Genetic marker doubles the risk of RA

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Genetic marker doubles the risk of RA

Rheumawire

Jul 7, 2004

Zosia Chustecka

Manhasset, NY - A genetic variation that doubles the risk of rheumatoid

arthritis (RA) has been identified by US researchers [1]. The single

nucleotide polymorphism (SNP) responsible is found in about 28% of

patients with rheumatoid arthritis and about 17% of the general

population and is located in a gene that codes for an enzyme known to be

involved in controlling the activation of T cells.

The study is published online June 18, 2004 in the American Journal of

Human Genetics.

" This is not an abnormal gene, " says lead researcher Dr Gregersen

(North Shore-Long Island Jewish Research Institute, Manhasset, NY). " 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 a complex disease, context is

everything, Gregersen comments. A genetic variant in the setting of a

certain environment and in the presence of other genes may have harmful

effects, whereas in another setting, the same variant could have

beneficial effects, he points out. " 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. "

Gregersen's team was working as part of the North American Rheumatoid

Arthritis Consortium (NARAC) and collaborated with 2 biotech firms,

Celera Diagnostics and Genomics Collaborative Inc.

The newly discovered SNP codes for a protein tyrosine phosphatase enzyme

(PTPN22, also known as Lyp). Under normal conditions, this enzyme works

as a " negative regulator, " inactivating specific signaling molecules,

which in turn interrupts communication lines and stops immune cells from

becoming overactive. However, in individuals who carry the SNP in either

1 or both copies of the gene for this enzyme, the negative regulation

appears to be inefficient. This allows T cells and other immune cells to

become hyperresponsive and leads to increased inflammation and tissue

damage.

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

identified in a US study that clearly seems to be involved in rheumatoid

arthritis, " says Dr Katz, director of the National Institute of

Arthritis, Musculoskeletal and Skin Diseases (NIAMS).

The NIAMS, as well as 2 bodies within the National Institutes of Health,

have 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, " Katz commented. " I

expect this discovery will spin off many more advances in the field, " he

added.

Already, there have been several related findings. Earlier this year,

the same SNP now shown to be linked to a doubling of the risk of RA was

reported to be involved in type 1 diabetes, in a paper published in

Nature Genetics [2]. In the current paper reporting the link with RA,

Gregersen and colleagues comment that the finding that a minor allele of

this SNP is implicated in type 1 diabetes suggests that the variant

phosphatase enzyme may increase overall reactivity of the immune system

and may heighten an individual carrier's risk for autoimmune disease.

Recent work by Gregersen and his team, which has yet to be published,

suggests that this same SNP may also increase the risk for other

autoimmune diseases, such as systemic lupus erythematosus and autoimmune

thyroid disease, according to a press release issued by the

North-Shore-Long Island Jewish Research Institute.

Sources

Begovich AB, Carlton VEH, Honigberg LA et al. A

missense single-nucleotide polymorphism in a gene encoding a protein

tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis.

Am J Hum Genet 2004; 75:330-337.

Bottini N, Musumeci L, Alonso A, et al. A functional

variant of lymphoid tyrosine phosphatase is associated with type I

diabetes. Nat Genet 2004; 36:337-338

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org