Genetic markers associated with psoriasis identified
31 January 2009
Scientists at the University of Michigan Department of Dermatology,
the U-M School of Public Health and their collaborators have found DNA
'hotspots' that may reveal how genetic differences among individuals
result in psoriasis, an autoimmune disease of the skin. Published in
Nature Genetics , the findings could lead to new drug targets
and tailored treatments for the disease.
"This discovery highlights the role of several genes in mediating the
immune responses that result in psoriasis," says Goncalo Abecasis,
Ph.D., co-principal investigator on the project, and associate professor
of biostatistics in the School of Public Health. "Some of the
highlighted genes, like those in the IL-23 pathway are already targeted
by effective psoriasis therapies. Others, like TNFAIP3 and TNIP1, may
become targets for the psoriasis treatments of the future."
Psoriasis affects some 7.5 million people in the United States,
causing sore, itchy patches of red, scaly skin. In many cases psoriasis
is not only disfiguring; between 10 and 30 percent of patients develop
psoriatic arthritis, a painful inflammation of the joints. Current
treatments, including different types of immunosuppressive agents,
aren't always effective, and they can cause serious side effects.
Psoriasis has a strong genetic component; a child with two affected
parents has a 50 percent chance of developing it; siblings have a three-
to six-fold risk. But the genes responsible for psoriasis haven't yet
been completely understood.
In this large, multi-center study, researchers used cutting-edge
genomic technology to identify subtle genetic signals influencing the
risk of psoriasis. They scanned millions of DNA variations in the genome
to find those that occur significantly more often in psoriasis patients
than unaffected people.
The study was led by James Elder, M.D., Ph.D., a professor in the
Department of Dermatology, and Abecasis. Among the first authors were
Rajan Nair, Ph.D., assistant research professor of dermatology, and Jun
Ding of the Biostatistics Department in the School of Public Health.
Within the past 18 months, researchers have increased the number of
independent genetic "hotspots," or loci, confidently associated with
psoriasis from one -- HLA-Cw6, previously identified by Elder, et al.,
in 2006 -- to 10. Four of these have been identified for the first time
by this study, and two more have since been confirmed by these
The team looked for single nucleotide polymorphisms (SNPs), or DNA
changes, at 438,670 sites in 1,359 psoriasis cases and 1,400 healthy
controls. Initial scans signaled differences in at least three
previously identified DNA sites, with HLA-Cw6 producing the strongest
genetic signal. They then expanded the study to look at 18 of the most
interesting loci in an additional 5,048 cases and 5,051 controls.
In all, seven of the 18 loci showed consistently strong association
with psoriasis. As a result, four proteins produced from the altered DNA
code now can be targeted for further study.
This study is the first to identify changes in the IL23A gene in
psoriasis patients. Notably, two of the previously identified psoriasis
genes (IL12B and IL23R) encode proteins that bind to IL23A protein.
Variations in the structure any of these three genes may predispose
people to chronic immune responses that ultimately result in psoriasis.
The team also found that genetic signals for proteins activated by
TNF-alpha, a key signaling molecule involved in inflammation, are
distinct from the patterns in healthy controls. Two genes activated by
TNF-alpha — TNFAIP3 and TNIP1 — show strong association with psoriasis.
Together, these genes limit immune responses. Genetic alterations in
this "brake" may allow the immune system to work overtime within the
skin. Variants of TNFAIP3 also have been associated with rheumatoid
arthritis and lupus, two other autoimmune conditions.
The fourth novel hotspot implicates two "next-door neighbor" genes,
IL4 and IL13. These genes support development of Th2 cells, a type of
immune system T cell. Any condition that leads to too few or too many
Th2 cells in relation to other types of T cells may result in disease,
This new research, together with recent immunology work by Elder and
colleagues, links four psoriasis loci (IL12B, IL23A, IL23R and IL4/IL13)
together in a common functional pathway.
The large library of genetic data increases the number of proteins
and pathways that can be targeted by emerging therapies to fight
Once the full catalogue of psoriasis genes has been identified, it
may be possible to generate a "psoriasis gene profile" that can
accurately predict one's risk of developing the disease. Such work may
one day help assess risk of heart attack and stroke, since psoriasis
carries an increased risk of coronary artery disease, and TNFAIP3 has
also been shown to influence risk of coronary artery disease in mice.
The number of disease genes that can be identified more than triples
if the study size can be increased two to three fold. "We invite
participation of psoriasis patients from across the country," says
Patients can enroll for this study by mail without a trip to Ann
Arbor. Elder has information at his Psoriasis Genetics Laboratory Web
. Interested patients in the US can also call 800-356-2840.
1. Nature Genetics, volume 41, no. 2, p. 199-204.
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