Genetic variation that doubles the risk for rheumatoid arthritis

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Genetic variation that doubles the risk for rheumatoid arthritis

Thursday, 24-Jun-2004, by News-Medical

A team of researchers has discovered a genetic variation that doubles the

risk for rheumatoid arthritis (RA).

The variation, referred to as a single nucleotide polymorphism (SNP,

pronounced " snip " ), is present in about 28 percent of individuals with

rheumatoid arthritis and 17 percent of the general population. This

discovery resulted from a collaboration between scientists from the North

American Rheumatoid Arthritis Consortium (NARAC), led by K. Gregersen,

MD, of the North Shore-Long Island Jewish Research Institute in Manhasset,

NY, Celera Diagnostics and Genomics Collaborative, Inc. The team's findings

are being published in the August 2004 issue of the American Journal of

Human Genetics.

" This is an important discovery, really a major genetic variant identified

in a U.S. study that clearly seems to be involved in rheumatoid arthritis, "

said I. Katz, MD, PhD, director of the National Institute of

Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the lead agency at

the National Institutes of Health (NIH) that supports NARAC.

While scientists still do not know the exact cause of RA, they do know it is

an autoimmune disease in which the body's natural immune system does not

function properly and attacks its own healthy joint tissues. This causes

inflammation and subsequent joint damage.

The SNP they linked to RA is located in a gene that codes for an enzyme

(called PTPN22) that is known to be involved in controlling the activation

of immune cells called T cells. Under normal conditions, the enzyme works as

a " negative regulator " --- meaning it inactivates a specific signaling

molecule, which in turn interrupts the communication lines and keeps immune

cells from becoming overactive. In cases where the SNP is present in one or

both copies of an individual's genes for this enzyme, the team found that

the negative regulation by this enzyme appears to be inefficient, so that T

cells and other immune cells are hyperresponsive, causing increased

inflammation and tissue damage.

" This is not an abnormal gene, " said Dr. Gregersen. " It is present in a

substantial fraction of the normal population, so it's probably there for a

good reason. It may, in fact, help defend against infection. " When it comes

to the genetics of complex diseases, context is everything. According to Dr.

Gregersen, a genetic variant in the setting of certain environments and in

the presence of other genes may have harmful effects, whereas the same

genetic variant may have beneficial effects in another genetic and

environmental context. " So this particular genetic variation may have

contributed to the survival of our ancestors. The price we have to pay for

that, however, is that some people are modestly predisposed to developing

rheumatoid arthritis. "

Using state-of-the-art technology developed by Celera Diagnostics, Ann B.

Begovich, PhD, director of inflammation at Celera Diagnostics, and her team

discovered the PTPN22 association. The technology allowed them -- in a short

period of time -- to look at tens of thousands of SNPs in thousands of DNA

samples from subjects with RA as well as normal control subjects. The

majority of the DNA samples analyzed in this study were carefully collected

from families with RA who contributed to the NARAC project. Genomics

Collaborative, Inc. provided additional samples.

" This collaboration has enabled us to make a significant contribution to a

very complex genetic problem in a relatively short period of time, something

that can only be achieved with a team effort, " said Dr. Begovich.

The Arthritis Foundation has been an important supporter of NARAC. " This

critical discovery is an illustration of the power of public-private

partnerships to solve complex issues, " said H. Klippel, MD, the

foundation's president and CEO.

Research has previously shown that autoimmune diseases such as type 1

diabetes, lupus and thyroid disease tend to group in families, but there has

been no previous direct genetic connection to explain the phenomenon.

Earlier this year, a study published in Nature Genetics linked this same SNP

with type 1 diabetes. Subsequent unpublished research by Dr. Gregersen and

his colleagues indicates that this particular gene variant may also increase

risk for other autoimmune diseases, such as systemic lupus and autoimmune

thyroid disease, as well as type 1 diabetes.

" NIH has provided strong scientific and financial support for the North

American Rheumatoid Arthritis Consortium over many years, and we are now

beginning to see the fruits of this investment, " said Dr. Katz. " I expect

this discovery will spin off many more advances in the field. " In addition

to NIAMS, the National Institute of Allergy and Infectious Diseases and the

Office of Research on Women's Health at the NIH also support NARAC.