of the Max - MDC

Genetics of Allergic Disease
Young-Ae Lee
The allergic diseases, particularly atopic dermatitis, food
allergy, asthma, and hay fever, are among the most common
chronic diseases in man. The prevalence of atopic diseases
has increased to epidemic dimensions over the past decades.
In the industrialized countries, 25-30% of the population are
affected. A strong genetic component in atopy and has been
recognized. Our group is using genetic and genomic approaches
to identify genes and genetic variants that predispose to atopic
dermatitis and atopy. The identification of the molecular pathways
underlying allergic disease will provide novel targets for
preclinical diagnosis, disease prevention, and therapeutic
intervention.
Clinical phenotyping
Genetic studies in complex human traits requires meticulous
phenotyping of numerous patients and their families.
Patient recruitment is performed at the Charité Children’s
Hospital. Atopic dermatitis in early childhood is an important
risk factor for the development of asthma and hayfever.
Most of the index children were below school age at the
time of initial enrollment and may not yet have manifested
allergic airways disease. The goal of the clinical phenotyping
group is therefore to perform a prospective reevaluation
of the families for atopic dermatitis and allergic airways disease
by questionnaires, physical examination, and lung
function testing. To obtain additional sub-phenotypes, a
subset of families is being investigated for genome-wide
gene expression levels from peripheral blood leukocytes.
Identification of a novel collagen gene
(COL29A1) a susceptibility gene for atopic
dermatitis on chromosome 3q21
We have previously mapped a major susceptibility locus for
atopic dermatitis to chromosome 3q21. We have used the
positional cloning approach to identify the susceptibility
gene for atopic dermatitis on chromosome 3q21. A dense
map of microsatellite markers and single nucleotide polymorphisms
was genotyped in the families in whom linkage
was initially found. We detected association with AD and
with allergic sensitization (elevated serum IgE antibodies).
In concordance with the linkage results, we found a maternal
transmission pattern. Furthermore, we demonstrated
that the same families contribute to linkage and association.
We replicated the association and the maternal effect
in a large independent family cohort. A common haplotype
showed strong association with AD (P = 0.000059). The
associated region contained a single gene, COL29A1, which
encodes a novel epidermal collagen. COL29A1 shows a specific
gene expression pattern with the highest transcript
levels in skin, lung, and the gastrointestinal tract which are
the major sites of allergic disease manifestation. We conclude
that lack of COL29A1 expression in the outer epidermis
of AD patients points to a role of collagen XXIX in epidermal
integrity and function, the breakdown of which is a clinical
hallmark of AD.
A common haplotype of the interleukin-31 gene
(IL31) influencing gene expression is associated
with nonatopic eczema
Interleukin-31 (IL-31) is a novel cytokine that, when overexpressed
in transgenic mice, induces severe itching dermatitis
resembling human eczema.
We aimed to evaluate the importance of polymorphisms in
the human IL-31 gene in the genetic susceptibility to
eczema.
We sequenced the entire IL-31 gene including the promoter
region and determined the haplotype structure. Single
nucleotide polymorphisms tagging the main haplotypes
were genotyped in three independent European populations
comprising 690 affected families. An association analysis of
IL-31 gene variants with atopic and nonatopic eczema was
performed.
We found significant association of a common IL-31 haplotype
with the nonatopic type of eczema in all three study
populations (combined P-value 4.5x10-5). Analysis of
peripheral blood mononuclear cells in healthy individuals
revealed a strong induction IL-31 mRNA expression upon
stimulation with anti-CD3 and anti-CD28 that was 3.8-fold
higher in individuals homozygous for the risk haplotype
(AA) in contrast to non-A haplotype carriers, suggesting
that altered regulation of IL31 gene expression is the disease
causing factor.
Our results lend strong support to an important role of IL-
31 in the pathogenesis of nonatopic eczema. This study
presents the first genetic risk factor for the nonatopic type
of eczema and indicates a primary role of IL-31 induced pruritus
in the initiation of this disease thus proposing a new
target for the prevention and therapy of eczema.
60 Cardiovascular and Metabolic Disease Research