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Peter K. Gregersen, MD, stares at x-rays of hands, searching out the 
telltale signs of inflamed joints and wrists from his research subjects with 
rheumatoid arthritis. With these clinical features at his side, he turns to 
the basic building blocks of life - the human genome - to figure out what 
makes these people susceptible to the disabling inflammatory condition.

Dr. Gregersen has finally closed the circle between key genes identified in 
his laboratory at the Robert S. Boas Center for Genomics and Human Genetics 
at The Feinstein Institute for Medical Research in Manhasset, NY and more 
than a 1,000 patients with rheumatoid arthritis. The genes will help tell 
the story of how the immune system works to create specific antibodies that 
in turn increase a person's risk for this crippling disease.

On Monday at the Federation of Clinical Immunology Services' (FOCIS) 
meetings in San Diego, CA, Dr. Gregersen and his colleagues will be 
presenting the lab's latest genetic findings. The group conducted 
genome-wide scans to identify polymorphisms, or genetic variants, that are 
associated with the inflammatory condition and can be used to understand the 
triggers of the disease. This will provide key insights into the pathways 
underlying rheumatoid arthritis and other autoimmune diseases. It may 
ultimately provide tests to predict who will respond to the available new 
treatments. Franak Batliwalla, PhD, also of The Feinstein Institute, will be 
presenting related studies on biomarkers and genetic influences on drug 
response at the same meeting.

Identifying Immune System Mediators

About one percent of the US population will develop rheumatoid arthritis, an 
autoimmune disease that leads to painful joint swelling. Scientists are 
cracking the genetic code that makes the immune system wage an attack on a 
person's joints. Over the last decade, Dr. Gregersen and his colleagues have 
been amassing a genetic database complete with siblings with rheumatoid 
arthritis (and some family members without it) in an attempt to single out 
those genes that are involved in the autoimmune process. In fact, in 2004, 
they identified a gene called PTPN2 that confers a two-fold risk for 
rheumatoid arthritis and a number of other autoimmune diseases. The 
Feinstein now holds the largest collection from rheumatoid arthritis 
patients in the world.

Following the cellular pathway, it has been shown that PTPN22 influences the 
"trigger point" for activation of T-cells, immune cells that are normally 
called on to wage battle against infection. In autoimmune diseases like 
rheumatoid arthritis, PTPN22 appears to put people at higher risk of a 
wayward T-cell response.

The group has since gone on to use modern genetic methods to search for 
single nucleotide polymorphisms, or SNPs, to identify players that have 
fallen under the radar of older methods. The group has discovered another 
signaling molecule that seems to increase a person's risk for rheumatoid 
arthritis by 30 percent. (The paper reporting the gene is in press.)

In collaborations with other scientists worldwide, Dr. Gregersen has also 
been able to show that certain markers are strongly linked to certain ethnic 
groups and others are not. "This will help us in figuring out what exactly 
is going on in this illness," he said. "It's pretty exciting."

Early on in the rheumatoid arthritis research game, when HLA popped out as a 
major genetic player in the condition in the 1980s, Dr. Gregersen discovered 
that there was a shared bit of DNA that traveled in the disease. What took 
two years to identify in the laboratory - shared bands of genetic material - 
would take two days today. And that speed is what excites Dr. Gregersen. "We 
have the tools to get at these genes rather quickly now," he said. "The more 
patients and controls that we have, the more power we will have to pull out 
new genes and make associations."

In another major breakthrough, scientists have discovered the importance of 
a substance called citrulline as a target for immune attack in rheumatoid 
arthritis (RA). This immune system antibody associated with rheumatoid 
arthritis recognizes citrulline, which seems to be a key player in the 
condition. Indeed, the HLA associations with RA have now been shown by Dr. 
Gregersen and others to directly regulate the immune response to proteins 
containing citrulline. Citrulline is formed when a specific enzyme comes in 
contact with arginine, one of 20 common amino acids in proteins. When one of 
the enzymes is present, nitrogen is removed from the chemical structure of 
arginine and it converts into citrulline.

Laboratories have developed a test to measure for anti-cyclic citrullinated 
peptide antibody, or anti-CCP. It is now being used as a diagnostic for 
rheumatoid arthritis. Scientists are now finding that patients have CCP 
antibodies months or years prior to the illness, suggesting a way to 
identify the disease before it starts and perhaps offer treatments to stave 
off the symptoms. It turns out that those with these antibodies who also 
have a particular variety of HLA, a complex of genes that regulate immune 
function, have a 30 times higher risk of developing rheumatoid arthritis 
than those without these genetic risk factors.

Scientists at the University of Colorado are now analyzing the genes from 
2,500 first degree relatives of rheumatoid arthritis patients and testing 
CCP levels to see whether there is a way to predict, based on these 
measurements, who will go on to develop rheumatoid arthritis.

Ultimately, understanding how the genes work to confer illness will help in 
the development of new treatments.

Normal Control Genetic Database

In addition, The Feinstein Institute is participating in a groundbreaking 
effort to release large amounts of genetic data on normal subjects for use 
by the scientific community. A key barrier to progress for many geneticists 
is the costs of obtaining genetic data from normal control populations to 
use for comparison to the genetic variation seen in people with disease.

In collaboration with the Children's Hospital of Philadelphia, The Feinstein 
will release genetics data on approximately 6,000 normal volunteers. A 
company that designs new genetic testing technology, Illumina, Inc. will 
maintain the database and make it available to scientists. The data will not 
include personal identifiers but scientists will have information on age and 
ethnicity to best match their groups to study.

Article: http://www.mooshee.com/article-2996670.htm