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Celera Dx-Led Team Identifies SNP Linked to Rheumatoid Arthritis Risk. Can Dx Be Far Off?


A consortium of academic and industry researchers co-led by Celera Diagnostics has found a new genetic marker that confers an increased risk for developing rheumatoid arthritis. The scientists believe their findings could become part of a more comprehensive diagnostic or prognostic test for the disease.

No good diagnostic test for RA currently exists, according to Peter Gregersen, director of the Center for Genomics and Human Genetics at the North Shore-Long Island Jewish Research Institute in Manhasset, NY and head of the NARAC, who is an author of the study. This makes it difficult for doctors to prescribe the appropriate therapy, he said.

This might play into Celera’s favor: Karen White, a spokeswoman for the Applera unit, told Pharmacogenomics Reporter this week that the company is “actively looking” for a partner to help it commercialize a test based on results from this and other similar trials. The partner could be either a reference laboratory or a manufacturer of RA therapeutics, she said.

The first test would most likely be sold as a homebrew, followed by an IVD later.

The researchers showed that a SNP in the PTPN22 gene, which encodes a protein that helps keep T cells in check, doubles the risk for rheumatoid arthritis. However, the baseline risk is less than one percent, according to Gregersen, so carriers of the gene variation only have a small absolute risk of developing the disease.

Earlier this year, researchers from the Burnham Institute reported in the journal Nature Genetics that the same gene variation is also associated with type 1 diabetes, indicating that it may play a wider role in autoimmune diseases.

The researchers published their findings in the August issue of the American Journal of Human Genetics. They first reported the findings during a meeting in Berlin in June, according to Celera Diagnostics.

About one third of Caucasian rheumatoid arthritis patients has the variation, compared with around 15 percent of Caucasian individuals in the general population, according to the study.

To arrive at their results, the scientists assayed 87 functional SNPs in RA candidate genes or linkage regions in 475 Caucasian RA patients and 475 matched controls. Genomics Collaborative, based in Cambridge, Mass., provided the samples. The team then confirmed the risk association with the PTPN22 SNP in 463 Caucasian RA patients from different families and 926 matched controls.

But PTPN22 is only one piece in a puzzle that comprises many genes. A diagnostic or prognostic test for the disease “would not be just a test for this one marker; it would be combined with other markers,”, said White.

The company is currently testing PTPN22 and several unpublished RA markers in additional case-controlled studies involving hundreds of individuals. The firm hopes “to identify the most informative set of markers that could be developed into a diagnostic test,” White said.

In February, Celera said it would deliver its first genetic test to a reference laboratory [see PGx Reporter 2/26/04] this month, most likely a test for Alzheimer’s disease.

The market size for a test that detects RA would depend on its indication, according to White. Possible indications would be to determine someone’s risk for developing the disease, for diagnosing the disease, to predict disease severity and progress, or to predict response to certain therapies.

Celera is “actively looking” for a partner to help it commercialize a test based on results from this and other similar trials. The partner could be either a reference laboratory or a manufacturer of RA therapeutics, according to White, the spokeswoman.

The first test would most likely be sold as a homebrew, followed by an IVD later, she said.

RA affects about one percent of adults worldwide and is two to three times more common in women than in men.

Currently, researchers have a number of markers to help them diagnose RA, including variations in the HLA-DRB1 gene and several antibodies. However, none is highly specific and sensitive, and doctors mostly rely on clinical symptoms, said Gregersen. Identifying with certainty which patient has true RA would “ultimately influence people’s comfort level with putting people on major drugs, like TNF inhibitors,” he said.

A commonly prescribed TNF inhibitor is Remicade, a monoclonal antibody made by Johnson & Johnson unit Centocor. Recent research has shown that treating the disease early with new monoclonal antibodies such as TNF inhibitors has “a more potent effect on stopping the disease in its tracks,” Gregersen said.

He said around 20 percent of patients with RA respond well to TNF inhibitors, while 30 percent show no response. A test based on several genetic markers could also identify those individuals who are most likely to respond to these new treatments.

The chemotherapeutic agent methotrexate is a traditional standard treatment for RA, he said, but it only alleviates symptoms and does not cure the disease.

The North American Rheumatoid Arthritis Consortium co-led the study with Celera.

— JK

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