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Tracking down RA genes
The pace of discovery is dramatically accelerating
Peter Gregersen, MD, Long Island, NY
 What do we really know about the genetics of
rheumatoid arthritis (RA)? We know that RA occasionally runs in families
(although most of the time it doesn't). Overall, first degree relatives (such as
siblings) of people with RA have about a 5-10 fold increase in risk for
developing RA themselves over the course of their lifetime. We also know that
other autoimmune diseases, such as lupus, autoimmune thyroid disease, and
juvenile diabetes also occur in family members of people with RA at a higher
rate than is expected. These facts, along with others, lead us to believe that
RA genetics is quite complicated, and that many genes are involved. Most of
these genes by themselves carry little risk for autoimmune disease, and indeed
in many people these genes may confer some benefit, such as an enhanced defense
against infections. However, when certain of these genes occur together in the
same individual, the risk for developing RA may be quite high.
Challenges and progress to date
In order to find the many different genes involved in RA, we have had to
overcome several scientific and technical hurdles. First, we needed to gather
large numbers of families and patients with RA. Over the last five years, this
has been accomplished through the efforts of a group of scientists and
rheumatologists participating in the North American Rheumatoid Arthritis
Consortium (NARAC), a unique, multimillion dollar collaboration of the Arthritis
Foundation and the National Institutes of Health. Several thousand patients with
RA and their family members have enrolled in NARAC, and this has made, and will
continue to make, an invaluable contribution to progress.
Genetics work used to be very time-consuming and
expensive. Over the last several years, there has been a truly astounding
acceleration of technical advances in the area of genetic mapping. It is now
routine to perform thousands of genetic analyses per day and the performance of
a million genetic tests per day is a reality for several large academic and
commercial genetics labs. The cost of these genetic tests has fallen by a factor
of 10, and will continue to drop in the next few years. This means that we are
on the verge of being able to study virtually every gene for a reasonable
cost.
There are several recent examples of how this
technological change is having an impact in RA. Earlier this year, a group in
Japan identified a variation in a gene known as PADI4 on chromosome 1. This gene
controls a modification of proteins called "citrullination" that is
likely to play an important role in RA. This protein modification ultimately
results in the formation of anti-citrulline antibodies, a type of antibody that
seems to be highly diagnostic for RA, and can be found in people even before
they develop RA. As another example, in the last several months, NARAC
scientists have performed nearly 3 million (!) genetic tests on a region of
chromosome 18 where one of the RA genes is located. This has focused attention
on a very small number of genes. We do not yet know which one is the culprit,
but it is likely that the exact gene will be identified in the next year.
How could genetics research help people
with RA?
Scientists are focusing so much attention on finding the genes involved with RA
because the resultant discoveries could improve the lives of people with RA in
many different ways. At a very basic level, such research helps us better
understand RA: Why does it happen? Is it just one disease or can we distinguish
subsets of patients who may need different types of treatment? Such knowledge
could lead to improved diagnostic tests and tailoring of treatment
recommendations. Genetic testing could help doctors better identify and monitor
people who may develop RA and allow the doctors to provide early treatment to
prevent joint damage and ultimately preventive strategies to reduce the risk of
RA. Learning about the relevant genes and their function is also critical for
the development of more effective, new drugs or gene therapy to treat RA and
eventually to cure and prevent it.
The Opportunity
The field of RA genetics is at a critical turning point, only hindered by the
availability of research funds. Over the last decade, there has been an
accumulation of advances, from the Human Genome Project to the development of
new high throughput genetic mapping techniques. More recently, a project called
the "HapMap" project is busy defining the full extent of genetic
variability in human populations. This is a massive effort that will continue to
fuel scientific progress. Each one of us has about 3 million differences from
each other across the human genome, and we are now entering a period where this
wealth of new information can be harvested in order to understand autoimmune
diseases like RA. Within the last year technology has been developed that will
allow us to complete a comprehensive description of the genetic differences
across the entire human genome that can be used to distinguish between people
with and without RA. All of the pieces are now in place to make a quantum leap
forward in our understanding of RA genetics!
  
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