Genes Boost Risk for Rheumatoid Arthritis, Lupus

WEDNESDAY, Sept. 5 (HealthDay News) -- Two genes boost the risk of painful rheumatoid arthritis, and one of them also increases the odds for lupus, according to two new reports.

In one report, a variant of the gene calledSTAT4is one of the five genes now identified to increase the risk of developing rheumatoid arthritis or lupus, both of which are autoimmune disorders, where the immune system attacks healthy tissue.

STAT4can boost a person's risk for the illnesses by 30 percent to 60 percent, depending on how many copies of the gene one has, the researchers found.

In the other study, a variant of theTRAF1-C5gene was found to be associated with an increased risk for rheumatoid arthritis.

"There has been a huge amount of optimism about what genetics can bring," said lead researcher Dr. Peter K. Gregersen, head of the Feinstein Institute's Robert S. Boas Center for Genomics & Human Genetics in Manhasset, N.Y. "But everyone working on complex disease underestimated the size of the problem, which it is why it has taken a decade to identify genes related to these problems," he said during a Tuesday morning teleconference.

There are now five genes "that we are quite certain are involved in [rheumatoid arthritis], and I suspect there are another three to five at least that are involved," Gregersen said. "We are talking about gene variants that are fairly common in the population -- variants that are present in 5 percent or more of the population," he said.

Gregersen believes that identifying these genes will lead to new ways of predicting who is likely to develop rheumatoid arthritis. It might also lead to personalized treatments and perhaps effective prevention for those found to be at higher risk.

In the first study, Gregersen's team looked at DNA from almost 4,200 individuals with rheumatoid arthritis or lupus. Using gene mapping, the researchers identifySTAT4as a gene involved in increasing the risk for both diseases.

"Although we don't know how this gene variant changes immune function, it is clear that this finding placesSTAT4pathways directly in a scheme of pathogenesis for both [rheumatoid arthritis] and lupus," Gregersen said. "This shows that a single gene can overlap autoimmune disorders."

Gregersen's group found that some 22 percent of people carry this particular form ofSTAT4, but that percentage rises to 27 percent in people with rheumatoid arthritis. ThisSTAT4variant increases the risk of developing rheumatoid arthritis by 32 percent. For people with two copies of this variant, the risk is increased by 60 percent, the researchers noted.

Patients with theSTAT4variant have about double the risk of developing lupus compared with people without the variant, the researchers reported.

In another study by Gregersen and colleagues,STAT4was identified as an important risk gene in Koreans with rheumatoid arthritis. That paper appears in the September issue ofMolecular Medicine.

Studies in mice with rheumatoid arthritis have shown that blockingSTAT4can prevent or relieve arthritis, suggesting thatSTAT4could be a target for new therapies, Gregersen noted. In addition,STAT4could help researchers identify triggers for rheumatoid arthritis, develop diagnostic tests, and to even predict who will best respond to treatments, he said.

Gregersen said his team is also looking at what role, if any,STAT4might play in other autoimmune diseases.

In the otherNew England Journal of Medicinestudy, Gregersen's team looked at the genotype of 1,522 people with rheumatoid arthritis. They then compared these with the genotype of 1,850 people without the disease.

They found that people with the variant ofTRAF1-C5had a 32 percent increased risk for developing rheumatoid arthritis compared with people without the variant.

Dr. Daniel Kastner, of the Genetics and Genomic Branch at the U.S. National Institute of Arthritis and Musculoskeletal and Skin Diseases, was a co-author of both of theNEJMstudies. He believes that the findings are groundbreaking.

"The fruits that have come forth from identifying new disease genes has had a significant impact on the care of our patients," Kastner said during the teleconference. "Although these fruits are still a way off for RA, I do have a sense of excitement that we are entering a new era with regards to our understanding of RA and some of the other autoimmune diseases," he said.

Another expert agreed.

"It is now possible to investigate disease association genes genome-wide," noted Dr. Kazuhiko Yamamoto, from the Graduate School of Medicine at the University of Tokyo, Japan, and author of an accompanyingNEJMeditorial.

"Genetic analyses will enhance our understanding of the disease and the development of new therapies, although more detailed, functional studies are needed," Yamamoto said. "Several associated genes will be revealed to many common diseases in the near future, but ethnic differences should be taken into consideration," he added.

More information

For more on rheumatoid arthritis, visit the U.S. National Institute of Arthritis and Musculoskeletal and Skin Diseases.

SOURCES: Sept. 4, 2007, teleconference with: Peter K. Gregersen, M.D., head, Feinstein Institutes Robert S. Boas Center for Genomics & Human Genetics, Manhasset, N.Y.; Daniel Kastner M.D., Ph.D., Genetics and Genomic Branch, U.S. National Institute of Arthritis and Musculoskeletal and Skin Diseases; Kazuhiko Yamamoto, M.D., Ph.D., Graduate School of Medicine, University of Tokyo, Japan; Sept. 6, 2007,New England Journal of Medicine