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Senior Citizen Health & Medicine
Discovery of Genes Involved in Lupus May Help Fight
Autoimmune Disease
NEJM editorial highlights significance and limitations of
the research
 Jan.
21, 2008 - Some 1.5 million Americans, most of them women,
suffer from lupus, a disease where the person’s immune system attacks
the body’s own tissue. This week marks a significant step forward in
understanding how the disease works with the online publication of four
new studies identifying genes involved in this often debilitating
chronic disease. It may also lead to learning more about other of these
autoimmune diseases that primarily strike senior citizens.
Mary K.Crow, M.D., associate chief of the division
of Rheumatology and director of Rheumatology research at Hospital for
Special Surgery in New York, has written an editorial in The New England
Journal of Medicine to accompany the papers.
One study appears in The New England Journal of
Medicine and the other three appear in Nature Genetics, all were
published online on Jan. 20.
In her editorial, Dr. Crow talks about the
importance of the studies and the questions they leave unanswered, along
with insights on next steps in lupus research.
“Overall, these papers confirm what investigators
have been finding over the past decades,” says Dr. Crow, the co-director
of the Mary Kirkland Center for Lupus Research and director of the
Autoimmunity and Inflammation Research Program at Hospital for Special
Surgery.
“They show that many aspects of the immune system
are involved in the development of the disease, but they also provide a
new level of detail regarding the specific molecular pathways that
contribute.”
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The Study & Results |
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The researchers studied the DNA of 720 women of
European descent with lupus and 2,337 women without lupus in a study
supported by the Alliance for Lupus Research and the National Institutes
of Health..
They scanned the entire genome for more than
317,000 single nucleotide polymorphisms (SNPs), which are locations on
chromosomes where a single unit of DNA, or genetic material, may vary
from one person to the next. The goal was to identify SNPs linked to
lupus. They confirmed these results in another independent set of 1,846
women with lupus and 1,825 women without lupus.
The scientists found evidence of an association
with multiple SNPs in three genes: ITGAM, KIAA1542 and PXK, and also at
SNP rs10798269, which is not within any known gene.
ITGAM is important for both the adherence of immune
cells and for cleaning up pathogens.
KIAA1542 is important for translating the DNA code
into proteins. PXK encodes a molecule that transmits signals and
controls complex processes in cells.
These scientists also found association in genes
previously associated with lupus and other autoimmune diseases.
“These findings underscore that numerous genes, which are often
immune-function related, contribute to the risk of developing
lupus,” said Carl D. Langefeld, Ph.D., senior author from Wake
Forest University School of Medicine and co-director of the
International Consortium for Systemic Lupus Erythematosus
Genetics .
The scientists are now focusing their attention on
specific pathways and genes identified in this study, trying to dissect
the precise molecular mechanisms by which these genes contribute to the
risk for lupus. Genetic factors likely predict specific complications or
patterns of complications. If so, it might be possible to intervene
earlier in the process to delay or prevent their onset.
“This initial, important discovery will prove
invaluable to all those affected by lupus,” said Barbara Boyts,
president of the Alliance for Lupus Research, which supported the study
and continues to support SLEGEN’s efforts to uncover genetic information
about lupus. “We are hopeful that this information will lead to new and
better treatment possibilities and, eventually, a cure for lupus.”
“Lupus is a decimating illness,” said John Harley,
M.D., Ph.D., lead author and SLEGEN director, from the Oklahoma Medical
Research Foundation. “As researchers, our goal is to reduce the burden
of suffering caused by this disease. These findings have opened many new
doors, and we’re excited to investigate what’s inside each of them.”
The findings, by scientists from Imperial College
London and institutions in the USA and Sweden, will enable researchers
to investigate the specific pathways and precise molecular mechanisms
involved in developing Lupus, potentially opening up options for new
therapies.
Other researchers in SLEGEN include: Marta E. Alarcon-Riquelme, M.D.,
Ph.D., the University of Uppsala in Sweden, Lindsey A. Criswell, M.D.,
MPH, the University of California at San Francisco, Chaim O. Jacob,
M.D., Ph.D., the University of Southern California, Betty P. Tsao,
Ph.D., the University of California at Los Angeles, Robert P. Kimberly,
M.D., the University of Alabama at Birmingham, Kathy L. Moser, Ph.D.,
the Oklahoma Medical Research Foundation, and Timothy J. Vyse, M.D.,
Ph.D., the Imperial College in London.
(www.SLEGEN.org)
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The new research looks at how variations in a
single DNA base pair, called single nucleotide polymorphisms (SNP), can
be used to identify genetic variations among individuals that are
associated with a diagnosis of lupus. In some cases, the SNPs call
attention to important genes but have no apparent functional importance
themselves.
In other cases, the variations might actually change the
protein product so that it functions differently in lupus patients and
healthy individuals.
For example, in one specific gene the frequency of
an “A” nucleotide in people with lupus might be significantly greater
than in healthy individuals without the disease. This small variation
may alter the expression or function of the protein encoded by that gene
in a way that contributes to the disease.
Two of the studies are comprehensive reports of
genomewide analyses looking for these types of small changes,
specifically for those that appear more frequently in lupus patients and
could predispose them to the disease.
A third study also used a total
genome analysis but focuses on those SNPs that are predicted to change
the amino acid sequence of the protein product, meaning there is a
greater chance the resulting protein’s expression, role or activity is
changed. The fourth study centers around one gene in particular, called
ITGAM.
“These genetic studies are the first step in
getting a detailed understanding of the molecular pathways that underlie
lupus,” says Dr. Crow. The results help direct researchers to the genes,
molecules and cells that are directly involved in the disease so that
they can eventually identify exactly which pathways they can target
therapeutically.
Dr. Crow was particularly intrigued by the research
on ITGAM, whose association with lupus was supported by three of the new
studies. The protein encoded by ITGAM is found on the immune system’s
white blood cells that are recruited to blood vessels when it is
activated.
Some of the characteristic clinical features of
lupus involve changes in blood vessels, including alterations in the
kidneys, eyes, skin and the premature atherosclerosis that is common in
lupus patients.
The ITGAM protein, which is an adhesion molecule, helps
leukocytes adhere to the cells lining blood vessels. The new genetic
analysis of ITGAM variations associated with the disease predicts that
it may promote vascular inflammation.
“The role of the target tissue, such as the blood
vessels, had been prominent in early lupus research,” says Dr. Crow,
“but in the past 25 to 30 years the focus has been primarily on the
immune system. The new research on ITGAM, I think, will help redirect
the attention of the scientific community back to this aspect of the
disease.”
While the immune system, as the attacker, is of
central importance in disease pathogenesis, it is also necessary to look
at the response of the tissues they are attacking, Dr. Crow explains.
Dr. Crow also praised the impressive collaborative
effort that was required to complete the reported studies. For one of
the studies, the International Consortium for Systemic Lupus
Erythematosus Genetics (SLEGEN) coordinated the planning and
organization of a large genotyping and data analysis effort that
involved contributions from more than 150 participants.
While some investigator groups have the patient
numbers and financial support to provide important new genetics data
independently, the success of the SLEGEN study supports broad
collaboration, with credit shared among the many essential contributors,
as a model that could be followed in investigation of the genetic
factors in other complex diseases.
However, three of the four studies, including both
large genomewide association studies, are also missing a critical
component – they don’t take into account the populations of people that
have the highest morbidity and mortality from the disease.
“In the major studies, all of the subjects were of
European descent,” says Dr. Crow, “but lupus is most severe in people
with African, Asian and Hispanic backgrounds. We need to confirm that
these same genes are involved in all of our patient populations and
identify any distinct genes that might be involved in those populations
at greatest risk for poor outcomes.”
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About the Disease |
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Your body's immune system
protects you from disease and infection. But if you have
an autoimmune disease, your immune system attacks itself
by mistake. Autoimmune diseases can affect many parts of
the body. These diseases tend to run in families. Women
- particularly African-American, Hispanic-American, and
Native-American women - have a higher risk for some
autoimmune diseases.
There are more than 80 types of
autoimmune diseases, and some have similar symptoms.
This makes it hard for your health care provider to know
if you really have one of these diseases, and if so,
which one. Getting diagnosed can be frustrating and
stressful. In many people, the first symptoms are being
tired, muscle aches and low fever.
Read more at MedlinePlus...
Also called: Discoid lupus,
Subacute cutaneous lupus, Systemic lupus
erythematosus
If you have lupus, your immune
system attacks healthy cells and tissues by mistake.
This can damage your joints, skin, blood vessels and
organs. There are many kinds of lupus. The most common
type, systemic lupus erythematosus, affects many parts
of the body. Discoid lupus causes a rash that doesn't go
away. Subacute cutaneous lupus causes sores after being
out in the sun. Another type can be caused by
medication. Neonatal lupus, which is rare, affects
newborns.
Anyone can get lupus, but women
are most at risk. Lupus is also more common in African
American, Hispanic, Asian and Native American women. The
cause of lupus is not known.
Read more at MedlinePlus...
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Editor’s Notes:
Hospital for Special Surgery has been a leader for
more than forty years in research into the underlying mechanisms of
lupus and was the nation’s first National Institutes of Health-sponsored
Specialized Center of Research in lupus. The Mary Kirkland Center for
Lupus Research at HSS combines novel research with patient programs to
provide the best care for its lupus patients.
Dr. Crow has studied the immunologic mechanisms
responsible for lupus for many years. Her recent research has looked at
the role of a family of molecules, the interferons, in lupus, their
association with disease activity and the mechanisms of type I
interferon production. Her recent findings from studies of lupus
families have shown that increased interferon-alpha levels are a
heritable risk factor for lupus.
All Hospital for Special Surgery medical staff are
on the faculty of Weil Cornell Medical College. The hospital’s research
division is internationally recognized as a leader in the investigation
of musculoskeletal and autoimmune diseases. Hospital for Special Surgery
is located in New York City and online at
www.hss.edu.
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