where each variation is present to some appreciable
degree within a population (e.g. >1%). SNPs have become
a favourite genetic tool in the investigation of complex
diseases, although many are nonfunctional and therefore
result in neutral phenotypic outcomes. However, func­
tional SNPs can predispose individuals to disease, or
influence its severity, progression or individual response
 186 Section 3 Atopic Dermatitis and Related Disorders
to medicine. At the molecular level, these SNPs can affect
the human phenotype by interfering on both levels of the
protein synthesis machinery: noncoding SNPs may dis­
rupt transcription factor binding sites, splice sites and
other regulatory elements on the transcriptional level,
whereas coding SNPs can cause an amino acid change
and alter the functional or structural properties of the
translated protein.
Whole genome linkage analysis aims at the identifica­
tion of chromosomal regions associated with a disease
by identifying genetic markers, e.g. microsatellites or
SNPs, co‐segregating with the disease within families.
Susceptibility regions identified in such hypothesis‐free
ATOPIC DERMATITIS
screens typically encompass several megabases of DNA
sequence and might contain hundreds of genes. Thus,
SECTION 3:
intensive follow‐up analyses are needed to narrow down
the region of interest and to determine single disease
genes. While this traditional approach has been extremely
successful in the identification of monogenic disease
genes [35], it has only limited power to detect risk genes
for complex traits due to epistasis, incomplete penetrance,
polygeneity or phenotypic heterogeneity. Very few link­
age approaches have led to the identification of causal
disease variants in this setting. For eczema several link­
age studies have identified various putative disease loci
in the past [36]. However, with the exception of the filag­
grin (FLG) gene, which partly explains the linkage signal
observed on chromosome 1q21 [37], it has not been pos­
sible to assign a disease gene to any of the linkage regions
identified so far.
Association studies are thought to provide a more
powerful method for detecting complex disease alleles,
in particular alleles that only confer a modest disease
risk. These studies statistically analyse the correlation
between a genetic marker, usually an SNP, and the dis­
ease in unrelated individuals (case‐control and case‐
cohort studies) or their transmission in families
(family‐based design) [38]. An association between the
genotype and the phenotype is assumed if the genetic
marker and the disease occur together more often than
expected by chance. Due to technical limitations,
genetic association studies have been limited to the
study of candidate genes, i.e. genes located in a region
showing linkage in previous screening studies and/or
because of their function and expression patterns
(positional and/or functional candidate genes) [39].
Based on the assumption that the primary defect in
eczema is immunological and prior to the discovery of
FLG (see Filaggrin), for many years candidate genes
involved in antigen presentation and cell‐mediated/
humoral immune response, and cell signalling/cellular
movement have been investigated, as well as genes
that had been associated with asthma and/or atopy.
More than 100 associated risk genes for eczema were
reported up to 2009 by candidate gene association
studies [40], but most of these studies lack stringent
replication and have to be interpreted with caution.
Potential reasons for irreproducibility of results
include low power (as a result of small sample sizes),
inappropriate selection of candidate loci and markers,
inadequate assessment of the trait of interest and
i­nappropriate controls, variable study designs, inap­
propriate statistical modelling and failure to correct
for multiple comparisons, genetic and environmental
heterogeneity, publication bias (more positive reports
are submitted to and accepted by journals) and lack of
independent replication [26,41].
Since the turn of the millennium, association studies
have been revolutionized through newly developed
high‐throughput SNP genotyping platforms and
knowledge gained from the HapMap project, which
showed that the human genome is organized into
blocks of haplotypes with limited diversity within each
of these blocks [42]. Association studies aim at the
detection of proxy variants, which are in linkage dise­
quilibrium (LD) with the causal variant. LD refers to
the nonindependent inheritance of alleles, e.g. SNPs, at
two or more loci, which extend over relatively short
distances and may contain either a single gene or a few
genes only [38]. As a consequence of this genomic
architecture a limited set of SNPs can capture the vast
majority of common variations and ‘tag’ the haplotype
pattern sufficiently.
Since 2005, commercial SNP‐typing arrays have been
available and allow the simultaneous investigation of
up to 4 million SNPs. The markers used are selected to
provide maximal coverage of all common variations via
LD‐based tagging, or even spacing within the genome
[43]. These hypothesis‐free genome‐wide association
studies (GWAS) were successfully used to identify com­
mon disease‐associated variants (defined as those present
in more than 5% of the population). Another useful source
for genetic association studies was provided by the
1000 Genomes project (http://www.internationalgenome.
org), which between 2008 and 2015 sequenced the
genomes of more than 2500 individuals from 26 different
populations, thereby providing a comprehensive data set
of common as well as low‐frequency variants.
Technical improvements in recent years have also led
to a substantial decrease in costs of next‐generation
sequencing technologies. In contrast to genetic associa­
tion studies that analyse a limited number of prese­
lected single nucleotide variants distributed over the
genome, DNA sequencing provides information on
each single base constituting an individual human DNA
sequence. Whereas whole genome sequencing still is
rather costly, whole exome sequencing approaches,
which exclusively target the coding DNA regions of the
human genome, already allow the identification of as
yet unknown rare functional variants within larger
numbers of samples at reasonable costs. This approach
has already been very successfully applied within fami­
lies affected by rare monogenic diseases, and will
undoubtedly increase our knowledge of genetic risk
factors for common complex diseases like eczema.
Due to genetic studies the aetiological concept of
eczema underwent a profound change within recent
years from a primarily immune‐mediated disorder to one
that is equally, or may even be primarily, based on a skin
barrier malfunction.
 Chapter 14 Genetics and Aetiology of Atopic Dermatitis 187

Genes implicated in the aetiology
of eczema
Association studies, in particular those using genome‐
wide or targeted high‐throughput approaches, have
robustly identified more than 30 susceptibility regions for
eczema (Table 14.1) [44–52]. These loci together explain
approximately 20% of the estimated heritability. Most of
them harbour candidate genes that contribute to immune
mechanisms, in particular to innate immune signalling
and T‐cell activation and specification (Table 14.1,
Fig. 14.1), and appear to impact the susceptibility for a
range of immune‐mediated diseases rather than being
highly specific for eczema [48,54–56]. Further, for most of
these loci the causative gene or gene product as well as
the underlying molecular mechanisms remain to be
identified and characterized. Some notable exceptions are
presented here.
Filaggrin
Filaggrin (filament aggregating protein; FLG) was first
described in 1977 as an insoluble protein purified from rat
epidermis that interacted with intermediate filaments in
vitro [57]. It represents a structural protein with key func­
tions in the formation and maintenance of the cornified

ATOPIC DERMATITIS
SECTION 3:
Table 14.1 Susceptibility loci and most plausible candidate genes identified through genome‐wide association studies for atopic eczema

Associated Candidate gene Known/proposed function

locus

1q21.2 CIART Circadian transcriptional repressor

1q21.3 FLG Terminal epidermal differentiation; aggregation of keratin intermediate filaments
1q21.3 IL6R Subunit of the IL‐6 receptor; differentiation of multiple immune cells, especially B cells
2p13.3 CD207 C‐type lectin with mannose binding specificity; major receptor on Langerhans cells; antigen
uptake, processing and presentation
2p16.1 PUS10 Posttranscriptional modification of structural RNAs; involved in apoptosis
2p25.1 LINC00299 Long noncoding RNA; no known function
2q12.1 IL1RL1 Subunit of the IL‐33 receptor; Th cell function
IL18R1/IL18RAP Subunits of the IL‐18 receptor; regulation of inflammatory response via NF‐κB
2q24.3 XIRP2 Actin cytoskeleton and cell–cell junction organization; protection of actin filaments from
depolymerization
3p21.1 RFT1 Oligosaccharide transporter; protein N‐glycosylation
3p22.3 CCR4 C‐C chemokine receptor; leucocyte trafficking
3q13.2 CCDC80 Cell adhesion and matrix assembly
4q27 IL2/IL21 Differentiation, proliferation and activation of multiple immune cells (T cells, B cells,
macrophages, natural killer cells)
5p13.2 IL7R Subunit of the IL‐7 and TSLP receptor; proliferation of lymphoid progenitors; release of T‐cell‐
attracting chemokines; promotion of Th2‐cell response
5q22.1 TSLP Release of T‐cell‐attracting chemokines; promotion of Th2‐cell response; AMP activity in the oral
cavity and on the skin
5q31.1 IL13/IL4 Mainly produced by activated Th2 cells; B‐cell proliferation; IgE isotype switching
6p21.32 HLA‐DRB Antigen processing and presentation MHC class II
6p21.33 MICB Stress‐induced self‐antigen; activation of cytolytic response of NK cells, αβ T cells, and γδ T cells
7p22.2 CARD11 TCR‐mediated T cell activation; NF‐κB activation
8q21.13 ZBTB10 Transcription regulation
9p21.3 DMRTA1 Transcription regulation
10p15.1 IL15RA/IL2RA IL‐15 and IL‐2 receptor subunits; proliferation and stimulation of different lymphocytes
10q21.2 ZNF365 Mitotic cytokinesis; maintenance of genome stability
11p13‐12 PRR5L Regulation of protein kinase C phosphorylation; survival and organization of the cytoskeleton;
cell migration
11p15.4 NLRP10 Regulation of the innate immune system; pro‐inflammatory cytokine release; inhibition of
apoptosis; anti‐inflammatory activity
11q13.1 OVOL1 Transcription factor; hair formation and spermatogenesis
11q13.5 LRRC32 Regulation of Treg function and TGF‐β activation
11q24.3 ETS1 Transcription factor; direct control of cytokine and chemokine expression
14q13.2 PPP2R3C Regulation of protein phosphatases; activation‐induced cell death of B cells
16p13.13 CLEC16A C‐type lectin; regulation of mitophagy/autophagy and mitochondrial health
17q21.2 STAT3 Signal transducer and transcription activator; mediation of cellular responses to interleukins
17q21.32‐33 ZNF652 Transcription regulation
19p13.2 ACTL9 Cytoskeletal functions
ADAMTS10 Metalloprotease; assembly of extracellular matrix components
20q13.2 CYP24A1 Vitamin D metabolism
20q13.33 TNFRSF6B TNF receptor superfamily; protection against apoptosis

Sorted by chromosome; AMP, antimicrobial peptide; IL, interleukin; MHC, major histocompatibility complex; NF‐κB, nuclear factor ‘kappa‐light‐chain‐enhancer’
of activated B cells; NK cells, natural killer cells; RNA, ribonucleic acid; TCR, T‐cell receptor; TGF‐β, transforming growth factor β; Th cell, T‐helper cell; TNF,
tumour necrosis factor; TSLP, thymic stromal lymphopoietin.
 188 Section 3 Atopic Dermatitis and Related Disorders

Epidermal barrier Environmental sensing

FLG, OVOL1, CARD11,
ACTL9/ADAMTS10 HLA-DRB, MICB
ATOPIC DERMATITIS
SECTION 3:

Tissue response
Immune regulation CCDC80, CYP24A1,
IL1RL1/IL18R1/IL18RAP LRRC32, NLRP10, PRR5L,
IL2/IL21, IL4/IL13, TNFRSF6B,
IL6R, CLEC16A ZNF365, ZNF652
Fig. 14.1 Functional overview for selected candidate
genes identified through genome‐wide association
studies. Source: Adapted from Weidinger and Novak
(2016) [53].

envelope within the outermost layer of the human
epidermis, and is essential for the prevention of penetra­
tion of environmental agents such as microbes or allergens
into the organism and also, on the other hand, for controlling
transepidermal water loss (TEWL) [58,59].
Profilaggrin is expressed as a large inactive precursor
protein of 400 kDa in the stratum granulosum of the epi­
dermis, where it represents the main constituent of the
keratohyalin F granules (Fig. 14.2). It is composed of
10–12 tandem repeats, each encoding a functionally active
FLG monomer. Upon cornification of keratinocytes, pro­
filaggrin is dephosphorylated and proteolytically cleaved
into its active subunits. These monomers lead to a dense
bundling of keratin intermediate filaments, leading to
collapse of the keratinocyte’s cytoskeleton during their
differentiation into corneocytes, and finally to desquama­
tion of the stratum corneum. Concurrently, the amino
(N)‐terminus of the protein is translocated into the cell
nucleus, where it is believed to fulfill an additional but as
yet unknown role in regulation of terminal differentia­
tion. Moreover, degradation products of FLG, free hygro­
scopic amino acids and their derivatives, constitute a
large part of the pool of so‐called natural moisturizing
factors (NMFs) within the skin [61]. NMFs play an impor­
tant role in regulation of skin hydration and skin pH, the
latter of which is closely linked to protease activity and
antimicrobial defence [62]. The importance of FLG‐
derived breakdown products for skin barrier function is
supported by the remarkably short half‐life of FLG,
which exists only for 6 hours before its full proteolysis
into NMFs.
FLG was suspected of involvement in keratinization
disorders such as ichthyosis vulgaris (IV) more than
25 years ago, and its expression was found to be clearly
reduced in the epidermis of individuals with this disease
[63,64]. However, in‐depth analysis of the protein‐encoding
gene transpired to be technically difficult because of its
repetitive structural nature, and the sequence of the entire
FLG gene was finally published in 2006, identifying two
loss‐of‐function variants (p.R501X and c.2282del4) to be
the cause of IV [65]. Subsequently the same group
detected significant associations between these variants
and eczema [66].
Since that time more than 50 recurrent and family‐
specific variants have been identified within the FLG
gene in European and Asian populations [67]. These are
present in up to 10% of the general European population,
and up to 40% of eczema patients are carriers of at least
one of the five most recurrent null variants (p.R501X,
c.2282del4, p.S3247X, p.R2447X and c.3702delG), which
account for about 95% of all known variants within FLG
[67]. Interestingly, frequency appears to increase from
southern to northern Europe, which might reflect eth­
nic differences. In populations from UK and Ireland,
FLG loss‐of‐function variants seem to be more prevalent
compared to continental Europe [65,68–72]. Of the more
than 20 described loss‐of‐function variants found in
the European population, the majority could not be found
in Asian individuals [65,73,74] and vice versa. Similarly,
no FLG loss‐of‐function variants predominate in
African‐American children; however, uncommon
FLG loss‐of‐function variants in African‐American chil­
dren have been identified and shown to be associated
with more persistent AD [75]. Each ethnic group seems to
have its own exclusive null variants showing the same
strong impact on the development of eczema. All reported
variants are frameshift or nonsense variants leading to a
premature translation stop and hence truncation of the
 Chapter 14 Genetics and Aetiology of Atopic Dermatitis 189

Putative filaggrin functions

Outer stratum corneum

Hydration through hygroscopic
amino acids UCA and PCA
Inner stratum corneum Possible contribution to acid mantle
through acid degradation products
Lipid bilayer
Filament binding, barrier integrity
Granular layer Profilaggrin in granular layer:
Pro-protein, nonfunctional

(a) (b)

ATOPIC DERMATITIS
SECTION 3:
PCA
H2O

PADs 1+3 Caspase 14

+PCA
TGMs Profilaggrin A domain
“NMF”
Profilaggrin B domain
Ca2+
Matriptase Profilaggrin tail domain
Dephosphorylation LEKTI
CAP1/Prss Filaggrin

Keratohyalin F granule
Nucleus
Free amino acid

(c)
Fig. 14.2 Filaggrin expression and putative functions in the skin barrier. (a) The precursor pro‐protein profilaggrin is strongly expressed within keratohyalin
granules, tightly limited to and accounting for the typical appearance of the granular layer. The stratum corneum stains strongly positive for filaggrin. (b)
Filaggrin has several proposed site‐specific functions under the influence of the epidermal terminal differentiation programme through the outer granular
layer (cleavage of profilaggrin to filaggrin), lipid bilayer of the inner stratum corneum (filament compaction, contribution to barrier integrity) and during
desquamation of the outer stratum corneum (production of amino acid degradation products that contribute to the hydration of these outer layers and
probably contribute to the ‘acid mantle’). (c) Current knowledge of molecular control of filaggrin homeostasis. Profilaggrin is dephosphorylated in
conditions of increasing calcium concentration and then proteolytically cleaved by the proteases matriptase (inhibited by the protease inhibitor LETKI) and
CAP1/Prss. Post proteolysis, the filaggrin tail domain locates to the nucleus as part of the terminal differentiation process. Free filaggrin protein is cross‐
linked to keratin filaments by transglutaminases (TGMs) and subsequently deiminated by peptidylarginine deiminases (PADs) 1 and 3. Further posttransla-
tional modification is undertaken by caspase 14 to produce the free amino acid hygroscopic degradation products urocanic acid (UCA) and pyrrolidone
carboxylic acid (PCA), collectively known as natural moisturizing factor (NMF), which contributes to stratum corneum hydration. Source: O’Regan et al.
2008 [60]. Reproduced with permission of Elsevier.

profilaggrin molecule. The two most common variants,
p.R501X (a nonsense variant of the arginine codon 501 to
a stop codon) and c.2282del4 (a frameshift variant at posi­
tion 2282 due to a four base pair [bp] deletion), in the first
repeat of the gene impede any FLG synthesis from these
alleles. As the 3′ gene sequence seems to be important for
posttranslational processing into functional FLG subu­
nits, even variants located in this region prevent or reduce
production of free FLG in the stratum corneum [62,69].
Scientific evidence for this gene as one of the strongest
risk factors for eczema is compelling due to numerous
replication studies and meta‐analyses, which revealed an
overall odds ratio of >3.0 for eczema [76]. Due to the dis­
covery of FLG, susceptibility genes for eczema are now
divided into two major functional groups: genes contrib­
uting to epidermal or epithelial structures, and genes
encoding immune regulatory proteins.
Th2 cytokine cluster
One of the most consistent associations with eczema and
a variety of other immune‐related disorders such as
Crohn’s disease, asthma and psoriasis has been observed
for the T‐helper 2 (Th2) cytokine cluster on chromosome
5q31 [77,78], a locus that harbours the genes encoding
interleukin (IL)‐3, IL‐4, IL‐5 and IL‐13. These cytokines
are mainly produced by differentiated CD4+ Th2 cells
that are responsible for the antibody‐mediated immune
response against parasites, allergens and bacteria. Th2
cytokines show a great functional overlap and are
involved in Th2 cell development and polarization, B‐cell
proliferation and differentiation, IgE antibody produc­
tion, and activation and recruitment of certain immune
cell subsets such as mast cells and eosinophils to inflam­
matory sites. Different potential risk SNPs have been
identified throughout the whole region, and functionally
 190 Section 3 Atopic Dermatitis and Related Disorders
disruptive variants within IL4 and IL13 genes are con­
vincingly associated with total IgE levels and atopic dis­
eases including eczema (reviewed in [79]). Additionally,
various GWAS identified associated SNPs within RAD50,
a gene situated within the cytokine cluster between
IL4/IL13 and IL5, encoding a DNA repair protein that is
ubiquitously expressed and therefore lacks any direct bio­
logical connection to eczema. However, in mouse models
RAD50 has been shown to contain an evolutionarily con­
served locus control region (LCR), which is supposed to
tightly control expression of the neighbouring Th2
cytokines [80]. Hence, associated polymorphisms in
RAD50 influence regulation of Th2 cytokine gene tran­
ATOPIC DERMATITIS
scription rather than RAD50 gene function itself.
Regulation through the LCR within RAD50 occurs via a
SECTION 3:
complex recruitment of transcription factors and other
regulatory molecules and includes epigenetic remodelling
of the three‐dimensional structure of chromatin within
this region. An intrachromosomal loop allows direct
interaction of the transcription factor machinery bound to
the LCR with the Th2 cytokine gene promoter regions in
order to activate or repress their expression [81,82]. The
LCR has also been shown to be rapidly demethylated in
murine cell lines of stimulated Th2 cells [83], linking the
epigenetic mechanism of DNA methylation with activa­
tion of Th2 cytokine expression. Inactivation of the LCR
in mice leads to a reduction of Th2 cytokine and IgE levels
[84], and variants within the LCR impact its transcrip­
tional activity [85].
Together, genetic as well as epigenetic elements seem to
regulate expression of this important immune gene clus­
ter, and variants might interfere with both mechanisms,
thereby promoting Th2‐dominated immune reactions
characteristically for atopy‐related disorders like eczema.
Given the number of immune‐mediated diseases that
have been linked to the Th2 cytokine cluster, it seems very
likely that variants within this region are more relevant
for the atopic state sensu lato than for any individual
distinct atopic disease.
Identification of further causal variants that probably
exist within this important risk locus is hampered by the
complex marker–marker correlation in this genomic
region and the gene–gene interactions through overlap­
ping functional pathways.
GARP (glycoprotein A repetitions
predominant)/LRRC32 (leucine‐rich
repeat‐containing protein 32)
Another consistently‐replicated eczema risk locus has
been identified on chromosome 11q13.5, with the strong­
est association observed for an SNP located in an inter­
genic region between the two annotated genes chromosome
11 open reading frame 30 (C11orf30) and leucine rich repeat
containing 32 (LRRC32). Assignment of the signal to one of
its neighbouring genes could not be accomplished, as
both are attractive candidates due to their known func­
tions in epithelial immunity and differentiation and acti­
vation of regulatory T cells, respectively, and the causative
risk gene marked by the associated SNP has more recently
been identified [86]. Genetic fine mapping of the region
by targeted next‐generation sequencing revealed a
number of low‐frequency variants within the coding
region of LRRC32 to be strongly associated with eczema.
LRRC32 encodes the protein glycoprotein A repetitions
predominant (GARP), a cell surface receptor mainly
expressed on activated regulatory T cells (Tregs), which
binds and activates latent TGF‐β, thereby regulating the
bioavailability of this multifunctional cytokine [87]. All of
the identified variants lead to an amino acid exchange
within the primary structure of the protein, and structural
modelling of GARP predicted a defective posttransla­
tional modification due to the identified variants, finally
leading to incorrect folding and constrained transporta­
tion of GARP to the outer cell membrane. Overexpression
experiments of mutated GARP indeed showed reduction
of the membrane‐bound protein, and a reduced conver­
sion rate of CD4+/CD25− T cells into Tregs was observed
when obtained from individuals carrying the identified
variants [86]. Tregs are of high importance for suppres­
sion of effector T cells and other leucocytes and for con­
trol of inflammatory immune responses and autoimmunity
[88], and experimental deactivation of GARP has been
shown to lead to a reduction in the suppressor activity of
these cells [89]. It is possible to speculate that the missing
membrane expression of GARP on activated Tregs leads
to a decreased activation rate of TGF‐β and thereby affects
downstream function of this important cytokine, finally
resulting in an overshooting inflammatory immune reac­
tion. Moreover, Tregs are suspected to be involved in a
variety of other diseases, and association of the previ­
ously mentioned eczema marker has also been detected
in a GWAS on Crohn’s disease, implying that the 11q13.5
locus and GARP are also important within the disease
pathophysiology of further (auto)immune diseases.
Conclusions and future directions
Despite much progress over the past two decades, our
understanding of the complex genetic susceptibility to
eczema is still incomplete. In particular, there is a lack of
follow‐up studies in order to determine affected genes and
downstream mechanisms. Thus far only the 1q21.3, 5q31
and 11q13.5 loci have been functionally explored. The
important role of the skin barrier within eczema has been
clearly evidenced with the identification and validation of
FLG variants as the strongest known genetic risk factors for
the disease. This paradigm change has now also led to early
intervention studies of primary prevention of the disease by
improving the skin barrier function with daily emollient
applications. The results of these randomized intervention
studies have been an approximate 50% reduction of eczema
incidence in high‐risk newborns [90, 91], lending further
support for the key importance of a functionally intact skin
barrier. Likewise, genetic findings that imply an important
role of variation in genes affecting (auto‐)immune regula­
tion, in particular innate signalling and T‐cell activation and
specification, have contributed to the development of drugs
modifying immune pathways, some of which are already in
advanced stages of development and showed encouraging
results in clinical trials [92–94].
 Chapter 14
In order to deepen our understanding of the genetic
architecture of eczema, there is a need for further large‐
scale and detailed whole‐genome studies, follow‐up
studies for fine‐mapping and functional investigations,
and holistic approaches that integrate phenotypic varia­
bles and information from different molecular levels. In
addition, it will be necessary to revisit traditional pheno­
type definitions based on familial components, heritable
endophenotypes and genetic markers. To better define
pathophysiological mechanisms and to identify novel
therapeutic targets and biomarkers that predict therapeu­
tic response, there has been increasing interest in develop­
ing computational analysis and predictive models of AD
[95]. The final frontier will certainly be to translate genetic
findings into an improved classification and the develop­
ment of more targeted interventions.
References
1 Bieber T. Atopic dermatitis. N Engl J Med 2008;358:1483–94.
2 Wuthrich B. The natural history of atopic dermatitis. In: Ring J,
Przybilla B, Ruzicka T (eds) Handbook of Atopic Dermatitis, 2nd edn.
Berlin: Springer Verlag, 2006:150–6.
3 Novak N, Bieber T. Allergic and nonallergic forms of atopic diseases.
J Allergy Clin Immunol 2003;112:252–62.
4 Wuthrich B, Schmid‐Grendelmeier P. The atopic eczema/dermatitis
syndrome. Epidemiology, natural course, and immunology of the
IgE‐associated (“extrinsic”) and the nonallergic ("intrinsic") AEDS.
J Investig Allergol Clin Immunol 2003;13:1–5.
5 Johansson SG, Bieber T, Dahl R et al. Revised nomenclature for allergy
for global use: Report of the Nomenclature Review Committee of the
World Allergy Organization, October 2003. J Allergy Clin Immunol
2004;113:832–6.
6 Bergmann RL, Edenharter G, Bergmann KE et al. Atopic dermatitis in
early infancy predicts allergic airway disease at 5 years. Clin Exp
Allergy 1998;28:965–70.
7 Gustafsson D, Sjoberg O, Foucard T. Development of allergies and
asthma in infants and young children with atopic dermatitis—a pro­
spective follow‐up to 7 years of age. Allergy 2000;55:240–5.
8 Hakansson K, Thomsen SF, Ulrik CS et al. Increase in the prevalence
of rhinitis among Danish children from 1986 to 2001. Pediatr Allergy
Immunol 2007;18:154–9.
9 Spergel JM. From atopic dermatitis to asthma: the atopic march. Ann
Allergy Asthma Immunol 2010;105:99–106.
10 Illi S, von Mutius E, Lau S et al. The natural course of atopic dermatitis
from birth to age 7 years and the association with asthma. J Allergy
Clin Immunol 2004;113:925–31.
11 Williams H, Flohr C. How epidemiology has challenged 3 prevailing
concepts about atopic dermatitis. J Allergy Clin Immunol 2006;
118:209–13.
12 Flohr C, Weiland SK, Weinmayr G et al. The role of atopic sensitiza­
tion in flexural eczema: findings from the International Study of
Asthma and Allergies in Childhood Phase Two. J Allergy Clin
Immunol 2008;121:141–7.e4.
13 He R, Oyoshi MK, Garibyan L et al. TSLP acts on infiltrating effector
T cells to drive allergic skin inflammation. Proc Natl Acad Sci U S A
2008;105:11875–80.
14 Demehri S, Morimoto M, Holtzman MJ, Kopan R. Skin‐derived TSLP
triggers progression from epidermal‐barrier defects to asthma. PLoS
Biol 2009;7:e1000067.
15 Williams HC, Burney PG, Hay RJ et al. The U.K. Working Party’s
Diagnostic Criteria for Atopic Dermatitis. I. Derivation of a minimum
set of discriminators for atopic dermatitis. Br J Dermatol 1994;131:
383–96.
16 Brenninkmeijer EE, Schram ME, Leeflang MM et al. Diagnostic crite­
ria for atopic dermatitis: a systematic review. Br J Dermatol 2008;
158:754–65.
17 Johansson SG, Hourihane JO, Bousquet J et al. A revised nomencla­
ture for allergy. An EAACI position statement from the EAACI
nomenclature task force. Allergy 2001;56:813–24.
18 Cooke R, van der Veer A. Human sensitization. J Immunol
1916;1:201–5.
Genetics and Aetiology of Atopic Dermatitis 191
19 Sneddon IB. The management of infantile eczema. Med Press 1951;
226:329–33.
20 Schaffer N. Atopic dermatitis in the older child. J Asthma Res
1966;3:189–91.
21 Larsen FS, Holm NV, Henningsen K. Atopic dermatitis. A genetic‐
epidemiologic study in a population‐based twin sample. J Am Acad
Dermatol 1986;15:487–94.
22 Schultz Larsen F. Atopic dermatitis: a genetic‐epidemiologic study in
a population‐based twin sample. J Am Acad Dermatol 1993;
28:719–23.
23 Thomsen SF, Ulrik CS, Kyvik KO et al. Importance of genetic factors
in the etiology of atopic dermatitis: a twin study. Allergy Asthma Proc
2007;28:535–9.
24 van Beijsterveldt CE, Boomsma DI. Genetics of parentally reported
asthma, eczema and rhinitis in 5‐yr‐old twins. Eur Respir J 2007;
29:516–21.
ATOPIC DERMATITIS
25 Phillips PC. Epistasis—the essential role of gene interactions in the
structure and evolution of genetic systems. Nat Rev Genet
2008;9:855–67.
SECTION 3:
26 Glazier AM, Nadeau JH, Aitman TJ. Finding genes that underlie com­
plex traits. Science 2002;298:2345–9.
27 Williams H, Robertson C, Stewart A et al. Worldwide variations in the
prevalence of symptoms of atopic eczema in the International Study
of Asthma and Allergies in Childhood. J Allergy Clin Immunol
1999;103:125–38.
28 Asher MI, Montefort S, Bjorksten B et al. Worldwide time trends in the
prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and
eczema in childhood: ISAAC Phases One and Three repeat multi­
country cross‐sectional surveys. Lancet 2006;368:733–43.
29 Moffatt MF, Cookson WO. The genetics of asthma. Maternal effects in
atopic disease. Clin Exp Allergy 1998;28(suppl 1):56–61.
30 Warner JA, Jones CA, Jones AC, Warner JO. Prenatal origins of allergic
disease. J Allergy Clin Immunol 2000;105:S493–8.
31 Dold S, Wjst M, von Mutius E et al. Genetic risk for asthma, allergic
rhinitis, and atopic dermatitis. Arch Dis Child 1992;67:1018–22.
32 Ruiz RG, Kemeny DM, Price JF. Higher risk of infantile atopic
dermatitis from maternal atopy than from paternal atopy. Clin Exp
Allergy 1992;22:762–6.
33 Diepgen TL, Blettner M. Analysis of familial aggregation of atopic
eczema and other atopic diseases by ODDS RATIO regression models.
J Invest Dermatol 1996;106:977–81.
34 Reik W, Walter J. Genomic imprinting: parental influence on the
genome. Nat Rev Genet 2001;2:21–32.
35 McKusick VA. Mendelian Inheritance in Man and its online version,
OMIM. Am J Hum Genet 2007;80:588–604.
36 Lee YA, Wahn U, Kehrt R et al. A major susceptibility locus for atopic
dermatitis maps to chromosome 3q21. Nat Genet 2000;26:470–3.
37 Morar N, Edster P, Street T et al. Fine mapping of susceptibility genes
for atopic dermatitis in the epidermal differentiation complex on
chromosome 1q21. Br J Dermatol 2007;157:3.
38 Altshuler D, Daly MJ, Lander ES. Genetic mapping in human disease.
Science 2008;322:881–8.
39 Tabor HK, Risch NJ, Myers RM. Candidate‐gene approaches for stud­
ying complex genetic traits: practical considerations. Nat Rev Genet
2002;3:391–7.
40 Barnes KC. An update on the genetics of atopic dermatitis: scratching
the surface in 2009. J Allergy Clin Immunol 2010;125:16–29.e1–11.
41 Lohmueller KE, Pearce CL, Pike M et al. Meta‐analysis of genetic
association studies supports a contribution of common variants to
susceptibility to common disease. Nat Genet 2003;33:177–82.
42 The International HapMap Consortium. The International HapMap
Project. Nature 2003;426:789–96.
43 Grant SF, Hakonarson H. Microarray technology and applications in
the arena of genome‐wide association. Clin Chem 2008;54:1116–24.
44 Esparza‐Gordillo J, Weidinger S, Folster‐Holst R et al. A common
variant on chromosome 11q13 is associated with atopic dermatitis.
Nat Genet 2009;41:596–601.
45 Sun LD, Xiao FL, Li Y et al. Genome‐wide association study identifies
two new susceptibility loci for atopic dermatitis in the Chinese Han
population. Nat Genet 2011;43:690–4.
46 Hirota T, Takahashi A, Kubo M et al. Genome‐wide association study
identifies eight new susceptibility loci for atopic dermatitis in the
Japanese population. Nat Genet 2012;44:1222–6.
47 Paternoster L, Standl M, Chen CM et al. Meta‐analysis of genome‐
wide association studies identifies three new risk loci for atopic
dermatitis. Nat Genet 2012;44:187–92.
 192 Section 3 Atopic Dermatitis and Related Disorders
48 Ellinghaus D, Baurecht H, Esparza‐Gordillo J et al. High‐density
genotyping study identifies four new susceptibility loci for atopic
dermatitis. Nat Genet 2013;45:808–12.
49 Esparza‐Gordillo J, Schaarschmidt H, Liang L et al. A functional IL‐6
receptor (IL6R) variant is a risk factor for persistent atopic dermatitis.
J Allergy Clin Immunol 2013;132:371–7.
50 Weidinger S, Willis‐Owen SA, Kamatani Y et al. A genome‐wide
association study of atopic dermatitis identifies loci with overlapping
effects on asthma and psoriasis. Hum Mol Genet 2013;22:4841–56.
51 Paternoster L, Standl M, Waage J et al. Multi‐ancestry genome‐wide
association study of 21,000 cases and 95,000 controls identifies new
risk loci for atopic dermatitis. Nat Genet 2015;47:1449–56.
52 Schaarschmidt H, Ellinghaus D, Rodriguez E et al. A genome‐wide
association study reveals 2 new susceptibility loci for atopic dermati­
tis. J Allergy Clin Immunol 2015;136:802–6.
53 Weidinger S, Novak N. Atopic dermatitis. Lancet 2016;387:1109–22.
ATOPIC DERMATITIS
54 Ellinghaus D, Jostins L, Spain SL et al. Analysis of five chronic inflam­
matory diseases identifies 27 new associations and highlights disease‐
specific patterns at shared loci. Nat Genet 2016;48:510–18.
SECTION 3:
55 Ferreira MAR, Vonk JM, Baurecht H et al. Eleven loci with new repro­
ducible genetic associations with allergic disease risk. J Allergy Clin
Immunol 2019;143(2):691–9.
56 Devos M, Mogilenko DA, Fleury S et al. Keratinocyte expression of
A20/TNFAIP3 controls skin inflammation associated with atopic der­
matitis and psoriasis. J Invest Dermatol 2019;139:135–45.
57 Dale BA. Purification and characterization of a basic protein from the
stratum corneum of mammalian epidermis. Biochim Biophys Acta
1977;491:193–204.
58 Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell
death in the skin. Nat Rev Mol Cell Biol 2005;6:328–40.
59 Proksch E, Brandner JM, Jensen JM. The skin: an indispensable bar­
rier. Exp Dermatol 2008;17:1063–72.
60 O’Regan GM, Sandilands A, McLean WH, Irvine AD. Filaggrin in
atopic dermatitis. J Allergy Clin Immunol 2008;122:689–93.
61 Rawlings AV, Harding CR. Moisturization and skin barrier function.
Dermatol Ther 2004;17(suppl 1):43–8.
62 Sandilands A, Sutherland C, Irvine AD, McLean WH. Filaggrin in the
frontline: role in skin barrier function and disease. J Cell Sci
2009;122:1285–94.
63 Fleckman P, Holbrook KA, Dale BA, Sybert VP. Keratinocytes cul­
tured from subjects with ichthyosis vulgaris are phenotypically
abnormal. J Invest Dermatol 1987;88:640–5.
64 Sybert VP, Dale BA, Holbrook KA. Ichthyosis vulgaris: identification
of a defect in synthesis of filaggrin correlated with an absence of kera­
tohyaline granules. J Invest Dermatol 1985;84:191–4.
65 Smith FJ, Irvine AD, Terron‐Kwiatkowski A et al. Loss‐of‐function
mutations in the gene encoding filaggrin cause ichthyosis vulgaris.
Nat Genet 2006;38:337–42.
66 Palmer CN, Irvine AD, Terron‐Kwiatkowski A 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.
67 Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated
with skin and allergic diseases. N Engl J Med 2011;365:1315–27.
68 Barker JN, Palmer CN, Zhao Y et al. Null mutations in the filaggrin
gene (FLG) determine major susceptibility to early‐onset atopic
dermatitis that persists into adulthood. J Invest Dermatol 2007;
127:564–7.
69 Sandilands A, Terron‐Kwiatkowski A, Hull PR et al. Com­
prehensive analysis of the gene encoding filaggrin uncovers prevalent
and rare mutations in ichthyosis vulgaris and atopic eczema. Nat Genet
2007;39:650–4.
70 Brown SJ, Relton CL, Liao H et al. Filaggrin null mutations and child­
hood atopic eczema: a population‐based case‐control study. J Allergy
Clin Immunol 2008;121:940–46.e3.
71 Rice NE, Patel BD, Lang IA et al. Filaggrin gene mutations are associ­
ated with asthma and eczema in later life. J Allergy Clin Immunol
2008;122:834–6.
72 Weidinger S, O’Sullivan M, Illig T et al. Filaggrin mutations, atopic
eczema, hay fever, and asthma in children. J Allergy Clin Immunol
2008;121:1203–9.
73 Nomura T, Sandilands A, Akiyama M et al. Unique mutations in the
filaggrin gene in Japanese patients with ichthyosis vulgaris and atopic
dermatitis. J Invest Dermatol 2007;119:434–40.
74 Nomura T, Akiyama M, Sandilands A et al. Prevalent and rare muta­
tions in the gene encoding filaggrin in Japanese patients with ichthyo­
sis vulgaris and atopic dermatitis. J Invest Dermatol 2009;129:1302–5.
75 Margolis DJ, Mitra N, Gochnauer H et al. Uncommon filaggrin vari­
ants are associated with persistent atopic dermatitis in African
Americans. J Invest Dermatol 2018;138:1501–6.
76 Rodriguez E, Baurecht H, Herberich E et al. Meta‐analysis of filag-
grin polymorphisms in eczema and asthma: robust risk factors in
atopic disease. J Allergy Clin Immunol 2009;123:1361–70.e7.
77 Rioux JD, Daly MJ, Silverberg MS et al. Genetic variation in the 5q31
cytokine gene cluster confers susceptibility to Crohn disease. Nat
Genet 2001;29:223–8.
78 Li Y, Chang M, Schrodi SJ et al. The 5q31 variants associated with
psoriasis and Crohn’s disease are distinct. Hum Mol Genet
2008;17:2978–85.
79 Vercelli D. Discovering susceptibility genes for asthma and
allergy. Nat Rev Immunol 2008;8:169–82.
80 Lee GR, Fields PE, Griffin TJ, Flavell RA. Regulation of the Th2
cytokine locus by a locus control region. Immunity 2003;19:
145–53.
81 Spilianakis CG, Flavell RA. Long‐range intrachromosomal interac­
tions in the T helper type 2 cytokine locus. Nat Immunol 2004;
5:1017–27.
82 Lee GR, Spilianakis CG, Flavell RA. Hypersensitive site 7 of the TH2
locus control region is essential for expressing TH2 cytokine genes
and for long‐range intrachromosomal interactions. Nat Immunol
2005;6:42–8.
83 Kim ST, Fields PE, Flavell RA. Demethylation of a specific hypersensi­
tive site in the Th2 locus control region. Proc Natl Acad Sci U S A
2007;104:17052–7.
84 Koh BH, Hwang SS, Kim JY et al. Th2 LCR is essential for regulation
of Th2 cytokine genes and for pathogenesis of allergic asthma. Proc
Natl Acad Sci U S A 2010;107:10614–19.
85 Kretschmer A, Moller G, Lee H et al. A common atopy‐associated
variant in the Th2 cytokine locus control region impacts transcrip­
tional regulation and alters SMAD3 and SP1 binding. Allergy 2014;
69:632–42.
86 Manz J, Rodriguez E, ElSharawy A et al. Targeted resequencing and
functional testing identifies low‐frequency missense variants in
the gene encoding GARP as significant contributors to atopic der-
matitis risk. J Invest Dermatol 2016;136:2380–6.
87 Wang R, Zhu J, Dong X et al. GARP regulates the bioavailability and
activation of TGFbeta. Mol Biol Cell 2012;23:1129–39.
88 Zhang H, Kong H, Zeng X et al. Subsets of regulatory T cells and their
roles in allergy. J Transl Med 2014;12:125.
89 Fridrich S, Hahn SA, Linzmaier M et al. How soluble GARP enhances
TGFbeta activation. PLoS One 2016;11:e0153290.
90 Horimukai K, Morita K, Narita M et al. Application of moisturizer to
neonates prevents development of atopic dermatitis. J Allergy Clin
Immunol 2014;134:824–30.e6.
91 Simpson EL, Chalmers JR, Hanifin JM et al. Emollient enhancement of
the skin barrier from birth offers effective atopic dermatitis preven­
tion. J Allergy Clin Immunol 2014;134:818–23.
92 Beck LA, Thaci D, Hamilton JD et al. Dupilumab treatment in adults
with moderate‐to‐severe atopic dermatitis. N Engl J Med 2014;
371:130–9.
93 Simpson EL, Bieber T, Guttman‐Yassky E et al. Two Phase 3 trials of
dupilumab versus placebo in atopic dermatitis. N Engl J Med
2016;375:2335–48.
94 Thaci D, Simpson EL, Beck LA et al. Efficacy and safety of dupilumab
in adults with moderate‐to‐severe atopic dermatitis inadequately
controlled by topical treatments: a randomised, placebo‐controlled,
dose‐ranging phase 2b trial. Lancet 2016;387:40–52.
95 Eyerich K, Brown SJ, Perez White BE et al. Human and computational
models of atopic dermatitis: a review and perspectives by an expert
panel of the International Eczema Council. J Allergy Clin Immunol
2019;143(1):36–45.